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 Part I Sample Intrinsic factors Yes Part III US EU NR No Part II EU US NR Extrinsic Factors Yes Necessary Conditions No Necessary Conditions Part IV Application of E5 Guideline: Part I Target Disease Population Clinical Trial (y1, y2, … , yn) Sample Estimation of Efficacy Two Major Concerns: (i) high quality protocol Regulatory review system (ii) high quality of data GCP Application of E5 Guideline: Part II Genetic variation Sample from EU Intrinsic Factors US Sample from a Same Probability Space Sample from US No EU (yEU1, yEU2, … , yEUn1) (yUS1, yUS2, … , yUSn2) NR Sample from NR (yNR1, yNR2, … , yNRn3) ˆ EU ˆ US ˆ NR Application of E5 Guideline: Part III Question: Are these samples (EU, US, and NR) derived from a same target disease population? Intrinsic Factors Yes US Genetic variation EU NR Answer: No ˆ EU ˆ US ˆ NR Need adjustment for intrinsic factors to have a common population among three regions ˆ Ad ( EU ) ˆ Ad (US ) ˆAd ( NR ) Application of E5 Guideline: Part IV Extrinsic Factors Yes No Necessary conditions Necessary conditions 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 Quality Control - Protocol Review System - GCP Safety Issues - surveillance Future Application: Past Experience Western Data Bridging Study 1 Region 1 Bridging Study 2 Region 2 Bridging Study 3 Region 3 (i) No clear scientific evidence regarding racial difference (ii) No clear statistical approach - similarity, sample size (iii) No unified regulatory authority requirements (i) Scientific Evidence Homogeneous target population Clear definition of efficacy Statistical approach/Sample size NEJM - Two drugs in heart failure May 3, 2001 - Two editorials Importance of pharmacogenomics (ii) Statistical Evidence Shih､Lui - Consistency among trials Ware, Morris - Empirical Bayes Akahira and Takahashi, Takeuchi - Consistency by bootstrap Quality control of trials - Regulatory review system - GCP (iii) Regulatory Requirements APEC Meeting in Taiwan in May,01 Future Application Western Data Similar regions Region 1 Region 2 Region 3 Similar region: - Intrinsic factors - Extrinsic factors (medical practice, clinical trial environment,etc) - GCP Future Challenge Target Disease Pop. EU US (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 Asia Clear def. of probability space 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
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