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MODULE B:Overview of the Clinical Trial &
Protocol
Jane FendlMarch 31, 2010
Version: Final 31- Mar-2010
Version: Final 31- Mar-2010 2
Phases of the Clinical Trial
Phase 1 – “human pharmacology trials”First time tested in man Healthy normal volunteersTo gather information about the drug’s safety and the
effect of the drug on the human bodyPharmacokinetic evaluation – how the drug is absorbed
the way it is absorbed, distributed in the body, metabolized and excreted
Dose is progressively increased until a tolerable toxicity level is achieved
Measures AEs Determine maximum tolerable dose
21 CFR 312.21
Version: Final 31- Mar-2010 3
Phase 2 – “therapeutic exploratory trials”
Volunteers with targeted disease stateTesting for safety and efficacyTo determine the potential effectiveness Identify common adverse events Ensure the drug has suitable risk to benefit ratioTo determine the optimal effective doseTo prove efficacy by evaluating an objective or
comparative measurement such as:Positive change in the disease processImprovement in quality of lifeReduction in mortalityImprovement in symptomatology
21 CFR 312.21
Version: Final 31- Mar-2010 4
Phase 3a – “therapeutic confirmatory trials”To evaluate safety and efficacy in a large number of subjectsEmphasis on assessing the tolerance to the drugAdditional gathering of information about drug interactions and addiction potentialPotential effectiveness of the productIdentify common adverse events within a heterogeneous populationExpanded number of subjects with specific problem or indication
21 CFR 312.21
Version: Final 31- Mar-2010 5
Phase 3b – “therapeutic use trials”Further safety and efficacy as well as new
indicationsMore subjectsLonger period of timeTested for long-term effectsUnderstand how the product is prescribedMay include thousands of subjects Subjects with different stratifying characteristics such as age, race & concomitant medicationsGather information such as:
Response to productSafety in general populationSafety for subjects with certain characteristicsSafety in association with other drugAffect on Subject’s quality of life
21 CFR 312.21
Version: Final 31- Mar-2010 6
Phase 4 – “post-marketing trials”May be at the request of regulatory authorities
as a condition of approvalSponsor may wish to compare the drug with
other active agents for:
Marketing reasonsCost-benefit ratio for insurance/managed health care
purposesInvestigate new indications or formulationsInterested in surveying safety data in large populations
Version: Final 31- Mar-2010 7
Phases of Drug Development1 2 3a & 3b 4
Average Time
1 week to 1 month
Several months to 2 years
Several months to 4 years
Several months to several years
Average # of Subjects
20 – 100 Several hundred
Several hundred to several thousands
50 to several thousand
Types of Subjects
Healthy volunteers
Subjects with disease
Subjects with disease
Subjects with disease
Main Purpose
Determine safe dose in man
Determine effectiveness at safe dose
Determine safety & effectiveness in varied large population of a long time period
As a condition for approval or approval for new indication
Version: Final 31- Mar-2010 8
What is a protocol?Recipe or overall master plan for the trial
Guide or road map for the Investigator, site
staff, and the IRB to follow
What is the purpose?
Provides consistency of processes across
all
sites involved
Helps ensure consistent collection of data
Version: Final 31- Mar-2010 9
What is the trial purpose?What will be proven?How and why the trial is being conducted?How many subjects?Who will be the subjects?What is the qualifying criteria?How long will it last?
ICH GCP 1.44
What questions does it answer?
Version: Final 31- Mar-2010 10
General informationBackground
informationTrial objectives and
purposeTrial designSelection and
withdrawal of subjectsTreatment of subjectsAssessment of efficacy
Assessment of safetyStatisticsDirect access to source
data and documentsEthicsData handling and
record keeping Financing and
insurancePublication policySupplements
ICH GCP 6.0
What should be included in the protocol?
