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Introduction to clinical research-Publish or Perish-
Introduction to clinical research-Publish or Perish-
林隆堯
Long-Yau Lin MD MPH ScDChung-Shan Medical University
林隆堯
Long-Yau Lin MD MPH ScDChung-Shan Medical University
Considerations of study design
Considerations of study design
1 The question to be answered or hypothesis to be answered2 Subjects3 Research models and methods4 Methods of data acquisition5 Type of data analysis6 Data reporting
1 The question to be answered or hypothesis to be answered2 Subjects3 Research models and methods4 Methods of data acquisition5 Type of data analysis6 Data reporting
Steps in Clinical ResearchSteps in Clinical Research
1 Develop a question engendered andor motivated by experience2 State the question as a testable hypothesis ( if you cannot do it you still do not have a good question)3 Search the literature to see if it has been answered totally or partially4 Revise ( perhaps) the question and hypothesis based on your reading of the literature
1 Develop a question engendered andor motivated by experience2 State the question as a testable hypothesis ( if you cannot do it you still do not have a good question)3 Search the literature to see if it has been answered totally or partially4 Revise ( perhaps) the question and hypothesis based on your reading of the literature
Step in Clinical Research-continued
Step in Clinical Research-continued
5 Determine what tools materials personnel time and so forth are necessary to obtain and analyzed the data based on your reading of the literature6 Given the preceding requirements is the study feasible7 Revise ( perhaps) the question and hypothesis andor alter the variables according to your resources and time8 Choose the appropriate subjects ( including controls if appropriate) from whom data on the variables can be obtained
5 Determine what tools materials personnel time and so forth are necessary to obtain and analyzed the data based on your reading of the literature6 Given the preceding requirements is the study feasible7 Revise ( perhaps) the question and hypothesis andor alter the variables according to your resources and time8 Choose the appropriate subjects ( including controls if appropriate) from whom data on the variables can be obtained
Steps in Clinical Research-continued
Steps in Clinical Research-continued
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
Steps in Clinical Research-continued
Steps in Clinical Research-continued
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
The question to be answered or hypothesis to be answeredThe question to be answered or hypothesis to be answered
The questionThe question
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
The Question-continuedThe Question-continued4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Considerations of study design
Considerations of study design
1 The question to be answered or hypothesis to be answered2 Subjects3 Research models and methods4 Methods of data acquisition5 Type of data analysis6 Data reporting
1 The question to be answered or hypothesis to be answered2 Subjects3 Research models and methods4 Methods of data acquisition5 Type of data analysis6 Data reporting
Steps in Clinical ResearchSteps in Clinical Research
1 Develop a question engendered andor motivated by experience2 State the question as a testable hypothesis ( if you cannot do it you still do not have a good question)3 Search the literature to see if it has been answered totally or partially4 Revise ( perhaps) the question and hypothesis based on your reading of the literature
1 Develop a question engendered andor motivated by experience2 State the question as a testable hypothesis ( if you cannot do it you still do not have a good question)3 Search the literature to see if it has been answered totally or partially4 Revise ( perhaps) the question and hypothesis based on your reading of the literature
Step in Clinical Research-continued
Step in Clinical Research-continued
5 Determine what tools materials personnel time and so forth are necessary to obtain and analyzed the data based on your reading of the literature6 Given the preceding requirements is the study feasible7 Revise ( perhaps) the question and hypothesis andor alter the variables according to your resources and time8 Choose the appropriate subjects ( including controls if appropriate) from whom data on the variables can be obtained
5 Determine what tools materials personnel time and so forth are necessary to obtain and analyzed the data based on your reading of the literature6 Given the preceding requirements is the study feasible7 Revise ( perhaps) the question and hypothesis andor alter the variables according to your resources and time8 Choose the appropriate subjects ( including controls if appropriate) from whom data on the variables can be obtained
Steps in Clinical Research-continued
Steps in Clinical Research-continued
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
Steps in Clinical Research-continued
Steps in Clinical Research-continued
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
The question to be answered or hypothesis to be answeredThe question to be answered or hypothesis to be answered
The questionThe question
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
The Question-continuedThe Question-continued4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Steps in Clinical ResearchSteps in Clinical Research
1 Develop a question engendered andor motivated by experience2 State the question as a testable hypothesis ( if you cannot do it you still do not have a good question)3 Search the literature to see if it has been answered totally or partially4 Revise ( perhaps) the question and hypothesis based on your reading of the literature
1 Develop a question engendered andor motivated by experience2 State the question as a testable hypothesis ( if you cannot do it you still do not have a good question)3 Search the literature to see if it has been answered totally or partially4 Revise ( perhaps) the question and hypothesis based on your reading of the literature
Step in Clinical Research-continued
Step in Clinical Research-continued
