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 ?

Part III Application of E5 Guideline Target Disease Population Part I Sample Intrinsic factors Yes No Part II US EU NR EU US NR Extrinsic Factors Yes No Necessary Conditions Necessary Conditions 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 Regulatory review system (ii) high quality of data GCP

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

 ˆ

EU

 ˆ

US

 ˆ

NR

Sample from a Same Probability Space

Application of E5 Guideline: Part III Question: Are these samples (EU, US, and NR) derived from a same target disease population?

Intrinsic Factors Yes Genetic variation Answer: No US EU

 ˆ

EU

  ˆ

US

  ˆ

NR

NR Need adjustment for intrinsic factors to have a common population among three regions

 ˆ

Ad

(

EU

)   ˆ

Ad

(

US

)   ˆ

Ad

(

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

Homogeneous target population Clear definition of efficacy Statistical approach/Sample size (i) Scientific Evidence NEJM - Two drugs in heart failure May 3, 2001 - Two editorials Importance of pharmacogenomics Quality control of trials - Regulatory review system - GCP (ii) Statistical Evidence Shih

､

Lui - Consistency among trials Ware, Morris - Empirical Bayes Akahira and Takahashi, Takeuchi - Consistency by bootstrap (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 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 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