1. 1 Points to Consider of Protocol on Multinational Trial Masaaki Kuwahara, Ph.D. Takeda Chemical Industries, Ltd. The 4th Kitasato-Harvard symposium, 2003.10.28

2. 2 Clinical Study Package of Bridging Studies(1) 19961997199819992000200120022003 JPN Phase Ⅰ Ⅱ USA and/or EU Phase Ⅰ Ⅱ Ⅲ NDA

3. 3 Clinical Study Package of Bridging Studies(2) 200220032004200520062007 JPN Phase Ⅰ Ⅱ USA and/or EU Phase Ⅰ Ⅱ Ⅲ NDA ？？

4. 4 Challenges in Multinational Trial 200320042005200620072008 JPN Phase Ⅰ Ⅱ Ⅲ USA and/or EU Phase Ⅰ Ⅱ Ⅲ NDA

5. 5 Premise of Multinational Trial Environments for Clinical Trials in Japan Regulatory requirements  Place of compound on medical treatment  Adequate characterization of pharmacokinetics in the population of relevant region

6. 6 Target phases of Multinational Trial ⅠⅡⅢⅣ Phases of Development Therapeutic Use Therapeutic Confirmatory Therapeutic Exploratory Human Pharmacology

7. 7 Key success factor for Multinational trial  Global data management  Design of trial (protocol, CRF)  Speed of Enrollment  Quality and Quantity of trial  Language

8. IDMC Principal Investigator Regional Investigator Medical Expert Regional Investigator Medical Expert Central Steering Committee Central Trial Control Center Regional Steering Committee Regional Trial Control Center Trial Site Investigator, CRC Join Central SC about Preparation and Revise of Protocol Decision Making of Schedule and Overall Implementation of Trial Advisory on issue of Overall Safety and Implementation of Trial Report and Instruction on Decision of Central SC Information Control of Preparation and Revise of Protocol Transfer and Provision of Safety Information, Data of CRF and IB, etc Safety Information, Dispatch of CRA, Document of Protocol, CRF Collection, Pts Data Sharing, SDV and Preparation of IRB document on Regional Site Structure of Global development Committee on Multinational Trial

9. 9 Flexibility of Protocol Design （ 1 ） Primary Objective should be same Secondary Objective should be same additional item is possible

10. 10 Flexibility of Protocol Design （ 2 ） Study Population patients diagnosed with similar assessment Inclusion Criteria main criteria should be same Exclusion Criteria main criteria should be same

11. 11 Flexibility of Protocol Design （ 3 ） Washout Period should be similar Dose and Mode of Administration should be same Duration of Treatment should be same

12. 12 Flexibility of Protocol Design （ 4 ） Excluded medication should be similar pharmacological class Dose and Mode of Active control should be same

13. 13 Flexibility of Protocol Design （ 5 ） Primary Endpoint should be same Secondary Endpoint should be same additional item is possible

14. 14 Flexibility of Protocol Design （ 6 ） Vital signs main items should be same Clinical Laboratory tests central laboratory should be utilized or main items should be same

15. 15 Flexibility of Protocol Design （ 7 ） Record adverse events definition, severity, causality should be assessed using same categories Dropouts and/or End of Study should be assessed using same categories