5 Determine what tools materials personnel time and so forth are necessary to obtain and analyzed the data based on your reading of the literature6 Given the preceding requirements is the study feasible7 Revise ( perhaps) the question and hypothesis andor alter the variables according to your resources and time8 Choose the appropriate subjects ( including controls if appropriate) from whom data on the variables can be obtained
5 Determine what tools materials personnel time and so forth are necessary to obtain and analyzed the data based on your reading of the literature6 Given the preceding requirements is the study feasible7 Revise ( perhaps) the question and hypothesis andor alter the variables according to your resources and time8 Choose the appropriate subjects ( including controls if appropriate) from whom data on the variables can be obtained
Steps in Clinical Research-continued
Steps in Clinical Research-continued
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
Steps in Clinical Research-continued
Steps in Clinical Research-continued
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
The question to be answered or hypothesis to be answeredThe question to be answered or hypothesis to be answered
The questionThe question
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
The Question-continuedThe Question-continued4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Step in Clinical Research-continued
Step in Clinical Research-continued
5 Determine what tools materials personnel time and so forth are necessary to obtain and analyzed the data based on your reading of the literature6 Given the preceding requirements is the study feasible7 Revise ( perhaps) the question and hypothesis andor alter the variables according to your resources and time8 Choose the appropriate subjects ( including controls if appropriate) from whom data on the variables can be obtained
5 Determine what tools materials personnel time and so forth are necessary to obtain and analyzed the data based on your reading of the literature6 Given the preceding requirements is the study feasible7 Revise ( perhaps) the question and hypothesis andor alter the variables according to your resources and time8 Choose the appropriate subjects ( including controls if appropriate) from whom data on the variables can be obtained
Steps in Clinical Research-continued
Steps in Clinical Research-continued
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
Steps in Clinical Research-continued
Steps in Clinical Research-continued
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
The question to be answered or hypothesis to be answeredThe question to be answered or hypothesis to be answered
The questionThe question
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
The Question-continuedThe Question-continued4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Steps in Clinical Research-continued
Steps in Clinical Research-continued
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
9 Revised ( perhaps) the question hypothesisand variables to match the subjects to whom you have access10 If you are still interested ( and this is what separates the true clinical researchers from the dabblers) devise your methods to collect the data from subjects11 Discuss your proposed study with a biostatistician or some experienced epidemiologist in clinical research12 Only now should you collect the data Unfortunately many novices begin this step too soon thereby compromising the studyrsquos worth
Steps in Clinical Research-continued
Steps in Clinical Research-continued
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
The question to be answered or hypothesis to be answeredThe question to be answered or hypothesis to be answered
The questionThe question
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
The Question-continuedThe Question-continued4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Steps in Clinical Research-continued
Steps in Clinical Research-continued
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
13 Analyze the data with the help of a biostatistician14 Write it up for publication ( this is what separates the academic from the nonacademic clinical researchers)15 After it is accepted ( and it might take several attempts) REJOICE and take your spouse out to dinner Better yet let him or her take you out to dinner
The question to be answered or hypothesis to be answeredThe question to be answered or hypothesis to be answered
The questionThe question
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
The Question-continuedThe Question-continued4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
The question to be answered or hypothesis to be answeredThe question to be answered or hypothesis to be answered
The questionThe question
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
The Question-continuedThe Question-continued4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
The questionThe question
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
1 The importance of the questionHow big a burden of the illness
How important is the answer to cost-containment in providing health servicesIs the answer to this question a key component of a larger question
2 What is the status of the areaHow much exploring is still neededIs the researcher still fishing or stalking the game
3 How well supported is the hypothesis
The Question-continuedThe Question-continued4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
The Question-continuedThe Question-continued4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
4 What are the characteristics of the phenomena involved in the question
The incidence or prevalence of exposure or riskThe time span over which the phenomena evolveThe incidence or prevalence of the outcome
5 Is it ethical to conduct an experimental study to answer the question
Will some of the subjects be exposed to undue risk
6 Is the research plan practical7 Does the investigator have the necessary time and resources to implement8 Will the answer be unambiguous
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Factors that might possibly help to develop a reasonable
research question
Factors that might possibly help to develop a reasonable
research question1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
