Drug Development in Asia – an Industry perspective

1. Drug Development in Asia – an Industry perspective Stephen Uden Pfizer Inc.

2. ? ? ? MHLW Industry Academia

3. Drug Development in Asia – an Industry perspective • Where are we today • Where can we go in the future • Path 1. Ever greater contribution to pharmaceutical and regulatory science • Path 2. Simple bridging on the margins of drug research

4. Key accomplishments • ICH established • Adoption of GCP based on ICH • Kikoh and PMDEC consultation process • Time clock introduced • MHLW vision • Increasing interest in Clinical Research in Asia • Scientific progress • Statistical methods • Pharmacogenomics

5. Clinical trial activity – is it increasing? • Clinical trials started to • decline long before ICH • was implemented • Recently activity seems • be increasing

6. Clinical trial activity – is it increasing? Clinical trial activity in Japan – patient recruitment experience from four companies Number of new informed consents Year

7. Bridging out of Asia(Japan as an example)

8. PMDEC analysis Approval Time NCEs and LEs As of June 2001

9. Increasing sophistication of scientific methodology • Pharmacogenomics • Metabolic differences well understood • Some advances in pharmacodynamics • Preclinical assessment • Metabolic pathways • Statistical methodology • Sub-population analysis

10. Remaining Obstacles for Enhanced Drug Development

11. Remaining Obstacles for Enhanced Drug Development • Ambiguity in drug development • Need for routine repetition of basic PK

12. 14.0 Japanese subject 12.0 Western subject 10.0 8.0 Plasma concentration (ng/mL) 6.0 4.0 2.0 0.0 0 24 48 72 96 Time post dose (h) Remaining Obstacles for Enhanced Drug Development • Ambiguity in drug development • Need for routine repetition of basic PK • Japanese and Western young males (resident in Japan) • Similar PK profiles in two populations

13. Remaining Obstacles for Enhanced Drug Development Large differences in cost between different areas discourage investment Relative cost per patient for a large scale global outcomes study

14. Unlike Phase II/III sites Japanese commercial Phase I units are internationally competitive • Relative costs for a Phase I multiple dose study comparing Japanese and Caucasian normal volunteers Relative cost

15. Remaining Obstacles to Enhanced Drug Development • Mind set • Unwillingness to collaborate • Beliefs prevailing over scientific evidence and methodology • Sponsors unaware of changes • Drug development expertise stagnating • Repetition of routine work inhibits development of new methodology

16. Path 1 – the improvement trend continues

17. Path 1 – the improvement trend continues • Bridging evolves into making best use of data generated throughout the world

18. Path 1 – the trend continues • Commitment to Asia being a centre of drug development excellence • Regulators • Companies • Academics • Costs brought under control in Japan • Investigators/Departments reimbursed directly • Institutional overhead costs controlled • Adoption of robust scientific methodologies to cope with inevitable differences • Statistical • Pharmacogenomics • Clinical technology

19. Discovery to first in man • Asian development centres identify critical issues for global development • Opportunities for special population work in Asia • Sub populations prevalent in Asia • Metabolic groups • Patterns of medical practice • End points validated in Asian patients • Statistical methodologies to analyse sub-populations in the global database that are useful to Asian regulators and physicians

20. Clinical Pharmacology Programme • Pre-clinical assessment to determine likelihood of significant PK issues • Application of statistical methodology to generate data relevant to Asians as part of global development programme

21. Integrated global PK programme

22. Integrated global PK programme Statistical methodology applied to characterise PK in Japanese/Asians

23. Phase III • Basic Efficacy accepted as relevant to all regions • Integrated global strategy to determine how drug can best be used in individual patients • Best doses in sub-populations • Sex • Co-morbid illness • Concomitant medication • Metabolic status

