Significance of Extrapolation of Foreign Clinical Data to Asian Countries Masahiro Takeuchi Div. of Biostatistics Kitasato University Graduate School The 2nd Kitasato-Harvard Symposium, 10/22/01

Acknowledgment Bridging Study Working Group* Div. of Biostatistics Kitasato University Graduate School Kazuhiro Abe, Isao Kawachi, Masahiro Takeuchi, Masako Nishikawa, Keiichiro Hirose, Yoshiharu Horie, Kazuhiro Matsui

Outline Introduction E5 Guideline Application of E5 Guideline from Statistical Point of View Future Application

Introduction ICH - General Purpose –Unification of Necessary Documentation and its Formats for NDA Submission ICH - Extrapolation –Avoidance of Unnecessary Clinical Trials Ethically Speaking Globalization –Good Drugs in a Faster Time

Conditions for Extrapolation Two factors –Intrinsic Factors –Extrinsic Factors

Review of Two Factors (APPENDIX A) Intrinsic Factors –Genetic: race, drug metabolism, genetic diseases –Physiological and pathological conditions: Age ( children-elderly), Liver, Kidney, Cardiovascular functions, Diseases Extrinsic Factors –Culture, Medical Practice, Regulatory practice/GCP, Methodology/Endpoints

Implication of Two Factors Intrinsic Factors –Do we have an clearly defined comparative population to targeted/existed foreign population? Extrinsic Factors –Can we conduct a planned clinical trial ?

Application of E5 Guideline Target Disease Population Sample US EU US Intrinsic factors No Yes Extrinsic Factors No Yes EU NR Necessary Conditions Necessary Conditions Part I Part II Part III Part IV

Application of E5 Guideline: Part I Target Disease Population Sample Clinical Trial (y 1, y 2, …, y n ) Estimation of Efficacy Two Major Concerns: (i) high quality protocol (ii) high quality of data Regulatory review system GCP

Application of E5 Guideline: Part II Intrinsic Factors No EUUSNR Sample from EU Sample from US Sample from NR (y EU1, y EU2, …, y EUn1 ) (y US1, y US2, …, y USn2 ) (y NR1, y NR2, …, y NRn3 ) Sample from a Same Probability Space Genetic variation

Application of E5 Guideline: Part III Intrinsic Factors EU NR US Yes Question: Are these samples (EU, US, and NR) derived from a same target disease population? Answer: No Need adjustment for intrinsic factors to have a common population among three regions Genetic variation

Application of E5 Guideline: Part IV Extrinsic Factors NoYes Necessary conditions Quality Control - Protocol Review System - GCP Safety Issues - surveillance Conduct of suitable clinical trials subject to medical practice, clinical trial environment Study Design - placebo vs active - choice of endpoint Language& culture - subsets of primary endpoint

Future Application: Past Experience Western Data Region 1Region 2Region 3 (i) No clear scientific evidence regarding racial difference (ii) No clear statistical approach - similarity, sample size (iii) No unified regulatory authority requirements Bridging Study 1Bridging Study 2Bridging Study 3

(i) Scientific Evidence NEJM - Two drugs in heart failure May 3, Two editorials Importance of pharmacogenomics (ii) Statistical Evidence Shih ､ Lui - Consistency among trials Ware, Morris - Empirical Bayes Akahira and Takahashi, Takeuchi - Consistency by bootstrap Homogeneous target population Clear definition of efficacy Statistical approach/Sample size (iii) Regulatory Requirements APEC Meeting in Taiwan in May,01 Quality control of trials - Regulatory review system - GCP

Future Application Western Data Similar regions Region 1Region 2Region 3 Similar region: - Intrinsic factors - Extrinsic factors (medical practice, clinical trial environment,etc) - GCP

Future Challenge EU US Asia (i) one global protocol - def. of target population - def. of expected efficacy - study design (ii) modification subject to - intrinsic factors - extrinsic factors (iii) quality control of trials - protocol review - GCP Clear def. of probability space Target Disease Pop. Each sample derived from the PS Quality assurance

Good Drugs in a Faster Time Correctly Targeted Disease Population Thoroughly Planned and Collected Sample High Quality Data