Clinical trials A properly planned experiment and executed clinical trial is a powerful experimental...
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CLINICAL TRIALS
Clinical trials A properly planned experiment and executed clinical trial is a powerful experimental technique for assessing the effectiveness of an intervention
Clinical trials A properly planned experiment and executed
clinical trial is a powerful experimental technique for assessing
the effectiveness of an intervention. Friedman, Furer and
Demets
Slide 3
Definition The term clinical means bedside. It may be applied
to any form of planned experiment, which involves patients and is
designed to elucidate the most appropriate treatment for future
patients, with a given medical condition. A clinical trial must
employ one or more intervention techniques and these may be
prophylactic, diagnostic or therapeutics agents, devices, regimens,
procedures etc. A clinical trial must contain a control group
against which the intervention is compared. At baseline, the
control group must be similar in relevant respects to the
intervention group so that differences in the outcome may
reasonably be attributed to action of intervention.
Slide 4
Why are clinical trials needed? Evaluation of safety and
efficacy of therapies, for which the results need to be:
Non-subjective Scientifically valid Opportunity to screen new drugs
in a drug development program Carefully designed trials are the
only means to detect the usually small differences between drugs or
methods of treatment or the advantages of one over another.
Slide 5
Types of trials Therapeutic trials measure the efficacy of
drugs or other therapeutic procedures (for example: diet, bed-
rest, surgery, physiotherapy and ionizing radiation). Preventive
trial measure the effect of preventive measures on the health of
populations (for example, control of pollution of water supplies,
immunizations, change of diet, change of smoking habits,
fortification of foodstuffs, weight reduction, contraception).
Slide 6
Phases of drug trials Phase I trials: clinical pharmacology and
toxicity These first experiments in man are primarily concerned
with drug safety, not efficacy and usually performed on human
volunteers. Phase I involves studies of: Acceptable single drug
dosage Drug metabolism Bioavailability Phase II trials: initial
clinical investigation for treatment effect These are small-scale
investigation into the efficacy and safety of a drug and require
close monitoring of each patient. Seldom phase II trials go beyond
100-200 patients on drug.
Slide 7
Phase III trials: full scale evaluation of treatment. This is
done to compare the drug with the current standard treatment(s) for
the same condition in a large trial involving substantial number of
patient. Phase IV trials : post-marketing surveillance After drug
being approved for marketing, research to be undertaken as regards
monitoring for adverse effects and additional large scale, long
term studies of morbidity and mortality.
Slide 8
Fundamental aspects of trial design a) Which patients are
eligible? b) Which treatments are to be evaluated? c) How each
patients response is to be assessed?
Slide 9
Questions Each clinical trial must have a primary question. The
primary question as well as any secondary or subsidiary question,
should be carefully selected, clearly defined and stated in
advance.
Slide 10
Primary question Should be one the investigators are interested
in answering It is the one on which sample size of study is based
and that must be emphasized in the reporting of trials results. May
be framed in the form of testing of hypothesis.
Slide 11
Secondary question Variety of subsidiary or secondary question
related to primary question can be studies. They can be of two
types: 1. the response variable is different from that in primary
question (eg: Primary question: Mortality from any cause is altered
by the intervention) Secondary question might relate to cause
specific death rates) 2. Second type of secondary question relates
to sub-group hypothesis (for e.g.: the investigator may want to
specifically at people by stage of disease at entry)
Slide 12
Subgroup hypothesis should be 1. Specified before data
collection begins 2. Based on reasonable expectations 3. Limited in
number
Slide 13
Study population Definition The study population is the subset
of the population with the condition or characteristic of interest
defined by the eligibility criteria. Fundamental point The study
population should be defined in advance stating unambiguous
inclusion (eligibility) criteria. These criteria will have an
impact on study design, ability to generalize and participant
recruitment.
Slide 14
Selection of study group This can be done in the following two
ways: 1. Accural: in which the subjects needed for the trial is
recruited during the course, of study. 2. Non accural: in which the
subjects needed are recruited before the study begins.