24. US/Canada Pivotal efficacy study I Comparative efficacy N = 500 EU/Europe Pivotal efficacy study II Comparative efficacy N = 500 Japan/Asia Pivotal efficacy study III Comparative efficacy N = 500 Integrated Phase III strategy - 1 • Data combined to analyse for clinically important sub-populations • Sex • Co-morbid illness • Concomitant medication • Metabolic status

25. Study 1 Japan/other Asia/US/Canada/EU/Eastern Europe Confirmation of efficacy Study 2 Japan/other Asia/US/Canada/EU/Eastern Europe Efficacy comparative to different class of drug Study 2 Japan/other Asia/US/Canada/EU/Eastern Europe Efficacy in special population Integrated Phase III strategy - 2 • Regional specific issues • Resolved through pre- • Planned use of: • Pop PK • Sub Group analysis • Pharmacogenomics

26. Integrated Phase III strategy - 3 Global Outcomes study in Asia, Americas, Europe • Regional specific issues • Resolved through pre- • Planned use of: • Pop PK • Sub Group analysis • Pharmacogenomics Sub study A Sub study B Sub study C

27. Clinical trial activity – definitely increases? • Return to 1993 level? • Studies more complex • and “value added”?

28. A successful simultaneous development bridging strategy with simultaneous filing/approval Global Development Phase I and II Year 1 Year 2 Year 3 Year 4 Year 5 US or EU Asia = Phase III start = Filing

29. A successful simultaneous development bridging strategy with simultaneous filing/approval Global Development Phase I and II Year 1 Year 2 Year 3 Year 4 Year 5 US or EU Asia = Phase III start = Filing

30. Path 2 – stagnation or reversal

31. Path 2 – stagnation or reversal • Bridging degenerates into multiple repetitive studies throughout Asia • Japan destined to perform basic PK studies and routine (Phase II) Bridging studies

32. Path 2 – stagnation or reversal • Nationality seen as more important than physiological or pathological status • Only nationally produced data is seen as relevant • Costs continue to escalate particularly in Japan • Investigators demotivated as not rewarded for their efforts • Advances in scientific methodology ignored or rejected • Sponsor companies maintain prejudices about difficulty of work in Asia

33. Phase I – a routine after thought • Japan Phase • First in humans • - Multiple dose PK • - Fed Fasting study Japan Pop PK

34. Phase I – a routine after thought • Japan Phase • First in humans • - Multiple dose PK • - Fed Fasting study Japan Pop PK EU/US dominated PK programme

35. Phase I – a routine after thought No new data • Japan Phase • First in humans • - Multiple dose PK • - Fed Fasting study Japan Pop PK EU/US dominated PK programme

36. Phase I – a routine after thought No new data Capability stagnates • Japan Phase • First in humans • - Multiple dose PK • - Fed Fasting study Japan Pop PK EU/US dominated PK programme

37. Clinical trial activity – why invest more? Companies continue to do minimum work for approval

38. Japan Bridging Study N = 200

39. Japan Bridging Study N = 200 Korea Bridging Study N = 200

40. Japan Bridging Study N = 200 China Bridging Study N = 200 Korea Bridging Study N = 200

41. Japan Bridging Study N = 200 China Bridging Study N = 200 Korea Bridging Study N = 200 Taiwan Bridging Study N = 200

42. Japan Bridging Study N = 200 China Bridging Study N = 200 Korea Bridging Study N = 200 Philippine Bridging Study N = 200 Taiwan Bridging Study N = 200

43. Japan Bridging Study N = 200 China Bridging Study N = 200 Korea Bridging Study N = 200 Thai Bridging Study N = 200 Philippine Bridging Study N = 200 Taiwan Bridging Study N = 200

44. Is this really the way ahead? Japan Bridging Study N = 200 China Bridging Study N = 200 Korea Bridging Study N = 200 Thai Bridging Study N = 200 Philippine Bridging Study N = 200 Taiwan Bridging Study N = 200

45. ? ? ? MHLW Industry Academia

46. MHLW Industry Academia