phase iii and iv clinical trials methodology and...
TRANSCRIPT
Helping the people of Canada maintain
and improve their health
Aider les Canadiens et les Canadiennes
à maintenir et à améliorer leur santé
Phase III and IV Clinical Trials
Methodology and Design
August 22, 2007
•8:45-11:45
Nora Wolfson MD
Biologics and Genetic
Therapies Directorate
August 5, 2015
Helping the people of Canada maintain
and improve their health
Aider les Canadiens et les Canadiennes
à maintenir et à améliorer leur santé
August 22, 2007
•8:45-11:45
Nora Wolfson, MD
Biologics and Genetic
Therapies Directorate
August 5, 2015
Disclaimer: The information within this presentation
is based on the presenter's expertise and
experience, and represents the views of the
presenter for the purposes of a training course
Health Products and Food Branch
Goals of Clinical Trials:
• Increase knowledge
• Obtain Safety/Efficacy data
• Justify/confirm use for an indication to
get market approval
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Health Products and Food Branch
Study Design
As described in ICH E6 (Guideline for Good Clinical
Practice, Section 6.4, Trial Design): “The scientific
integrity of the trial and the credibility of the data from
the trial depend substantially on the trial design”
A description of the trial design should include a
specific statement of the primary endpoints and the
secondary endpoints, if any, to be measured during
the trial
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Health Products and Food Branch
Design
A good clinical trial design will be:
simple
measure important clinical parameters
precise (reduce errors of chance),
eliminate bias
provide validity
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Health Products and Food Branch
Clinical Trials
•Are classified in different phases:
Phase I
Phase II
Phase III
Phase IV
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Health Products and Food Branch
Clinical Trials• Phase I: PK, PD, early measurement of drug activity, MTD-
Healthy volunteers or target population – Single, ascending
doses – Small sample size – Short duration
• Phase II: -Exploratory Trials- Evidence of drug’s efficacy –
Safety risks – Target population –placebo/active controlled –
Larger sample size – Longer duration
• Phase III: -Confirmatory Trials- Effectiveness – Safety –
Target population – Randomized-controlled, 2, 3 treatment arms
– Much larger sample size - Duration: years
• Phase IV: Monitor ongoing Safety/Efficacy – Target population
– Uncontrolled - Very large sample size (after the product is
approved) (Post-market Surveillance, real clinical setting)
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Health Products and Food Branch
Written Protocol should describe:
(before the study starts )
• Objectives
• Design
Methods to minimise bias: R & B
• Endpoints
• Patient population
• Selection of Control Group
• Number of Subjects
• Response Variables
• Conduct
• Analysis (analytical approaches to common problems including early
study withdrawal and protocol violations, should be incorporated).
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Health Products and Food Branch
Study Design Considerations
Primary endpoint: is directly related to the primary
objective of the trial (there should be one primary
endpoint)
Should be supported by evidence that it can provide a
valid and reliable measure of a clinically relevant and
important benefit in the target population
Should be carefully selected as it is the variable used
when estimating the sample size
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Health Products and Food Branch
Study Design ConsiderationsMultiple primary endpoints:
May be desirable in some trials
Should be clearly pre-specified: how the results will be
interpreted; i.e.: what is considered necessary to achieve
the trial objectives
Type I error (making false positive conclusions) should be
addressed because of the potential for multiplicity problems
(arising from numerous comparisons made)
“The usual concern with multiplicity is that, if not properly handled, unsubstantiated claims for the effectiveness of a drug may be made as a consequence of an inflated rate of false positive conclusions.”
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Health Products and Food Branch
Study Design Considerations
Secondary endpoints:
Should be pre-defined in the protocol, and their role in the interpretation of the trial results should be clearly stated, for example, are they considered part of the confirmatory strategy for the trial?