1 Literature review2 Time3 Cost of materials tests assistantsetc4 Sufficient number and types of subjects5 Ability to gather and store data6 Critical mass of colleagues interested in clinical research7 Ethical issues
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
General suggestions for generations for generating a
reasonable question
General suggestions for generations for generating a
reasonable question1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
1 Generate on idea2 Identify a simple question3 Modify the question4 Form a hypothesis
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Literature SearchLiterature Search
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
As in your mind so in your sort of search yoursquoll find what you desire -Robert Browning
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
MedlineMedlineThe United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
The United States National Library of Medicine has developed 16 different data bases that contain 12 million citations and author abstracts from over 4800 biomedical journals published in US and 70 other countries This is ( Medical Literature Analysis and Retrieval System or MEDLARS) One of these data bases is called MEDLINE It is a bibliographic file of articles and it is the most comprehensive economical and widely used systemCitations in MEDLINE are assigned subject headings from the MeSH vocabulary to assist users in their searches
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
PubMed ( wwwpubmedgov)PubMed ( wwwpubmedgov)PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
PubMed a service of the National Library of Medicine provides access to over 11 million citations from MEDLINE (the NLMs premier bibliographic database covering the fields of medicine nursing dentistry veterinary medicine the health care system and preclinical sciences) and additional life sciences journals PubMed includes links to many sites providing full text articles and other related sourcesPubMed provides access to bibliographic information that includes MEDLINE OLDMEDLINE as well as
ｷ The out-of-scope citations (eg articles on plate tectonics or astrophysics) from certain MEDLINE journals primarily general science and chemistry journals for which the life sciences articles are indexed for MEDLINE ｷ Citations that precede the date that a journal was selected for MEDLINE indexing ｷ Some additional life science journals that submit full text to PubMedCentral and receive a qualitative review by NLM
Note 1 PubMed provides access to citations from Medline and HealthStar and other additional NLM databases 2 Coverage extends back to the early 1950rsquos and continues to the present with new data added weekly
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Cochrane data basesCochrane data basesThe Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
The Cochrane Collaboration is an international non-profit and independent organization dedicated to making up-to-date accurate information about the effects of healthcare readily available worldwide It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions The Cochrane Collaboration was founded in 1993 and named for the British epidemiologist Archie Cochrane
The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of The Cochrane Library
Those who prepare the reviews are mostly health care professionals who volunteer to work in one of the many Collaborative Review Groups with editorial teams overseeing th ti d i t f th i ll
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
SubjectsSubjects
There are more men ennobled by study than by nature
There are more men ennobled by study than by nature
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Sample selectionsSample selections1 Probability sampling
Simple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
1 Probability samplingSimple random samplingSystemic samplingStratified random samplingCluster sampling
2 Non-probability samplingConvenience samplingQuota samplingPurposive samplingHaphazard sampling
3 Combination of probability and non-probability samples
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Sample sizeSample sizeThe size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
The size of the sample for a study should be large enough to show clinically relevant differences between study groups with statistical significance and small enough to be practical and feasibleUsing confidence intervals ( as opposed to p value only) allows the investigator not only to reject or accept a hypothesis within a known degree of uncertainty but also to estimate the size of the treatment effect together with some measure of the uncertainty in the estimateAttrition of subjects should be considered in advance
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Attrition of study subjectsAttrition of study subjects
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Attrition rates greater than 30 percent make interpretation of the results very difficultThe original estimates of adequate sample size must take into account
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Methods for assignment of participants to each groupMethods for assignment of participants to each group
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Case control group A proper comparison requires that the performance of the comparison group is an adequate proxy for the performance of the treatment group if they had not received the interventionRandom allocation the groups are same with respect to
1 The dependent variable before the independent variable was introduced2Variables other than those considered to be independent and dependent through the life of study
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Random allocationRandom allocationRandom allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
Random allocation allows us to assume within calculable limits of probability that the groups are the same with respect to
1 The dependent variable before the independent variable was introduced2 Variables other than those considered to be independent and dependent throughout the life of study
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
