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

2. IndustryAcademia MHLW ???

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

7. CompanyUSEUOther Asia ANo BYes C D No E FYes G HNo Yes 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. Ambiguity in drug development –Need for routine repetition of basic PK

12. 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) Ü Similar PK profiles in two populations

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

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

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. –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 Discovery to first in man

20. –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 Clinical Pharmacology Programme

21. Integrated global PK programme Routine Phase I programme at Discovery site - First in humans - Multiple dose PK - Fed Fasting study - Surrogate efficacy/Phase IIa USEUJapan Solid form Bio-equivalence Elderly PK study PK/PD study Special study e.g. end point validation Interaction study E Hepatic Impairment study Renal Impairment study Interaction study A Interaction study B Commercial Form Bio- equivalence Poor metaboliser study PK in smokers Interaction study C Interaction study D Special Study e.g. cognitive function New formulation BE Phase II/III population PK programme

22. Integrated global PK programme Routine Phase I programme at Discovery site - First in humans - Multiple dose PK - Fed Fasting study - Surrogate efficacy/Phase IIa USEUJapan Solid form Bio-equivalence Elderly PK study PK/PD study Special study e.g. end point validation Interaction study E Hepatic Impairment study Renal Impairment study Interaction study A Interaction study B Commercial Form Bio- equivalence Poor metaboliser study PK in smokers Interaction study C Interaction study D Special Study e.g. cognitive function New formulation BE Phase II/III population 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. Integrated Phase III strategy - 1 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 Data combined to analyse for clinically important sub-populations Sex Co-morbid illness Concomitant medication Metabolic status

25. Integrated Phase III strategy - 2 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 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 ASub study BSub 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 Year 1Year 2Year 3Year 4Year 5 Phase I and II Global Development Asia = Phase III start US or EU = Filing

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

30. Path 2 – stagnation or reversal

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

32. 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 ÜInvestigators demotivated as not rewarded for their efforts Advances in scientific methodology ignored or rejected Sponsor companies maintain prejudices about difficulty of work in Asia Path 2 – stagnation or reversal

33. Phase I – a routine after thought Routine Phase I programme at Discovery site - First in humans - Multiple dose PK - Fed Fasting study - Surrogate efficacy/Phase IIa USEU Solid form Bio-equivalence Elderly PK study PK/PD study Special study e.g. end point validation Interaction study E Poor metaboliser study PK in smokers Interaction study C Hepatic Impairment study Renal Impairment study Interaction study A Interaction study B Commercial Form Bio-equivalence Special Study e.g. cognitive function New formulation BE Interaction study D Phase II/III population PK programme Japan Phase -First in humans - Multiple dose PK - Fed Fasting study Japan Pop PK

34. Phase I – a routine after thought Routine Phase I programme at Discovery site - First in humans - Multiple dose PK - Fed Fasting study - Surrogate efficacy/Phase IIa USEU Solid form Bio-equivalence Elderly PK study PK/PD study Special study e.g. end point validation Interaction study E Poor metaboliser study PK in smokers Interaction study C Hepatic Impairment study Renal Impairment study Interaction study A Interaction study B Commercial Form Bio-equivalence Special Study e.g. cognitive function New formulation BE Interaction study D Phase II/III population PK programme 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 Routine Phase I programme at Discovery site - First in humans - Multiple dose PK - Fed Fasting study - Surrogate efficacy/Phase IIa USEU Solid form Bio-equivalence Elderly PK study PK/PD study Special study e.g. end point validation Interaction study E Poor metaboliser study PK in smokers Interaction study C Hepatic Impairment study Renal Impairment study Interaction study A Interaction study B Commercial Form Bio-equivalence Special Study e.g. cognitive function New formulation BE Interaction study D Phase II/III population PK programme Japan Phase -First in humans - Multiple dose PK - Fed Fasting study Japan Pop PK EU/US dominated PK programme No new data

36. Phase I – a routine after thought Routine Phase I programme at Discovery site - First in humans - Multiple dose PK - Fed Fasting study - Surrogate efficacy/Phase IIa USEU Solid form Bio-equivalence Elderly PK study PK/PD study Special study e.g. end point validation Interaction study E Poor metaboliser study PK in smokers Interaction study C Hepatic Impairment study Renal Impairment study Interaction study A Interaction study B Commercial Form Bio-equivalence Special Study e.g. cognitive function New formulation BE Interaction study D Phase II/III population PK programme Japan Phase -First in humans - Multiple dose PK - Fed Fasting study Japan Pop PK EU/US dominated PK programme No new data Capability stagnates

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 Korea Bridging Study N = 200 China Bridging Study N = 200

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

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

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

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

45. IndustryAcademia MHLW ? ? ?

46. IndustryAcademia MHLW