Presentation on theme: "Robert T. O’Neill, Ph.D. Director, Office of Biostatistics CDER, FDA"— Presentation transcript:
1 Robert T. O’Neill, Ph.D. Director, Office of Biostatistics CDER, FDA The ICH E5 Guidance: A Regulatory Perspective on its Evolution and ImplementationRobert T. O’Neill, Ph.D.Director, Office of BiostatisticsCDER, FDAFor presentation at the2nd Kitasato -Harvard Symposium, October 22-23, 2001
2 Outline of talkThe evolution of the E5 Guidance from the perspective of a working group memberKey aspects of the final E5 GuidanceThe intent of bridging studies and gaining experience with foreign clinical trials done in compliance with ICH GuidancesSome specific issues of study design and study objectives for bridgingConcluding 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 JapanSigned off in February, 1998 after many years of effort regarding what should be its purpose, focus, content, and guidanceI 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 safetyTwo 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 resultsAlgorithms to clearly show paths to follow for acceptance of foreign dataTriage the amount of information needed according toprofile 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 RegionExtrapolation of Foreign Clinical Data to New Region (role of ethnic factors)Bridging StudiesGlobal Development Strategies
7 Ethnic Factor Definition intrinsic factors: characteristics associated with the drug recipient (ADME studies)race, age, gender, organ dysfunction, genetic polymorphismextrinsic 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 medicine’s 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 polymorphismHigh 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/noQuestion 2: Extrapolation of foreign data appropriate - yes/noQuestion 3: Further clinical study (ies) needed for acceptability by the new region - yes/noQuestion 4: Acceptability in the new region - yes/no
10 Meets regulatory requirements Issues of evidenceConfirmatory evidence; two or more studies showing treatment effectsInterpreting 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 evidenceActive control / non-inferiority designsPlacebo or active control / show a difference designs
11 The sources of data for an application (implementation) All clinical studies for efficacy performed in foreign regionOne study in the United States, one or more foreign clinical studiesMulti-center/ multi-region clinical trials form the basis for efficacy
12 Considerations for evaluating clinical efficacy between regions Study design differencesMagnitude of treatment effect sizesEffect size variability; subgroup differencesImpact of intrinsic factors - determined when ?Impact of Extrinsic factorstrial conduct and monitoringusage of concomitant medicationsprotocol adherence
13 Bridging StudiesWhenWhyWhat typeE5 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/PDAnother clinical trial of the primary clinical endpointequivalence/non-inferiority: treatment effect acceptably close - margin or deltadose response studysuperiority design - estimate treatment effect size for comparison
15 Issues of Statistical Design and Study Analysis/Inference E5 did not attempt to deal with statistical design or analysis issues.Nor did it deal with statistical formulations of concepts such as similarity, extrapolation, generalizabilityThe systematic study of associations and responses that may differ according to ethnic categorization has many design and analysis aspects.
16 The Spirit and Intent of E5 Not intended to request bridging studies every timeIntended 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.
17 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 issueWhen the experience with clinical trials in that region is minimalWhen there is concern with ability to confirm a finding from a study(ies)A confirmatory clinical trial is the bridging study
18 Reasons for concernWe 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 regionsWhat (bridging data) can explain the differences ?information gained prior to the studiesinformation gained after studies completed
19 Some FDA experienceSome 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 USshow a difference (a treatment effect)non-inferiority active control (indirect inference for efficacy)Multi-regional multi-center trials
20 Concluding RemarksMost 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 applicationsQuality of the trial and its results are the determining factor, not necessarily where it was conductedBridging concept is used in pediatrics - request phase 3 trials in some casesIs it time to collect our experience on the types of studies being conducted ?