MatchingMatchingPair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Pair matching it is a specific match in which comparison subject is found for each intervention subjectNon-paired matching There is no attempt is made to find specific comparison subjects for each intervention subjects
1 Frequency matching The distribution of the confounding variable in the experimental intervention group is stratified and one attempts to equalize the number of experimental intervention and comparison subjects in each stratum2 Mean matching Attempts are made to match the sample means for the confounding variable in question
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Types of Research Models and Methods
Types of Research Models and Methods
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Attributes of Study DesignAttributes of Study Design
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
1 Strength of causation ( speculation versus assertion)2 Orientation in time3 Orientation to the process prospective versus retrospective4 Description versus comparison5 Observation versus experimentation
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Requirement of all studiesRequirement of all studies
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
1 Firmly establishing a study objective or hypothesis2 Methods of assembling groups of study subjects including developing specific case definition and avoiding systemic errors3 Making valid and reliable observations consideration of biased surveillance blinding and variability among observers4 Handling incomplete observations such as individuals who are lost to follow-up who fail to return questionnaire or who appear to change their status during the study5 Selecting appropriate comparison groups including identifying and controlling for important factors that may impact on the study hypothesis
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Tests for causationTests for causation1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
1 Is there evidence from true experiments in humans2 Is the association strong3Is the association consistent from study to study4 Is the temporal relationship correct5 Is there a dose-response gradient6 Does the association make epidemiologic sense7 Does the association make biologic sense8 Is the association specific9 Is the association analogous to a previously proven causal association
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
The Evidence PyramidThe Evidence Pyramid
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Orientation to the processOrientation to the processProspective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Prospective Concurrent or non-concurrent the researcher assembles a group of individuals who will be exposed to a risk factor or intervention and then waits to observe an outcomeRetrospective The researcher selects a group of individuals expressly because they already experienced the outcome under study It is then asked in retrospect if any of them have experienced certain events that they may have experienced certain events that may lead to the outcome
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Descriptive versus Comparative StudiesDescriptive versus
Comparative StudiesDescriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Descriptive It reveals the reality of the issue of interestComparative It involves the hypothesis testingIt is important to emphases that both kinds of studies can have important scientific value when used to address the appropriate question
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Observational or Experimental Studies
Observational or Experimental Studies
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Observational study does not involve any intervention experimental or otherwiseExperimental Study A study in which conditions are under the direct control of the investigator
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Cross-sectional StudiesCross-sectional Studies
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
1 They avoid the difficult task of tracking individuals over long periods of time2 Information is generally available from public sources3 By far the biggest problem of cross-sectional studies is their inability to show temporal sequence in support of a claim of causality
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Ecology StudyEcology Study
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Study based on group environment rather than individual environmentThese studies subject to ecologic fallacyEcologic variables may be used in many study designs not just those that are cross-sectional They are frequently found in time series analyses
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Observational Study Case-Control Study
Observational Study Case-Control Study
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Potential economyGood for rare diseaseGood for multiple risk factorsThe results can only give approximations of actual rates with which the outcome occursPast exposure is sometimes not reliableThe control group should be carefully selected5-steps in case-control study Hypothesis development establishment of definitions case selections control selection and exposure determination
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Range of usage of case-control study( examples)Range of usage of case-control study( examples)
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Why some patients respond well to therapy while others do not ( cases would be those who did not respond and controls a similar set of patients who had responded)Why only some medical students present for vaccination against hepatitis BWhy some patients develop postoperative complications ( the cases) and others undergoing the same operation do not ( the controls) In this example both cases and controls have a disease ( which is the reason for their surgery) It is the experience of postoperative complications which identifies the cases
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Observation Study Cohort StudyObservation Study Cohort StudyIndividuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Individuals with certain baseline characteristics are observed from this baseline until a previously defined endpoint is reachedFour ways 1 Single heterogeneous group followed from
baseline to outcome2Two homogenous group followed from baseline