Slide 15
Reasons for specifying the study population 1. If an
intervention is shown to be successful or unsuccessful, the medical
and scientific communities must know what kinds of people the
finding apply. 2. Knowledge of study population helps other
investigators to assess the studys merit and appropriateness. 3. In
order for other investigators to be able to replicate the study,
they need data descriptive of the participants enrolled.
Slide 16
Controls A control group is used to compare the history of
exposure in the case with that in individuals who are free of the
exposure. The control series is intended to provide an estimate of
the disease rate that would be expected to occur in cases if there
were no association between the study disease and exposure.
Individuals selected as controls should not be free of study
disease/exposure but should also be similar to the cases in regard
to the past potential for exposure/disease during the time period
of risk under consideration.
Slide 17
Source of controls Controls may be selected either from
hospitals or from the community. If cases are chosen from the
hospitals or groups of hospitals, considerations of practicality
and cost confine the selection of controls to persons admitted to
the same hospitals but with a disease or condition different from
that under study, such persons are called Hospital controls.
Slide 18
Eligibility criteria Definition Eligibility criteria relate to
participant safety and anticipated effect of intervention. Outline
of eligibility criteria to be framed are: Participants who have the
potential to benefit from the intervention are obviously candidates
for enrollment into the study. In selecting participants to be
studied, not only does the investigator requires people in whom the
intervention might be worth, he also wants to choose people In whom
there is a high likelihood that he can detect the hypothesized
results of the intervention.
Slide 19
Eligibility criteria When deciding on these criteria, using
excessive restrictions in all effort to obtain a pure (or
homogenous) sample can lead to extreme difficulty in getting
sufficient participants. Capacity to recruit participants and carry
out trial effectively could greatly depend on the eligibility
criteria that are set.
Slide 20
Response variable A single response variable should be
identified to answer the primary question. If more than one are
used, the probability of getting nominally significant result by
chance alone is increased. If several response variables give
inconsistent results, interpretation becomes difficult.
Slide 21
Response variable Combining events to make up a response
variable might be useful if any one event occurs infrequently for
the investigator reasonably to expect a significant difference
without using a large number of participants.
Slide 22
Response variable Investigators should define and write the
question in advance as specific as possible. The primary response
variable must be capable of being assessed in all participants.
Selecting one response variable must be capable of being assessed
in all participants. Selecting one response variable to answer the
primary question from some participant and another variable to
answer the same question from other participant is not a legitimate
practice. Unless there is a combination of primary response
variable in which the participant remains at risk of having
additional events, participation generally ends when primary
response variable occurs. Response variable should be capable of
unbiased assessment. Truly, double blind studies have a distinct
advantage over other studies in this regard. It is important to
have response variable that can be ascertained as completely as
possible. In long terms participants may fail to return for
follow-up. If response variable is based on return to follow-up,
then information may be lost.
Slide 23
Bias Bias is a distortion in the perception of the effects of a
treatment or in the measurement of differences between the effects
of two treatments.
Slide 24
Source of bias Systematic differences between treatment groups
at admission into the trial. Example: Suppose treatments A and B
are assigned to two groups of children with leukemia. Patients
receiving A are two to six years old and parents receiving B are
either younger or older. It has been shown by several
investigations that middle age children have a better prognosis
than others. If results of the trial show a significant difference
between groups A and B, there is no way to find out whether the
difference is due to treatment alone, age alone or a combined
effect of treatment and age.
Slide 25
Methods of reducing bias Randomization Blinding Uniform
handling of procedures
Slide 26
Need for randomization Three possibilities of why the observed
difference between the two groups is not due to chance: The two
groups differ appreciably in factors related to their prognosis.
The two groups have been handled and looked after in different
ways. The particular therapy being examined has a beneficial
effect. Randomization is the best method to ensure that the groups
are similar in all respects except for the intervention given.
Slide 27
Source of bias Differential assessment of outcome in treatment
groups Example: The patients in the treatment group might be showed
more interests than those in the control group receiving a placebo.
Differential exclusion or withdrawal of subjects from the study
Example: elimination of patients who were judged ineligible after
enrollment by personnel who were aware of treatment assignment and
course of treatment.
