Risk Communication in NDA (New Drug Application)

1. Risk Communication inNDA (New Drug Application) Massie Ikeda MD, PhD Chief Medical Reviewer Pharmaceuticals and Medical Devices Agency

2. Standard Disclaimer • This is not an official PMDA/MHLW guidance or policy statement. • No official support of endorsement by PMDA/MHLW is intended or should be inferred.

3. Today’s TopicsWhy do we need: • Clinical trials ? • Regulatory body ? • Risk communication ?

4. “New Drug” reminds you of・・・ • Newspaper Articles • Tough Diseases: HIV, Cancer • High-Techs in Medicine • Severe Adverse Effects • Mega Pharma Companies • Clinical Trials

5. Why do we need clinical trials ? • Is it OK with animal data only ? • Let safe drugs only go into the market？ • Are clinical trials dangerous？ • Let us leave to the doctors？ • Why do we need placebo ?

6. We humans needour own human data.You never want dog or cat food on your dinner menu.The same with your drug.

7. Are you happy withalternative medicine only?You probably need drugs whose data have been scientifically reviewed.

8. Human Experiment Era

9. Today’s TopicsWhy do we need: • Clinical trials ? • Regulatory body ? • Risk communication ?

10. Benchmarking of Drugs: Who does it ?

11. Independent BodyRegulatory Authority • PMDA • FDA • EMEA In your home country?

12. MHLW JPMA ICH EMEA FDA PhRMA EFPIA

13. ICHInternational Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

14. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use • Japan, USA, EU • To make common regulations and share data on clinical trials • It is not an academic conference • Working on drugs but not on devices

15. 各種分科会がある

17. QE5分科会参加者名簿

18. What is ICH E5 for? • For providing good drugs faster to everybody in the world, especially ICH resions. • It is not intended to bypass important domestic clinical studies.

19. Importance of ethnic differences • Intrinsic PK/PD, genetic analysis (in future), etc. • Extrinsic differences in clinical practice, etc.

20. Ethnic Difference in Alcohol Dehydrogenase

21. Warfarin for NVAF Japan US

22. Coagulation factor mutation

23. SARS & HLA typing

24. An example of difference among Asians SARS & HLA typing HLAB46 Jpn 4.4 Krn 4.4 Vtnm 13.2 Sngp 15.1 Kanton 15.4

25. Importance of ethnic differences • Intrinsic PK/PD, genetic analysis (in future), etc. • Extrinsic differences in clinical practice, etc.

26. Japan USA Health insurance system A FDA approval MHLW approval Health insurance system B Universal health insurance coverage 国民皆保険 Health insurance system C

27. CTD(Common Technical Document)as CV of the Drug Our common ground to analyse the benefits and risks of the drug

28. CTD as a CV of the new drug CURRICULUM VITAE FORMATFORTENURE AND PROMOTION DOSSIERS NAME: ___________________________________________________________ (Last) (First) (Initial) EDUCATION: UNDERGRADUATE: ________________________________________ GRADUATE: _______________________________________________POST DOCTORAL: _________________________________________ ACADEMIC APPOINTMENTS (inclusive dates): OTHER APPOINTMENTS AND PROFESSIONAL CONSULTANTSHIPS (including other remunerated employment): LICENSURE AND CERTIFICATION: Disclosure & accountability is essential.

29. CTD as CV of the Drug • Disclosure & Accountability • It is not a brochure or propaganda • Disclosure of not only the benefit • Explain why • The drug is indicated to the target • The drug overcomes the rivals

30. CTD is • CV of the drug application • Common ground of communication • Key for disclosure and accountability

31. PMDEC/MHLWNDA FDA (CDER) Standard NDA approved year approvals median months to approval approvals median months to approval 1997 40 33.6 101 15.0 1998 58 36.6 65 12.0 1999 71 30.6 55 13.8 2000 84 18.8 78 12.0 2001 57 15.5 56 14.0 2002 67 15.3 Time to approval 52 15.8

32. Today’s TopicsWhy do we need: • Clinical trials ? • Regulatory body ? • Risk communication ?

33. Our Mission Risk Benefit

34. No bad news is bad news when people are not aware of its shadow.

35. Why not share the bad news ? because it comes out sooner or later.

36. Difficulties in risk communication • Liability • Conflicts of interests • Uncertainty & Variety • Adverse events: Drug-related on not • One understands A causes B but others do not • Changes as time goes by

37. But we have to share bad news because: • It will come out, anyway. • Early intervention before disaster • Stay calm & avoid panic • To correct the system effectively • To make no scapegoat

38. Common Flaws in NDA • Focus only on efficacy instead of safety • Insisting on safety: • No significant difference compared with the placebo • No causal relationship • Very low frequency • No similar case in PMS outside Japan

39. Our Common Aim-Regulatory Authority & Pharma Co-Good Drugs for People Not conflict but Cooperation

40. The sooner, the better ?The lessons from Rofecoxib ( Vioxx) • Cox2 Inhibitor • Stomach-friendly super aspirin • FDA approved in May 1999 • Voluntary withdrawal in September 2004 • Due to an increased risk of cardiovascular events (including heart attack and stroke)

41. Stop Confrontation Drug Co. Citizens Media Government

42. Future Issues • Synthesizing data on safety • Pharmacovigilance system • Harmonization on safety data • Safety and order-made medicine, e.g. SNP • Media Relation • Risk Communication with lay press & people