to outcome3 The purely descriptive cohort study4 Epidemiologic cohort
Four Steps in cohort study 1 Assembling the initial cohort2 Devising a scheme for tracking the cohortrsquos members3 Developing objective outcome criteria and an unbiased
method of ascertaining outcome status4 Measurement of other factors ( confounders) that might
influence the outcome
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Range of usage of Cohort Study ( examples)
Range of usage of Cohort Study ( examples)
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Determine whether patients need long term follow-upDetect long-term adverse effects of medical interventionInvestigate continued health care usageEvaluate patient well-being in the longer termClarify the natural history of a disease
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Experimental studyExperimental studyClinical Trials must be 「experimental
」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Clinical Trials must be 「experimental」testing hypotheses and not observational studies並不是一種「正規的標準治療方法」仍具有不確定的療效與危險性
新藥療效的評價因試驗的動物不同有所差異毒性反應亦可能有所不同
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Experimental Studies ( Clinical Trials)Experimental Studies ( Clinical Trials)1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
1 It is a concurrent prospective comparison of two or more groups 2 One or more of the groups is deliberately exposed to an intervention usually a medical therapy while at least one group(the controls) is not exposed or receives a more standard therapy3 The study groups are generated from a single homogeneous pool of subjects Assignment of individuals to each experimental or control group is determined by a method based on random events and without any consideration of which member of the pool is assigned to which group
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
4 All study participants (subjects treating clinicians and outcome evaluators) are unaware of which subjects are receiving an intervention and which are in a control group This ldquoblindingrdquo may also extend to various participants being unaware of the true study hypothesis or the nature of the outcome measure
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Experimental Studies ( Clinical Trials) continued
Experimental Studies ( Clinical Trials) continued
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
5 Control subjects receive an intervention that is either indistinguishable (to the subjects) from the actual intervention or is felt to have equivalent impact in ways that might effect the outcome to be measured This usually includes attention to psychological factors such as the placebo or Hawthorne effects through which some outcomes of behavior may change because individuals believe that they are being treated or because they know that they are being observed In general control and experimental groups should both experience some form of intervention and have an equivalent amount of contact with the research staff
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
新藥臨床試驗簡介新藥臨床試驗簡介
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
新藥研發是一成本高時間長的高科技專業從實驗室中確定新藥分子活性到病人體內反應 (From Bench to Bed)需經過多重的試驗階段包括臨床前的藥物合成藥物動力學藥效藥理毒性學評估等以及最重要的臨床試驗階段而這即是一般人有些許概念的臨床第一二三期試驗
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
臨床醫療
醫師
病人
對症下藥因人而
異
信賴
同儕審查
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗
試驗主持人
受試者
依計劃書
依GCP
試驗委託者稽核
法規單位查核
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
新藥臨床試驗的分類新藥臨床試驗的分類
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
Phase I ------ Investigation of safety PKPD dose finding
Phase II ----- Preliminary efficacy dose ranging small scale
Phase III ---- Efficacy and safety pivotal large scale
Phase IV ----- Large scale Post-marketing surveillance
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
No Drug Approval Without
Patient Benefit- feeling better
andor- living longer
Evidence-based efficacy and safety
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
療效的介定療效的介定
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
Primary efficacy endpoints臨床療效指標 vs 替代性指標---
二者具相關性且有因果關係
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
什麼是 Clinical endpoint什麼是 Clinical endpoint
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
通常指 clinical outcome 如下舉例
骨質疏鬆症骨折發生率癌症 活時間長短和存活率高血酯症心血管疾病死亡率Avoid misleading about the actual clinical effects
1 Arrhythmia Suppression encainide flecainide and moricizine ---VPC after MI --- mortality
2 Lipid Lowering clofibrate Niacin --- TG TC --- Mortality 3 Osteoporosis in Postmenopausal Women Sodium fluoride --- BMD ---
brittle fracture4 避免自行創造 endpoint5 選擇不恰當的 endpoint 會造成試驗失敗 血本無歸
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
什麼是 surrogate endpoint
什麼是 surrogate endpoint
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Reliably effective substitutefor the clinical outcome Lab measurements (LDL-C BP CD4 cell count viral load)BMD QT interval tumor response or physical signs
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
Randomized clinical trial of intraoperativeautotransfusion in surgery for abdominal aortic
aneurysm
British Journal of Surgery Vol 91 1443-1448Nov 2004
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
安全性AE安全性AEAdverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
Adverse Event Adverse Experience (AE)Adverse Drug Reaction (ADR)Serious Adverse Event (SAE)Toxicity (intoxication)(ex Apresoline Brain tumor HR increase 5 beats min shock SLE)
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
PhamacovigilancePhamacovigilance財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
財團法人藥害救濟中心
= Post-marketing surveillanceidentifying and quantitatively assess the risks related to the use of drugs in the entire population or in specific population subgroups
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
統計方法的選擇Randomization and stratificationHypothesis Testing (margin determination) ---Comparisons --- 較優性 (superiority) 不劣於 (non-inferiority) 相等性 (equivalence)Sample size power type 1 error p value 95 CI Missing value management etc Types of Hypothesis新的治療確有幫助嗎對照藥是 --- 安慰劑 ---符合倫理嗎其療效比目前所使用之治療方式來的更好嗎它會導致何種副作用其優點（療效）多於缺點（副作用）嗎哪一種病人在接受這種治療時最能得到幫助
「臨床試驗除罪化」 vs 「受試者權益不容忽視 」現今已有九家醫學中心成立臨床試驗中心可以執行第一二三期的臨床試驗
Clinical Trial Data Analysis Statistics-
