1. A Case Study in the Value of Harmonisation Yoshikazu HAYASHI Deputy Director Evaluation and Licensing Division Pharmaceutical & Food Safety Bureau Ministry of Health, Labour and Welfare, JAPAN

2. Philosophy/Purpose of ICH Eliminate Duplication in Tests to meet Different Regulatory Requirements More Efficient Use of Resources Timely Access of Patients to Safe and Effective “New Drugs”

3. Structure of ICH ICH Participants Six Parties: EU, FDA, MHLW, EFPIA, PhRMA, JPMA + Observers: WHO, EFTA, Canada Organization SC: Policy Issues EWG: Technical GLs Major Conferences: ICH 1 (’91) – ICH 5 (’00) ICH 6 (Osaka, Japan, Nov. 2003)

4. ICH Guidelines ICH is neither a forum of global politics nor a trade negotiation, but a scientific forum ICH covers “new drugs” ICH guidelines provide “how to collect data scientifically for marketing authorization”

5. ICH Process for Technical Issues Step 1: Consensus Building/Drafting of GL Step 2: SC Agrees to Releasing Draft GL Step 3: Regulatory Consultation/ Consolidation of Comments Step 4: Adoption of GL by Regulators/ Publishing ICH GL Step 5: Regulatory Implementation

6. Mode of Implementation 1. Formal Vehicles Amending Existing GLs Issuing New GLs Law Amendment 2. Supplemental Vehicles Q&A, Compendium in MHLW Notif. Seminars, Publications by Private Sectors (Japan Pharmacopoeia, etc.)

7. Harmonisation Process (“Mickey Mouse” Way of Progress!!) ICH Japan EU ICH USA

8. 12 Year Achievements of ICH Understanding of Innovation Common Regulatory Platform based on ca. 50 GLs (Q, S, E) Improvement of Scientific GLs Facilitating Communication Among Regulators & Between Regulators and Industries Toward the Common Goal Effective Use of R&D Resources including Data Collected in Other Regions

9. Achievement in ICH Phase I (1990 – ICH4 in 1997) 1. About 40 ICH GLs (Q, S, E) Substantially Completed 2. Scientific Basis for Testing and Evaluation Harmonised 3. Major Causes of Redundancy/ Duplication Eliminated

10. ICH Phase II Activity & Future (ICH 4 (1997) - ) 1. Dealing More on Regulation Common Technical Document (CTD) ADR Report: MedDRA/Electronic Transfer 2. New GLs on Emerging Issues 3. Finalizing Uncompleted GLs/Maintaining Existing GLs 4. Globalization of ICH Activities (e.g. GCG)

11. MHLW’s implementation of ICH GLs ( ～ July. 2003) Quality: Q1~7 Stability, Impurities, Quality of Biotech. Products, GMP for APIs, etc. Safety: S1~7 Carcinogenicity, PK, Reprotox, etc. Efficacy: E1~11 PSUR, Ethnic Factors, GCP, Pediatrics, etc. Multidisciplinary: M1~4 MedDRA, CTD, eCTD, etc.

12. Impact of ICH; Regulator’s View 1. General Science-Based Discussion with Industry and Other DRA Facilitated 2. Tests/Data for NDA Quality of Tests/Data Improved More Foreign Data Submitted 3. NDA Review To Improve NDA Review Review Reform Collaboration among DRA

13. Implementation of New GCP 1. Amended Regulations PAL (’96), GCP Ordinance (’97) Effective Step-by-Step, 100% in April ’98 2. “Hollowing Out” of Clinical Trials in Japan? MHLW’s Role/Responsibility to Encourage CTs Ethically Wrong to Depend on CTs Abroad? Japan’s CTs Exposed to Global Competition (Cost, Quality, etc.)

14. Acceptance of Foreign Clinical Data 1. MHLW’s Past Policy  Accept if GCP, Raw Data, Japan’s GL  PK, Dose-Finding, Ph3 DB on Japanese Population 2. New GL based on E5 & Expectation  Scientific Bridging Study  Consultation Encouraged on Completeness

15. Data-package for Bridging Study PK/PD study Japanese data Foreign data PK/PD study Bridging studyStudy for bridging Comparative study Long term study Study on patients with risk Comparative study Long term study Study on patients with risk

16. Number of Consultation

17. How CTD is implemented by MHLW GAIYO of Q,S,E NDA Application Form Report Q Report S Report E CTD Modules I II A II B II C IIIIVV Dossier + other region specific information

18. CTD will be facilitating Harmonized Application Dossier (Content and Format) Synchronized R&D Strategy Synchronized NDA Submission to EU, US and Japan NDA Review Cooperation Synchronized Approval and Marketing

19. Global Cooperation Group （ GCG) Created in 1999 to make information available on ICH activities and GLs Some principles  GCG Resource for information and data reference  GCG will not seek to impose its views  GCG will provide information upon request from non-ICH countries

20. Evolution of GCG Interaction with non-ICH Regional Harmonisation Initiatives (APEC, ASEAN, PAHO/PANDRH, SADC) The Challenges are:  Varying Capacities Across A Region  The Importance of Training  Implementation of any ICH GLs in a Stepwise Fashion  Interest in Specific Topics (GMP for APIs, GCP, Ethnic Factors, Stability)

21. ICH6 Program (Nov. 2003) Nov. 12Nov. 13Nov. 14Nov. 15 SatelliteICH6 Main Session Partnerships in Harmonisation (by ICH GCG) MedDRA User’s Group Gene Therapy Welcoming Remarks New Horizon for the Pharmaceutical Sector CTD – Shared Perspectives on Implementation CTD Breakout Sessions Quality: Q1D, E, F, Q3A&B(R), Q3C(M), Q4/Q6A, Q5E, Quality System (GMP) Pharmacovigilance and Regulatory Communication: E2C(A), E2D, E2E, E2B(M), MedDRA Safety and Efficacy: S7B, E14 (QT), E5, Immunotoxicology Global Cooperation Future Challenges Close of Conference

22. Challenging Topics in ICH6 Conference Shared Experience on the Implementation of CTD New Pharmacovigilance Topics Quality Systems for the 21 st Century (GMP) Comparability of Biotechnological/Biological Products Safety Pharmacology and Clinical Evaluation of QT/QTc Interval Prolongation Partnerships in Harmonisation Future Challenges facing ICH Gene Therapy

23. Do not miss the forthcoming ICH6! Final Announcement http://www.ich.org/ich6tris.html Conference Registration and Hotel Reservation are accessible

24. ICH in future Timely Access of Innovations for Patients around the World Changing Environment – Regulations and Sciences Maintenance and Implementation – CTD and GLs Pharmacovigilance Transparency – Global Cooperation, Large Conference

25. ICH Website Written Information Available on ICH Website: www.ich.org ご清聴ありがとうございました Thank You