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Health Products and Food Branch
Study Design Considerations
Description of the type of trial design:
Parallel group design: most common for confirmatory trials
subjects randomised to one of two or more arms
Crossover design:
each subject randomised to a sequence of one or more treatments, and hence acts as his own control (disadvantage: treatment must be short acting –no carry-over effect)
(Group A: Drug then control;
Group B: control then Drug)
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Health Products and Food Branch
Study Design Considerations
Description of the type of trial design:
Factorial designs: two or more treatments evaluated simultaneously through the use of varying combinations of treatments
Groups: 1) A; 2)B; 3) A+B; 4) Placebo
Adaptive: Allow for initial uncertainties in trial designed to be confirmed/adapted during the trial in a pre-planned manner
maintaining validity and integrity
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Health Products and Food Branch
Study Design Considerations
Trial designed to show superiority:
• placebo-controlled trial
• active control treatment
Important parameter: is the effect size
Defined as the treatment effect to be detected in a clinical trial, corresponding to the smallest difference between the treatment groups that is considered to be of clinical value
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Health Products and Food Branch
Study Design Considerations
Trial designed to show equivalence:
a test treatment differs from the standard active treatment by an amount that is clinically unimportant (the equivalence margin)
Trial designed to show non-inferiority:
a test treatment is not less effective than a standard
active treatment by a small predefined margin (the non-
inferiority margin)
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Health Products and Food Branch
Study Design Considerations
Non-Inferiority and equivalence trials should have:
• Assay sensitivity (AS): is the ability of a trial to distinguish an
effective treatment from a less effective treatment
Factors that reduce AS:
poor compliance with therapy
Poor responsiveness of the study population
Concomitant medications
Poor diagnostic criteria
Inappropriate measures of drug effect
Biased assessment of the endpoint
• Fairness of comparison
• Validity
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Health Products and Food Branch
Study Design Considerations
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• Statistical
issues are
complex
• Highly
recommended
that a
statistician be
involved in
reviewing all
aspects of the
CT
Health Products and Food Branch
Study Design ConsiderationsMeasures to minimize or avoid bias
• Blinding:• Double-blind approach: (optimal but not always practical)
• If a double-blind approach is not possible, the measures to minimise
bias should be clearly specified in the clinical trial protocol, especially for
open-label trials
• Randomization:Introduces a chance element in assigning treatments
Distribution of prognostic factors is similar (comparable groups)
Should be described in detail in the protocol
Provides the statistical basis for evaluating treatment effect
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Health Products and Food Branch
Study Design Considerations
• Sample Size (power): should be large
enough to provide a reliable answer to
the questions being addressed
• Required number of subjects usually
based on the primary endpoint
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Health Products and Food Branch
Study Conduct ConsiderationsTrial Conduct:
• Protocol should provide data of good quality
• Adherence to the study protocol is essential.
• Crucial for an adequate evaluation of the efficacy and safety of the
ID
Trial Monitoring
• Essential in generating quality data
Interim analysis (IA)
• Requires unblinded access to treatment group assignment and
comparative treatment group information
• The statistical plan for the IA should be described in the protocol to
avoid bias
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Health Products and Food Branch
Study Conduct Considerations
Changes that occur during the conduct of the
trial should be clearly justified and carefully
documented in a formal amendment to the
protocol
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Health Products and Food Branch
Statistical Considerations
Should include:
• Methods and timing for:
assessing-recording- and analysing efficacy
• Sample size determination
• Methods and timing for planned interim
analysis
• Handling of missing data
• How multiplicity will be addressed
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Health Products and Food Branch
Phase III Clinical Trials Regarded as Confirmatory clinical Trials
Are designed to evaluate the efficacy of an investigational drug and
gather more information about safety in the target population (closer to
the real clinical setting)
Controlled or uncontrolled
Larger sample (several hundreds to thousands of
patients)
Target population
Risk/Benefit assessment
Requires statistical analysis
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Health Products and Food Branch
Phase III Clinical Trials
• Phase III studies are intended to provide an
adequate basis for marketing approval.
• May also further explore:
the dose-response relationship,
the drug's use in wider populations,
the drug’s use in different stages of
disease
The drug’s use in combination with
another drug.
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Health Products and Food Branch
Success of a confirmatory clinical trial will
depend on the appropriateness of:
Study design
Study conduct
Analysis of trial results
ICH 8: Clinical trials should be designed,
conducted and analysed according to sound
scientific principles to achieve their objectives;
and should be reported appropriately.
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Health Products and Food Branch
Phase IV
• They are post marketing studies
• General population
• No limit duration
• Safety monitoring
• Good to identify:
• Drug interactions
• Uncommon ADRs
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Health Products and Food Branch
Phase IV
• Performed after drug approval and related to the
approved indication
• Are important for optimising the drug's use.
• Could be any type but should have valid
scientific objectives.
• Usually include additional:
drug-drug interaction
dose-response
safety
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Health Products and Food Branch
• ICH E8 General Considerations for
Clinical Trials
• Outlines studies for Special Populations:
• Pregnant Women
• Nursing Women
• Children
• ICH E7 addresses issues for geriatric patients
• ICH E5 patients from different ethnic groups
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Health Products and Food Branch
Useful References ICH Topic E 6 (R1): Guideline for Good
Clinical Practice (2002)
ICH E8: General Considerations for Clinical
Trials (1997)
ICH Topic E9: Statistical Principles for
Clinical trials (1998)
ICH Topic E10: Choice of Control Group
and Related Issues in Clinical Trials (2000)
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Health Products and Food Branch
Acknowledgements
• Dr. Norman Viner
• Dr. Catherine Njue
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Health Products and Food Branch
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Thank you