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Summary of Clinical TrialSummary of Clinical Trial以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
以科學研究言臨床試驗實是醫學研究中重要的一環一個設計嚴謹有科學意義且嚴格遵守ＧＣＰ規範執行的臨床試驗不論其結果是成功（治療有效）或失敗都提供了有用的資訊以促成醫學的進步衛生署積極推動人體試驗委員會的認證標準希望更進一步來規範及督促ＩＲＢ盡到確保臨床試驗品質及受試者人權的責任如此一來受試者就不必有白老鼠的擔憂
一個具科學意義且成功的優良臨床試驗不可諱言地常常伴隨有巨大商業利益但這也表示某種疾病的治療上有了新的進展對全球的病患帶來了一個好消息這些絕非金錢所能衡量
部分人士將臨床試驗視之為產業讓「臨床試驗」沾上了些許商業氣息也容易被污名化因而引起臨床試驗的受試者多淪為白老鼠的聯想（--- 爭議性）
好的臨床試驗可與國際接軌獲得第一手資料並來為本土的疾
病找尋出新藥以及新的療法
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
臨床試驗常見的缺失與困難臨床試驗常見的缺失與困難遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
遺失受試者同意書 (Informed Consent)以及人體試驗委員會(IRB) 同意書 (函) 的遺失最好影印數份分別保存
未按計劃書收納病患
隨機盲性作業之疏失
病人退出試驗（drop out）方面的疏失
Drug count 不符 (病人的用藥數量與給藥的數量或所剩的藥量不符)
試驗期中試驗計畫書 (protocol) 有所修改時尤其更改主要療效指標未呈送人體試驗委員會 (IRB) 和衛生署審核
未遵守 GCP 精神統計分析不對結論不適當
檢驗數據不全製造假數據藥物不良反應報告不實或病歷記載不全 個案報告表 (case report form) 填表不實或不全
研究協調者 (Research coordinator) 或研究護士 經驗不足試驗主持人 (Principal investigator) 經驗不足不夠敬業有些甚至掛名而已態度不夠嚴謹 試驗委託者 (Sponsor) 與受委託研究機構 (CRO) 人力不足結構不齊全經驗不足
受試者 (病人) 對試驗的認知不足
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Meta-analysisMeta-analysis
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
A statistical synthesis of the data from separate but similar ie comparable studies leading to a quantitative summary of the pooled results
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
SurveillanceSurveillance
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Systemic ongoing collection collation and analysis of data and the timely dissemination of information to those who need to know so that action can be takenExample
1 Alosetron ( Latronex GlaxoWellcome)2 Lorcainide
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Conditions not suited to experimental study
Conditions not suited to experimental study
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
1 Multiple therapeutic modalities ( because too many subjects are needed to evaluate the many possible therapeutic combinations)2 Small changes in a therapeutic plan ( then effort it takes to do the study may outweigh the potential significances of the outcome)3 Therapies that may be changes during the course of the study so that the results are at risk for becoming obsolete before the study is completed4 Treatments with only rare outcomes or outcomes that will only be observable at a time far distant in the future
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Unique considerations to clinical trials
Unique considerations to clinical trials
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
1 Defining the eligible population and selecting subjects2 Development of the treatment protocol3 Selecting alternative treatment
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Quasi-Experimental StudiesQuasi-Experimental Studies
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
1 The inability to randomize individual study subjects2 The availability of only a single study group3 The prohibition of keeping one group as a control ( being required to provide all groups with some intervention)4 The inability of pre-testing any of the groups to determine baseline characteristics
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Some examples of questions and the methods of research designSome examples of questions and the methods of research designQuestion1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Question1What is the history of infant feeding practices in Taiwan2 What anticipatory guidance is given for injury control on routine check-up3 What is the pattern of growth in children with Down Syndrome4 What are the characteristics of teenage youngsters on probation for drug abuse5 What is the relationship of dietary counseling during well-baby checks to iron deficiency anemia in infants6 What is the influence of policy on mean family income and hospital days per child using aggregated data7 Is prednisone combined with trimethoprrim-sulfamethoxazolealone8 What is the change in injury potential in a group of infants after parents are given an educational program
( assuming some factors such as maturation selective attrition effects of testing etc are unavoidable)
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Method1 Descriptive2 case studies
3 Observational (longitudinal) cohort4 Cross-sectional
5 Cross-sectional or Quasi-Experimental6 Ecologic
7 Clinical trial
8 Quasi-Experimental
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Data acquisitionData acquisition
Data Collection Management and Analysis
Data Collection Management and Analysis
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Heart of research design-data acquisition
Heart of research design-data acquisition
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
1 The investigatorsrsquo and the subjectsrsquoorientations in time2 The investigators and the subjectsrsquoorientation in the process3Description versus comparison of subjects4 Passive observation versus active experimentation to ldquomanipulaterdquo the subjects
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Deciding what to collectDeciding what to collectConsider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Consider exactly what information is needed to answer the research question and what is the most cost-effective way to obtain the dataConsider what type of data to be collected
Nominal People or events in unordered categories ( eg black or white dead or alive)Ordinal People or events in ordered categories (eg ranks score 1 or 2 plus of edema)
Continuous Numbers are assigned or attached that have absolute meaning as a count or measurement by an objective scale( eg age weight score ( sometimes)
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Deciding How to Collect the Data
Deciding How to Collect the Data
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
Routine Data collected routinely for other purposes independent of the study 9eg medical records vital statistics census data hospital discharge abstracts and national or local routine health surveys)Programmatic Data collected as part of a service program but not specifically related to a research project ( eg patient-visit data billing data and vouchers)Primary Data specifically collected to address research questions( eg questionnaire and patient observations)
