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
2Outline 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
3The 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)
4Evolution 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
5Evolution 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
6Key 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
7Ethnic 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
8Assessing 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
9Assessment 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
10Meets 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
11The 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
12Considerations 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
13Bridging Studies
E5 is purposely vague on how to do this or what
their design should be
14Study 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
15The 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.
16E5 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
17Reasons 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
18Some 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
19Concluding 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 ?