Slide 28
Randomization Randomization is a process by which all
participants are equally assigned to either the intervention or
control group.
Slide 29
Advantages of randomization Ensures that the physician running
the trial is not consciously or unconsciously allocating certain
patients to a particular group. Produces comparable groups Measured
and the unknown prognostic factors will be on an average evenly
balanced between the two groups. Validity of statistical tests of
significance are guaranteed.
Slide 30
Masking (Blinding) The knowledge of whether the participant was
in treatment or control group can influence the study, resulting in
biased inferences either consciously or subconsciously. To remove
this source of bias in observation, three procedures have been
evolved: 1. Single blind 2. Double blind 3. Triple blind 4.
Quadruple blinding (planner, patient, investigator, outcome
analyzer)
Slide 31
Single blinding/Masking The participants are not given any
indication whether they are in experimental or control group. The
objective of single blinding is to prevent participant from
introducing bias into the observations, and is usually accomplished
by means of a placebo.
Slide 32
Double blinding Double blinding seeks to remove biases that
occur as a result of either subject or the observer of the subject
being influenced by knowledge that the subject is in control or
experimental group.
Slide 33
Triple blinding Triple blinding studies carry the concept of
blinding the subject, observer of the subject and the person
analyzing the data are all blind with regard to the group to which
a specific individual belongs.
Slide 34
Protocol framework Plan of clinical trial should be stated in a
protocol that contains objective and specific procedures before
start of a trial.
Slide 35
Study protocol A: Background of study B: Objectives Primary
question and response variable Secondary question and response
variable Subgroup hypothesis Adverse effect
Slide 36
C: Design of the study 1. Study population a. Inclusion
criteria b. Exclusion criteria 2. Enrollment of participants a.
Informed consent b. Assessment of eligibility c. Baseline
examination d. Intervention allocation (e.g.: randomization
method)
Slide 37
4. Intervention a. Description and schedule b. Measure of
compliance 5. Follow-up visit description and schedule 6.
Ascertainment of response variable a. training b. data collection
c. Quality control 7. Data analysis a. Interim analysis b. Final
analysis 8. Termination policy
Slide 38
D. Organization 1. Participating investigators a. Statistical
unit or data coordinating center b. Lab and other special units c.
Clinical center(s) 2. Study administration a. Steering committees
and sub-committee b. Data monitoring committee c. Fund
organization
Slide 39
Adverse effect Most interventions are likely to have adverse
effects. The investigators needs to weigh these effects against
possible benefit when he evaluates the feasibility of the study.
However, any participant for whom the intervention is known to be
harmful should not be admitted to the trial.
Slide 40
Problems in timing of clinical trials Trials need to be
feasible: feasibility includes knowledge, tools, knowledge on
safety of intervention, outcomes to be assessed. Relative stability
of intervention: If the intended intervention becomes outmoded in
short duration, studying such intervention may be inappropriate.
(In such case the best approach is to postpone the trial until a
procedure has reached a plateau and is unlikely to change).
Slide 41
Ethics of clinical trial Safety of the drugs or methods of
treatment The existence of an honest hypothesis Informed consent of
the participants The right of participants to withdraw from the
study at any time without sanctions Confidentiality of information
The use of finders fee i.e. payment to physician for referring
participants to a clinical trial investigator is inappropriate in
that it might lead to undue pressure on a prospective participant.
Randomization is a problem for physicians to randomly assign a
therapy if the investigator believes that a preferred therapy
exists. Use of a placebo is acceptable if there is no known best
therapy and in other special circumstances.
Slide 42
Basic Study Designs Randomized Non randomized concurrent
Historical Cross-over Withdrawal studies Factorial Group
allocation
Slide 43
Randomized Control Studies Studies that compare an intervention
and a control group. Assignment is based on randomization Removes
the potential bias in the allocation of participants to the groups.
Produces comparable groups i.e. the measured and unknown prognostic
factors and other characteristics of the participants at the time
of randomization will be on the average evenly balanced between the
two groups. Validity of statistical tests is guaranteed.
