Robert T. O’Neill, Ph.D. Director, Office of Biostatistics CDER, FDA The ICH E5 Guidance: A Regulatory Perspective on its Evolution and Implementation Robert T. O’Neill, Ph.D. Director, Office of Biostatistics CDER, FDA For presentation at the 2nd Kitasato -Harvard Symposium, October 22-23, 2001

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

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)

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

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

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

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

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 polymorphism High likelihood of use in a setting of multiple co-medications

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

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

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

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

Bridging Studies When Why What type E5 is purposely vague on how to do this or what their design should be

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

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, generalizability The systematic study of associations and responses that may differ according to ethnic categorization has many design and analysis aspects.

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.

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

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

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

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 ?