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Significance of Extrapolation of Foreign Clinical Data to Asian Countries

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

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Significance of Extrapolation of Foreign Clinical Data to Asian Countries

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  1. 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

  2. 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

  3. Outline • Introduction • E5 Guideline • Application of E5 Guideline from Statistical Point of View • Future Application

  4. 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

  5. Conditions for Extrapolation • Two factors • Intrinsic Factors • Extrinsic Factors

  6. 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

  7. 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 ?

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

  9. Application of E5 Guideline: Part I Target Disease Population Clinical Trial (y1, y2, … , yn) Estimation of Efficacy Sample Two Major Concerns: (i) high quality protocol Regulatory review system (ii) high quality of data GCP

  10. Application of E5 Guideline: Part II Genetic variation Sample from EU Intrinsic Factors (yEU1, yEU2, … , yEUn1) Sample from US Sample from a Same Probability Space No (yUS1, yUS2, … , yUSn2) Sample from NR EU US NR (yNR1, yNR2, … , yNRn3)

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

  12. Application of E5 Guideline: Part IV Extrinsic Factors Yes No Necessary conditions Necessary conditions Quality Control - Protocol Review System - GCP Conduct of suitable clinical trials subject to medical practice, clinical trial environment Study Design - placebo vs active - choice of endpoint Safety Issues - surveillance Language& culture - subsets of primary endpoint

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

  14. (i) Scientific Evidence NEJM - Two drugs in heart failure May 3, 2001 - Two editorials Importance of pharmacogenomics Homogeneous target population Clear definition of efficacy Statistical approach/Sample size (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

  15. 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

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

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

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