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The ICH E5 Guidance: A Regulatory Perspective on its Evolution and Implementation

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Title: The ICH E5 Guidance: A Regulatory Perspective on its Evolution and Implementation


1
The ICH E5 GuidanceA Regulatory Perspective on
its Evolution and Implementation
  • Robert T. ONeill, Ph.D.
  • Director, Office of Biostatistics
  • CDER, FDA

For presentation at APEC, May 25, 2001
2
Outline of talk
  • The evolution of the E5 Guidance from the
    perspective of a working group member
  • Key aspects of the final E5 Guidance
  • The intent of bridging studies and gaining
    experience with foreign clinical trials done in
    compliance with ICH Guidances
  • Some specific issues of study design and study
    objectives for bridging
  • Concluding remarks with regard to implementation
    of E5 and experience

3
The evolution of the E5 Guidance from the
perspective of a working group member
  • Topic proposed to the ICH Steering Committee in
    1992 by Japan
  • Signed off in February, 1998 after many years of
    effort regarding what should be its purpose,
    focus, content, and guidance
  • I was one of two FDA expert working group members
    in the six party working group (regulator and
    industry reps from the US, Europe, Japan)

4
Evolution of Concepts
  • Objectives What is the guideline about ?
  • Amount of detail and flexibility in advice
    (decision trees, early emphasis was on Phase 1)
  • Operational definition of ethnicity ( term
    region used in general sense)
  • Later emphasis placed on evidence needed in
    each region to conclude efficacy and safety
  • Two situations Retrospective - what other data,
    given a completed application Prospective -
    Planning multi-regional drug development
    strategies

5
Evolution of concepts (cont.)
  • Similarity of issues to E4 (dose-response) and to
    E7 (special populations, Geriatrics)
  • Acceptance of data - Generalizability
    /extrapolation of phase 3 efficacy/safety results
  • Algorithms to clearly show paths to follow for
    acceptance of foreign data
  • Triage the amount of information needed according
    to
  • profile of the drug, the intended population,
    clinical experiences with drug (why E5 is not too
    prescriptive)
  • When is additional information needed Bridging
    data

6
Key Features of E5
  • Operational definition of ethnic factors
  • Clinical Data Package Fulfilling Regulatory
    Requirements in New Region
  • Extrapolation of Foreign Clinical Data to New
    Region (role of ethnic factors)
  • Bridging Studies
  • Global Development Strategies

7
Ethnic Factor Definition
  • intrinsic factors characteristics associated
    with the drug recipient (ADME studies)
  • race, age, gender, organ dysfunction, genetic
    polymorphism
  • extrinsic factors characteristics associated
    with the environment and culture in which one
    lives (clinical outcomes)
  • clinical trial conduct, diet, tobacco and alcohol
    use, compliance with prescribed medications

8
Assessing a medicines sensitivity to ethnic
factors(part of the screening process)
  • Properties of a compound making it more likely to
    be sensitive
  • Metabolism by enzymes known to show genetic
    polymorphism
  • High likelihood of use in a setting of multiple
    co-medications

9
Assessment of the Clinical Data Package (CDP) for
acceptability
  • Question 1 Meets regulatory requirements -
    yes/no
  • Question 2 Extrapolation of foreign data
    appropriate - yes/no
  • Question 3 Further clinical study (ies) needed
    for acceptability by the new region - yes/no
  • Question 4 Acceptability in the new region -
    yes/no

10
Meets regulatory requirements
  • Issues of evidence
  • Confirmatory evidence two or more studies
    showing treatment effects
  • Interpreting results of foreign clinical trials
    which provide that evidence (may be one study, or
    all studies, or part of a study)
  • Which study designs provide evidence
  • Active control / non-inferiority designs
  • Placebo or active control / show a difference
    designs

11
The sources of data for an application
(implementation)
  • All clinical studies for efficacy performed in
    foreign region
  • One study in the United States, one or more
    foreign clinical studies
  • Multi-center/ multi-region clinical trials form
    the basis for efficacy

12
Considerations for evaluating clinical efficacy
between regions
  • Study design differences
  • Magnitude of treatment effect sizes
  • Effect size variability subgroup differences
  • Impact of intrinsic factors - determined when ?
  • Impact of Extrinsic factors
  • trial conduct and monitoring
  • usage of concomitant medications
  • protocol adherence

13
Bridging Studies
  • When
  • Why
  • What type

E5 is purposely vague on how to do this or what
their design should be
14
Study design and study objectives(need examples
and experience)
  • What type of bridging study would be helpful for
    extrapolation -
  • PK/PD
  • Another clinical trial of the primary clinical
    endpoint
  • equivalence/non-inferiority treatment effect
    acceptably close - margin or delta
  • dose response study
  • superiority design - estimate treatment effect
    size for comparison

15
The Spirit and Intent of E5
  • Not intended to request bridging studies every
    time
  • Intended to permit the requesting of one
    confirmatory phase 3 clinical trial (bridge
    study) in the region (not specifically defined,
    nor meant as country) if needed or necessary to
    extrapolate.
  • Recognized that there would be a period of time
    where experience with foreign clinical studies
    would be accumulated and evaluated - not to be
    confused with always asking for a new
    confirmatory trial in local region.

16
E5 allows for a new study in the new region -
why is that needed ?
  • When all the clinical data is derived from a
    foreign region and extrapolation is an issue
  • When the experience with clinical trials in that
    region is minimal
  • When there is concern with ability to confirm a
    finding from a study(ies)
  • A confirmatory clinical trial is the bridging
    study

17
Reasons for concern
  • We observe regional differences in observed
    treatment effects within the same study (not
    always clear what is responsible, chance ?)
  • Differences in results of separate independent
    studies , each done in different regions
  • What (bridging data) can explain the differences
    ?
  • information gained prior to the studies
  • information gained after studies completed

18
Some FDA experience
  • Some licensure applications have contained
    clinical trials that appeared to demonstrate
    efficacy, where all the trials were performed
    outside the US, but where several other clinical
    trials requested to be done in the US did not
    confirm a treatment effect - no identifiable
    reason - an issue of evidence
  • Type of study design done in the US
  • show a difference (a treatment effect)
  • non-inferiority active control (indirect
    inference for efficacy)
  • Multi-regional multi-center trials

19
Concluding Remarks
  • Most experience with foreign trials from Europe
    (West East), New Zealand, Canada, Latin America
    - even here the possible heterogeneity of
    treatment effects is being evaluated (Merit -
    metoprolol in CHF)
  • Little experience with Asian trials included as
    primary evidence in NDA applications
  • Quality of the trial and its results are the
    determining factor, not necessarily where it was
    conducted
  • Bridging concept is used in pediatrics - request
    phase 3 trials in some cases
  • Is it time to collect our experience on the types
    of studies being conducted ?
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