1. ICH E-5 Overview and Current Topics Mamoru Narukawa

2. World Drug Sales in 11 leading countries (IMS 2001)

3. Origin of New Drugs in the World Market (Med Ad News vol.18 No.5 1999)

4. Reorganization of Pharmaceutical Industry GlaxoSmithKline (1) GlaxoWellcome SmithKline Beecham Pfizer (2) Warner-Lambert AstraZeneca (4) Zeneca, Astra Aventis (5) Hoechst, Rhone-Poulane Bristol-Myers Squibb (6) Dupont Novartis (7) Ciba-Geigy, Sandoz Johnson & Johnson (8) ALZA Pharmacia (9) Pharmacia & Upjohn Monsanto (Economist 2001.9.11)

5. ICH Europe (EU, EFPIA), Japan (MHLW, JPMA), and US (FDA, PhRMA) Discuss scientific and technical aspects of requirements for pharmaceuticals Eliminate unnecessary delay in the global development and availability of new drugs

6. ICH Topics – Efficacy (1) E1: The extent of population exposure to assess clinical safety E2A: Definitions and standards for expedited reporting E2B: Data elements for transmission of ADR reports E2C: Periodic safety update reports E3: Structure and content of clinical study reports E4: Dose-response information to support drug registration

7. ICH Topics – Efficacy (2) E5Ethnic factors in the acceptability of foreign clinical dataE5: Ethnic factors in the acceptability of foreign clinical data E6: Good clinical practice E7: Clinical trials in special population – Geriatrics E8: General considerations E9: Statistical principles E10: Choice of control group E11: Clinical investigation in the pediatrics E12A: Clinical trials on antihypertensives

8. History of ICH E-5 1992.3Discussion started 1997.3Draft Guideline agreed 1997.5Draft Guideline circulated 1998.2Final Guideline agreed 1998.8Guideline adopted by the MHW

9. Before E-5 Guideline Types of StudyAcceptance of Foreign Data ADME ◎ Tolerance○ Dose setting ◎ Clinical pharmacology○ Open trials○ Confirmative controlled trials ◎ ○: accept ◎ : accept, but domestic data also needed

10. After E-5 Guideline Necessity/Type of domestic clinical study (Bridging study) data is judged scientifically based on the E-5 Guideline

11. Intrinsic & Extrinsic Ethnic Factors Intrinsic FactorsExtrinsic Factors Race Genetic polymorphism Receptor sensitivity Age, Gender, Weight ・・・ Medical practice (Disease definition, Therapeutic approach) Methodology of clinical trial ・・・

12. What is “Bridging Study” ? A supplemental study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data to the new region. (E5 Guideline)

13. Types of Bridging Study and Ethnic Factors No Bridging Study (PK study) Intrinsic Factors Study using pharmacological endpoint Intrinsic (+ Extrinsic) Factors Study using clinical endpoint Intrinsic and Extrinsic Factors

14. Diagram of Bridging (1) Domestic dataForeign data PK data PD data Clinical data Extrapolation similar

15. Diagram of Bridging (2) Domestic dataForeign data PK data PD data Clinical data Extrapolation similar PD data

16. Diagram of Bridging (3) Domestic dataForeign data PK data PD data Clinical data Extrapolation similar PD data Clinical data

17. Recommended Bridging Study Similar study design Proper number of patients Quality of data

18. Race “Census: US diversity on rise - The nation is much more diverse, and that diversity is much more complex.” (USA TODAY: March 13, 2001) “Racial categorization may be only a surrogate marker for genetic or other factors.” (NEJM: May 3, 2001)

19. Intrinsic Ethnic Factors Race Individual Sequence of the Genome

20. Extrinsic Ethnic Factors Medical Practice Clinical Trial Methodology ・・・ Region Harmonization of Medical Practice/ Clinical Trial Methodology

21. Can E-5 Guideline be a solution to the “drug-lag” in Japan?

22. Types of worldwide development of new drugs TypesNo. of Drugs Precede in Japan 14 (18.4%) Simultaneously 16 (21.1%) Precede in the US 39 (51.3%) Precede in EU 7 ( 9.2%) Total 76 (JETRO 2001)

23. International multi-center cooperative study Use the same protocol Progress simultaneously worldwide Stratification by Region/Race

24. Circumstances of Clinical Trial in Japan Infrastructure of medical institutions has been improving (CRC, clinical research center, etc) Information dissemination activities by sponsors/medical institutions to recruit patients began to take effect Motivation of Investigators/Trial Staff ?

25. Number of Clinical Trials Started in Japan (YAKUMU-KOUHOU)

26. Future Perspectives International Competitiveness of New Drug Development Clinical Trials with –Quality –Speed