1. K. Shimatani/ K-H Symposium/ October 22-23, 20011 What Impact Will Globalization Have on Bridging Studies Katsuyoshi Shimatani J-Clin, Pfizer

2. K. Shimatani/ K-H Symposium/ October 22-23, 20012 Number of Consultation for Bridging Studies Kikoh Mr. Mori (07 October 2001) Successful cases: >20

3. K. Shimatani/ K-H Symposium/ October 22-23, 20013 Drug Approved Through the Use of Overseas Data (1) (NCE)

4. K. Shimatani/ K-H Symposium/ October 22-23, 20014 Drug Approved Through the Use of Overseas Data (2) (NCE) Year Number of Approvals Approvals with Overseas Data EvaluationReferenceTotal 1999393 (7.7%)2 (5.1%)1 (2.6%) 2000394 (10.3%)3 (7.7%)1 (2.6%) 2001*134 (25%)2 (8.3%)2 (16.7%) Total9111 (11.1%)7 (6.6%)4 (4.4%) *: as of October 1

5. K. Shimatani/ K-H Symposium/ October 22-23, 20015 Were the objectives of the bridging study achieved? zWas study duplication minimized? Studies not done in Japan for CCDP Phase II:1 Phase III:5 Long term study:3 Special study:3

6. K. Shimatani/ K-H Symposium/ October 22-23, 20016 Were the objectives of the bridging study achieved? zWas the time-lag (drug-lag) between J and W reduced? Time difference of approval between J and W Erectile dysfunction: 11 M Alzheimer’s disease: 36 M Influenza: 15 M Allergy: 55 M Breast cancer: 65 M Migraine:111 M, 52 M Average 49 M

7. K. Shimatani/ K-H Symposium/ October 22-23, 20017 Observations in Bridging Studies (1) zAre 20 successful consultations and 11 approval drugs in 3 years sufficient numbers? zThe drug-lag has shortened but has not disappeared z“Bridging” is broadly defined Would it be better to define bridging more narrowly? zMost of the drugs that have been approved are ones that meet special medical needs

8. K. Shimatani/ K-H Symposium/ October 22-23, 20018 Observations in Bridging Studies (2) zDosage differences yThere are no set results for determining dosage in bridging studies yShould dose response studies be conducted using the same dosage range as that used in the West, or a dosage range that is one step lower? yJapan is said to use lower dosages than the West, but is it really that the dosages are scientifically low, or is this simply a matter of culture/ custom?

9. K. Shimatani/ K-H Symposium/ October 22-23, 20019 Observations in Bridging Studies (3) zBridging is intended to mainly pursue similarity only, but has it been possible to adequately obtain the information required for Japanese prescribers and patients? zIs it necessary to re-confirm efficacy of the drugs in Japanese? zThere are a lot of cases in which extrinsic factors have been a bigger problem than intrinsic factors

10. K. Shimatani/ K-H Symposium/ October 22-23, 200110 Observations in Bridging Studies (4) zThere are therapeutic areas for which bridging is difficult yThe use of placebo in psychiatry yIt is necessary to have a large sample size in order to calculate the true end points in CV area zConducting only 1 bridging study is very risky. Depending on the therapeutic area, reproducibility may be low. Wise way to use overseas data should be considered in order to reduce duplication

11. K. Shimatani/ K-H Symposium/ October 22-23, 200111 Bridging Study Benefits 1. Drugs for which it would be difficult to obtain approval based only on the Japanese data have been approved through the use of overseas data 2.The duplication of clinical data has been minimized through the use of overseas data 3.The time required for development has been reduced With the introduction of the new GCP 4.The quality of Japanese clinical studies has improved 5.Awareness of clinical studies has improved among investigators, sponsors, and others

12. K. Shimatani/ K-H Symposium/ October 22-23, 200112 Bridging Study Transitions Retrospective bridging The bridging of similar aspects based on studies already conducted or underway in the West and Japan Prospective bridging The design and conduction of new studies in Japan that are similar to studies already conducted in the West Advanced bridging The design and conduction of new studies in both the West and Japan for the purpose of bridging

13. K. Shimatani/ K-H Symposium/ October 22-23, 200113 Future options of clinical trials under Globalization 1. Advanced bridging studies 2. Global studies

14. K. Shimatani/ K-H Symposium/ October 22-23, 200114 Advanced Bridging Studies (1) ( 1 )Protocols of overseas studies should be designed aiming to bridge Japanese studies. Japan must input to overseas protocols.

15. K. Shimatani/ K-H Symposium/ October 22-23, 200115 Advanced Bridging Studies (2) ( 2 )Even if Japan start later, the NDAs can be simultaneous West Japan Phase IPhase IIPhase III Phase IPhase II Simultaneous NDA This strategy could be applied for the therapeutic areas: yNo difference in medical practices yEnd points already validated (precedent) yEasy to get consistent results

16. K. Shimatani/ K-H Symposium/ October 22-23, 200116 Global Studies Why Global Studies? 1)ICH recommend to avoid redundancy of clinical studies which have been already done in overseas However, MHLW/ Japanese prescribers need to see Japanese data Global studies Simultaneous NDA 2) There are difficult areas to conduct clinical studies in Japan ySmall patient population (cancer and others) yMega-trial (cardiac events, bone fracture) yDifficult to have consistent result (psychiatry and others)

17. K. Shimatani/ K-H Symposium/ October 22-23, 200117 Points to be discussed in Global studies zSpeed and Quality zSample size zSimilarity zDosage zStudy design zMedical practice

18. K. Shimatani/ K-H Symposium/ October 22-23, 200118 Speed and Quality Has the Japanese clinical trial environment improved? Collaboration with Asian Countries YES, but…….

19. K. Shimatani/ K-H Symposium/ October 22-23, 200119 Collaboration with SMO

20. K. Shimatani/ K-H Symposium/ October 22-23, 200120 Sample size/ Similarity zIs it possible to reduce sample size? zIs it necessary to prove efficacy only in Japanese patients? BridgingGlobal study 1,000 200 400 1,000 W J Similarity Prove efficacy Similarity

21. K. Shimatani/ K-H Symposium/ October 22-23, 200121 Similarity

22. K. Shimatani/ K-H Symposium/ October 22-23, 200122 Dosage From PK profile WestLMH Japanoption 1LMH option 2 l LM option 3 conduct Phase IIa

23. K. Shimatani/ K-H Symposium/ October 22-23, 200123 Study design/ Medical practice To allow some flexibility in designing of protocol in order to satisfy with local needs - Diagnosis- Primary endpoints - Severity- Secondary endpoints - Demography- Dosage

24. K. Shimatani/ K-H Symposium/ October 22-23, 200124 zBridging studies minimize the duplication of studies and increase the chances of approval Summary (1) zDifferences in extrinsic factors are more important than intrinsic factors in bridging studies

25. K. Shimatani/ K-H Symposium/ October 22-23, 200125 Summary (2) zAs an important alternative to bridging studies, we should think to conduct global studies. In particular, we should be aggressive in looking into this for therapeutic areas in which clinical studies are difficult to conduct in Japan alone. In such cases, we should be flexible in choosing sample sizes and protocol designs that will allow both the global objectives as well as the local objectives to be achieved. zWe need to explore options that would allow us to collaborate with other countries in Asia when conducting global studies