What is not included in the protocol can be referenced in the Investigators Brochure
Version: Final 31- Mar-2010 11
Sections of the ProtocolGeneral InformationBackground
InformationTrial Objectives &
PurposeTrial DesignSelection and
Withdrawal of SubjectsInclusion CriteriaExclusion CriteriaWithdrawal CriteriaTreatment
EfficacySafetyAnalysis & StatisticsDirect Access to Source
Data & DocumentsEthicsData Handling & Record
KeepingFinancing & InsurancePublication PolicyAppendices/
SupplementsSignature & Agreement
Version: Final 31- Mar-2010 12
General Information Protocol title, number & dateSponsor informationName & title of the person authorized to sign the protocol & amendmentsName, title, address & telephone numbers of Sponsor’s medical experts
Version: Final 31- Mar-2010 13
Background InformationDescribe the investigational productMechanism of ActionSummaries of findings from previous studiesRisks and benefits of investigational productPopulation to be studiedDescription of the justification for the route of administration, dosage, & regimen
Trial Objectives & PurposeObjectives should describe what the trial is trying to proveObjectives should correlate with the trial design and what data will measure
Version: Final 31- Mar-2010 14
Trial DesignPrimary endpoints –
focus of the trialSecondary endpoints –
any other items that the trial may measure
Description of design and measures to minimize bias
Randomization – how maintained & procedures for breaking the code
Trial treatments & dose, the form, regimen, packaging & labeling
Length of subject participation, description of sequence & duration of all trial periods (visits)
Drug accountabilityRules for discontinuing
the investigational product and withdrawing the subject
Criteria for stopping parts of the trial or ending the trial
What is considered source data
Version: Final 31- Mar-2010 15
Inclusion Criteria
Exclusion Criteria
Statements which describe the qualification or conditions that a subject must meet to participate in the trial
Specific conditions that disqualify a subject from participating
Version: Final 31- Mar-2010 16
Withdrawal CriteriaWhen & how the investigational product must be stopped & subjects withdrawn from the trial
Product may be taperedThe conditions under which the Investigator should terminate a subject
Missed visitsHow the data is to be collected
Have the subject return, complete which visitThe type of information that is to be collected
Reason discontinuedInformation regarding replacement of subjects
Number of subjects needed to complete
Version: Final 31- Mar-2010 17
TreatmentName of all productsDose – milligrams, grams, ounces, etcDosing schedule – BID, TID, QID, PRNRoute or mode of administration – IV, oral, inhalerTreatment periods – length of time on productMedications or treatments permitted and those that are not permitted – treatments known to interfere with the action of the productProcedures for monitoring compliance – site staff is to count used and unused product to determine if subject took the product as directed
Version: Final 31- Mar-2010 18
EfficacyMethods and
measures to determine if the investigational product is effective
Example - Blood pressure decreases as predicted
How the efficacy measures will be recorded and analyzed
SafetyHow and when to
measure for the safety of the investigational product
How to capture, record and report adverse events, serious adverse events and concurrent illness
Type and duration of follow-up for subjects who experience AEs or SAEs
Version: Final 31- Mar-2010 19
Statistical methods used to analyze the information that is gathered from the dataNumber of subjects to be enrolledIf multi-center study may include # of subjects/siteJustification of sample sizeStatistical level of significanceCriteria for termination of the trial Procedures for accounting for missing, unused & false dataProcedures for reporting deviations from the
original SAPSelection of subject to included in the analysesAny planned interim analyses
Analysis & Statistics
Version: Final 31- Mar-2010 20
Source Documents & DocumentsSpecifies that the Sponsor or delegates should be permitted access to all documents relating to the trial for the purpose of monitoring, auditing, IRB review and regulatory inspections
EthicsDescribes any ethical considerations relating to the trial
Version: Final 31- Mar-2010 21
Methods used to collect, monitor, and maintain
source documents and filesInvestigators’ responsibility for ensuring
confidentiality and rules for disclosure of dataHow long data and records should be retainedRules for the accessibility of trial information for
Sponsor, IRB or inspectorsHow data is maintained in the source documents
and Case Report Forms
Data Handling & Record Keeping
Version: Final 31- Mar-2010 22
Publication PolicyMay be included – deals with the requirement of Sponsor permission and approval to disclosure data collected by the site and Investigator.
Appendices/SupplementsIncludes documents that are referenced in the protocol.Signature & AgreementInvestigator signs and dates the “Signature Page” or “Investigator’s Statement” signifying he/she will conduct the trial according to the protocol and will not deviate from the protocol.