Slide 44
Non randomized concurrent control studies Controls are obtained
at approximately the same time as the intervention group Historical
control studies Compares a group of participants on a standard
therapy. Source of historical data: Data available from literature
Obtained from medical charts Bias involved in historical controls:
Shift in diagnosis for a given disease because of improved
technology can cause major changes in the recorded frequency of the
disease and in the perceived prognosis of subjects with the
disease. Concern on the accuracy and completeness with which
control group data are collected.
Slide 45
Cross over design A special case of randomized control design
in which each patient serves as his own control. Avoids between
participant variation in estimating the intervention effect.
Requires a small sample size. Assumption: The effects of
intervention during the first period does not carry over into the
second period.
Slide 46
Withdrawal studies Studies in which the participant on a
particular treatment for a chronic disease are taken off therapy or
have the dosage reduced. Objective: Assess response to the
discontinuation or reduction. Used to validate the duration of
benefit of intervention already known to be useful. Limitations:
Highly selected sample only participants who benefit from the study
are likely to be on the study. Overestimates benefit and under
estimate toxicity. Both disease and patients states change over
time.
Slide 47
Randomized Controlled trial The purpose of RCT is to evaluate
the effectiveness of some intervention. To evaluate a new therapy,
requires comparing its results on a group of treated patients with
the results on a group with the same disease not so treated. These
two groups are usually called the treatment and control groups
respectively.
Slide 48
Types of Trials Clinical or therapeutic trial The study group
consists of persons with a particular disease or condition and the
treatment is therapeutic. Purpose: to determine if treatment can
effect a cure or remove manifestations of a disease already present
in the patients. Primary preventive trial the treatment under
investigation is prophylactic in that its purpose is the prevention
of a particular manifestation of disease which is not present at
the start of the trial. Secondary prevention trial in such trials
the subjects already have the disease in question, or have suffered
one event, and it is hoped to prevent or delay recurrences or
death.
Slide 49
Factorial Designs Attempts to evaluate two interventions with a
control in a single experiment Incomplete factorial designs when it
is inappropriate, infeasible or unethical to address every possible
treatment combination Intervention xControl Intervention Y Control
acac bdbd Cell Intervention a X + Y b Y + control c X + control d
control + control
Slide 50
Merits of factorial design A very essential design when there
are two or more interventions Allow effects of one intervention to
be estimated at all the levels of the other intervention Demerits
of factorial design The basic concern in a factorial design is the
existence of possible interaction and its impact on the sample size
When there are two separate outcomes, (eg: heart disease and
cancer) but one of the interventions have effect on both, then data
monitoring becomes complicated or sometimes impossible
Slide 51
Merits of factorial design A very essential design when there
are two or more interventions. Allow effects of one intervention to
be estimated at all the levels of the other intervention. Demerits
of factorial design The basic concern in a factorial design is the
existence of possible interaction and its impact on the sample
size. When there are two separate outcomes, (eg: heart and cancer)
but one of the interventions have effect on both, then data
monitoring becomes complicated or sometimes impossible.
Slide 52
Cross Over Designs A special type of RCT in which each
participant serves as his own control. The order in which A and B
are given to each participant is randomized. This is so that any
trend from first period (AB) to the second period (BA) can be
eliminated in the estimate of group differences in response. BB AA
AB BA
Slide 53
Assumptions of cross over design The effects of the
intervention during the first period must not be carried into the
second period Internal and external factors are constant over
time
Slide 54
Treatment effect, no period effect, no T X P interaction B A B
A AB BA 12
Slide 55
B A B A 1 2 AB BA
Slide 56
Treatment effect, no period effect, T X P interaction A B A B 1
2 AB B A
Slide 57
Merits of clinical trials The within patients treatment
differences can be measured rather than between patients. The
variance within patients is typically less than the variance
between patients. Small sample sizes are required Treatment effects
are adjusted for period differences.
Slide 58
Limitations of cross over trials The main drawback of this
trial design is the assumption of no period treatment interaction.
There should not be treatment carry over from period 1 to 2.
Treatment cannot change patients state i.e. patients should return
to patient 1 (baseline) Time may affect treatment difference (e.g.
Environment factors)