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
ValidityValidity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
1 Construct validity2 Content validity ( face validity)3 Criterion validity4 Internal consistency ( Cronbachrsquosalpha)5 External Validity
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
ReliabilityReliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
1 Inter-rater reliability2 Intra-rater reliability
Kappa alpha statistic
3 Test-retest reliability4 Split-half reliability
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Illustration of data collectionIllustration of data collection
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Use of matched birthinfant death recordsBirth weight codeMedical recordBilling dataNHIB prevalence incidence and case-fatality data
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Selecting InstrumentData Collection Method
Selecting InstrumentData Collection Method
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Relevance to the Research QuestionFeasibility of CollectionValidity and Reliability of MeasureData Management Procedure
Procedures manualCoding manualData entry
Data Analysis
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Common pitfalls of data analysis
Common pitfalls of data analysis
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
1 The failure to analyze data on those individuals who were eligible for the study but who for some reason were excluded2 The use of multiple tests of significance when comparing two groups3 Insufficient sample size
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Communication of resultsCommunication of results
Writing an abstractPresentationPublication
Writing an abstractPresentationPublication
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Funding considerationFunding considerationBecome acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Become acquainted with the basic facts about public and private funding sources in generalDefine areas of research interest and identify sources of support with similar research interests and prioritiesObtain detailed information on the funding history eligibility requirements ad application procedures of identified sources of supportWrite a letter of intent including the proposed funding necessary to those organizations that seem most appropriate For sources of support that respond with a request for a full proposal prepare and submit one that complies with the sourcersquos specific instructions regarding format content length number of copies and application deadlines
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Ethical standards for research involving human subjects
Ethical standards for research involving human subjects
Nuremburg CodesHelsinki DeclarationInformed consentIRB
Nuremburg CodesHelsinki DeclarationInformed consentIRB
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
1949The Nuremberg Code1949The Nuremberg Code美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
美國的法官於1947年在所謂的 「醫師的審判」（Doctors Trial）中訂定了紐倫堡條約（Nuremberg Code）為關於醫學研究倫理上最重要的文件 紐倫堡條約一共有十條第一條即開宗明義地說出「受試者的自願同意是絕對必要」 (The voluntary consent of the human subject is absolutely essential) 此後任何臨床醫學實驗在進行以前都必須獲得受試者的同意所謂之「同意」係指受試者必須處在沒有任何壓力脅迫利誘哄騙的情形下並且不受隱瞞實驗者必須明白告知受試者實驗的目的對個人的影響與研究成果對社會可能之預期貢獻等
Art 1 The voluntary consent of the human subject is absolutely essentialArt 9 During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to he to be impossible
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
1964 Helsinki Declaration1964 Helsinki Declaration
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
bull 世界醫學協會(World Medical Association)經過幾年的研議在1964年於芬蘭首都赫爾新基所召開的第十八屆總會中通過確認人體試驗的倫理規範 rdquoRecommendations guiding physicians in biomedical research involving human subjectsrdquo通稱為「赫爾新基宣言」
bull 1975 29th Tokyo Revisionbull 1983 35th Venice Revisionbull 1989 41th Hong Kong Revisionbull 1996 48th Somerset West Revisionbull 2000 52nd Edinburgh Revision
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Helsinki DeclarationHelsinki Declarationbull Introduction
bull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
bull Introductionbull The health of my patients will be my first considerationbull Medical progress is based on research which ultimately must rest in part in
experimentation involving human subjectsbull Clinical research vs Non-clinical research
bull Basic Principles（1）需事先徵求受試人在自由意志情況下之自願同意且此受試人必須具有同意之法律能力（2）受試人對於實驗所涉及之內容有一定程度之瞭解（3）實驗本身設計的目的是為人類社會之福祉（4）進行人體實驗前必須先有實驗室及動物實驗依據（5）盡力避免對人體身心的傷害一旦實驗進行中發現對人體有害應立即停止（6）必須在合法機關監督下由具備資格者進行實驗且必須事先擬好補償措施
bull Medical Research combined with clinical care (Clinical research)bull Non-therapeutic biomedical research involving human subjects(Non-clinical
biomedical research)bull 試驗計畫書(protocol)應經一獨立委員會審查ldquospecially appointed committee
independent of the investigator and the sponsorrdquo （通則第4條） 人體試驗委員會美國rdquoInstitutional Review Boardrdquo 台灣 ldquoEthics Committeerdquo赫爾辛基宣言之精神
自主受試驗者是在被充分告知相關訊息後自由決定要參加的
有益參加試驗的風險相對於可能有的好處是可以接受的受試驗者參加試驗後並不會犧牲其權利仍會受到已證明有效的最佳照顧
赫爾辛基宣言之功能- 道德勸說 效果hellip
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條
知情同意（Informed Consent）-Helsinki Declaration通則第 11 12 13 141516條「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndash
bull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
「說清楚很麻煩不說又不行」 --- 知道了解有效同意 ndashbull 受試者同意書是醫師和病人溝通的橋樑必須用非常淺顯口語
化的文字說明必須讓病人能了解計劃之目的病人需做的檢查及治療配合事項接受治療可能有的副作用以及其他權利及義務不可以過於誇大宣傳療效
告知之範圍受試者應被告知試驗目的方法收納排除退出標準其他可能的替代療法尊重病患隱私權並主動告知最新訊息受試者權益（ human rights）保護與保密 配套保障措施【保險非過失非故意】 彼此的義務與責任誠實說明感同身受組織檢體血液等的保存期限與用途實驗之預期利益及潛在風險並應被告知其有不加入以及任意退出之自由(赫爾辛基宣言通則第13條）
bull 告知之態度醫師應避免病患對醫師之依賴關係而「不得不」同意（consent under duress) (赫爾辛基宣言通則第14條）
bull 受試者為無行為能力人時應取得其法定代理人之同意受試者雖然為未成年人但只要具備意思能力也應一併取得其本人同意(赫爾辛基宣言通則第16條）
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
藥物臨床試驗責任險 富邦產開賣【20050121 經濟日報】
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
富邦產險新推出「藥物臨床試驗責任保險」這是繼第一產後第二家 ------ 傷亡的最高理賠金為每人200萬元累計的賠償金額不得超過1000萬元
受試者試驗主持人與其他成員的名單必須註明在保單契約內若受試者與醫療機構產生醫療試驗的糾紛其中的訴訟費用才可包含在承保範圍內
受試對象藥物種類成分及內外科別等因素會影響整體費率 根據市場經驗每張保費的平均價格約20萬元 ------ 費率差距甚大
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Real LifeReal Life
Check your work before you presentCheck your work before you present
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
楊XX涉擅作人體實驗 高雄長庚已停職接受調查中
20031103 1413 記者林澄洋高雄報導
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
高雄XX醫院一名醫師被檢舉違規私下進行人體實驗把病人當成白老鼠引起病人相當的恐慌醫院則是在緊急會議之後出面解釋這名醫師己經被停職調查衛生署強調如果醫師有違法情形-----
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Clinical Pharmaceutical Medicine
An Inexact Science with a large black box between molecular interactions and patient response
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
What we are dealing with
Molecular Molecular Pharmacological Pharmacological Clinical (if Clinical (if lucky) interactionslucky) interactions activityactivityEfficacySafetyEfficacySafety
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
But most of time you get this
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
上市前 vs 上市後上市前 vs 上市後
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
醫療藥品使用量醫療藥品使用量
美洲 40 歐洲 20 日本 15 台灣 05 韓國 15 中國大陸 2 ASEAN(東亞十國) 3 其它 15
International Conference on Harmonization (ICH) US EU and Japan
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】
輪狀病毒疫苗人體試驗 暫停收案 【20050120 民生報】 【記者楊惠
君報導】參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
參與口服輪狀病毒疫苗人體試驗的3個月大女嬰猝死雖然法醫相驗初步認為死因為窒息與疫苗關係不大但衛生署對此案十分重視負責該項人體試驗的台大小兒科教授黃立民昨前往說明 在法醫解剖報告及藥廠解碼之前4家參與臨床試驗的醫院即日起先暫停收新案
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004
默沙東治療關節炎藥品偉克適全球下市
中央社記者陳惠珍台北 1012004MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
MSD 藥廠 指出公司生產治療關節炎及急性疼痛藥物 (VIOXX)因病患服用十八個月後恐有增加心臟方面副作用的危險性---默沙東公司總裁表示「我們深信採取這樣的處理方式是為能顧及患者最大利益 ---股價由US50跌到落US26 消費者團體對 Merck 藥廠提出集體訴訟 ---接踵而來的訴訟及賠償將導致龐大的損失
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
醫葯新聞不同解讀見仁見智醫葯新聞不同解讀見仁見智
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
OO 醫學院 OOO 名譽教授宣布『白鳳豆錠劑抗癌通過臨床試驗』 -----
OO 電視台最新特報XX 醫院宣布 --- SARS疫苗將進入臨床試驗最快明年上市---
OOO 教授院士研發肝癌疫苗有成已經申請專利不排除和大藥廠合作進行臨床試驗---
吸煙也能抗癌中研院發表驚人的研究報告療效是目前最常用抗肺癌藥物的15到13倍已經申請專利預估兩年後上市---
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市--
2004111 頭版肺癌末期有救 華陽複方神奇療效 （記者王薇 羅樹明 台北報導）
旅美華裔科學家孫士銧研發的華陽複方可以延長肺癌末期病患的壽命平均長達335個月 FDA核准進行第三期臨床試驗預計2年後成為史上市-- 20041109衛署強調華陽複方仍算食
品業者聲稱抗癌療效將開罰《記者王菁菁台北報導 》
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
降血脂化瘀 紅麴菌三月上市報導記者方怡驊 940127
古早的中藥材紅麴菌被研究製成可以降血脂的藥品「壽美降脂一號」 經過三年的西藥臨床試驗與 Statin 的藥效類似是國內第一個依照西藥遊戲規則確認療效的中藥
將以西藥模式進軍降血脂（活血化瘀 ）藥品市場
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Monson check listMonson check listQ1Why was the study done
1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Q1Why was the study done 1 What is the question to be answered2 Is it a practical issue or a theoretical issue
Q2What are prior hypothesesQ3How would you label the study in epidemiology
1 Is it a descriptive study survey case control study cohort studyexperimental study meta-analysis or a surveillanceQ4What is the study subjectsQ5What are the comparison subjectsQ6Could there have been bias in the selection of study subjects and comparison subject
1 What is the population Is it a representative sample Did the subjects randomly selected
2 Are there any standard selection process Are there any rationale of the process
3 How did the sample size been determined4 Are there any missing data
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Monson check list ( continued)Monson check list ( continued)Q7Could there have been bias in the collection of information
1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
Q7Could there have been bias in the collection of information1 What is the measurement scale Quality or Quantity2 Any repeated measurement
Q8What provision was made to minimize confounding1 Restriction matching or stratification
Q9What was the measure of association and stability in the association
1 Relative risk or Odds ratio2 95confidence interval been presented
Q10What is the major result of the studyQ11How might bias have affected the resultsQ12How might random misclassification have affected the resultQ13Is the interpretation of the data appropriate
1 Did the conclusion been well supported Did the conclusion answer the proposed question
2 Did the biological plausibility been well generalized
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
ConsortConsortEffect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months randomised controlled trial
Linda Diggle senior research nurse a Jonathan Deeks senior medical statistician b
a Oxford Vaccine Group University Department of Paediatrics John Radcliffe Hospital Oxford OX3 9DU b ICRFNHS Centre for Statistics in Medicine Institute of Health Sciences University of Oxford Oxford OX3 7LF
Correspondence to L Digglelindadigglepaediatricsoxfordacuk
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
AbstractAbstractObjective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Objective To compare rates of local reactions associated with two needle sizes used to administer routine immunisations to infants Design Randomised controlled trial Setting Routine immunisation clinics in eight general practices in Buckinghamshire Participants Healthy infants attending for third primary immunisation due at 16 weeks of age 119 infants were recruited and 110 diary cards were analyzed Interventions Immunisation with 25 gauge 16 mm orange hub needle or 23 gauge 25 mm blue hub needle Main outcome measures Parental recordings of redness swelling and tenderness for three days after immunisation Results Rate of redness with the longer needle was initially two thirds the rate with the smaller needle (relative risk 066 (95 confidence interval 045 to 099) P=004) and by the third day this had decreased to a seventh (relative risk 013 (003 to 056) P=00006) Rate of swelling with the longer needle was initially about a third that with the smaller needle (relative risk 039 (023 to 067) P=00002) and this difference remained for all three days Rates of tenderness were also lower with the longer needle throughout follow up but not significantly (relative risk 060 (029 to 125) P=017) Conclusions Use of 25 mm needles significantly reduced rates of local reaction to routine infant immunisation On average for every five infants vaccinated use of the longer needle instead of the shorter needle would prevent one infant from experiencing any local reaction Vaccine manufacturers should review their policy of supplying the shorter needle in vaccine packs
Thank YouThank You
Thank YouThank You
