Several Years Experience on Bridging Studies and the Future

1. Several Years Experience on Bridging Studiesand the Future National Cancer Center Hospital Head, Breast and Medical Oncology Group Yasuhiro Fujiwara MD, PhD 3rd Kitasato-Harvarad Sympo

2. Drugs Approved with a Prospectively Conceptualized Bridging Strategy during Clinical Development • As of September 30, 2002 • fexofenadine approved on Sep 22, 2000 • oseltamivir approved on Dec 12, 2000 • anastrozole approved on Dec 22, 2000 • sumatriptan approved on Jun 20, 2001 • zolmitriptan approved on Jun 20, 2001 • palivizumabapproved on Jan 17, 2002 • oseltamivir dry-syrupapproved on Jan 17, 2002 • And 4 other drugs (Review reports are not open to public)

3. Time from NDA Submission to Approvalnote:Not TIME CLOCK ! • fexofenadine 14.0 months • oseltamivir 4.7 months(priority review) • anastrozole 13.3 months • sumaltriptan 10.7 months • zolmitriptan 15.5 months • palivizumab 12.9 months (priority review) • oseltamivir dry-syrup5.8 months (priority review)

4. Type of Bridging Study • fexofenadine : randomized placebo-controlled double-blind dose-finding study (allergic rhinitis n=310) • oseltamivir : randomized placebo-controlled double-blind phase III study (n=316) • anastrozole : randomized phase II study (n=31) • clinical pharmacological study (healthy n=48) • sumaltriptan : randomized placebo-controlled double-blind dose-finding study (n=274) • zolmitriptan : randomized placebo-controlled double- blind dose-finding study (n=289)

5. Type of Bridging Study cont. • palivizumab : single arm open trial (n=31) • oseltamivir dry-syrup : single arm open trial (n=71)

6. Common Complete Clinical Data Package US or EU Japan ① PK/PD study PK/PD study ② Bridging study Bridging corresponding study Therapeutic Confirmatory Long-term administration Special population ③

7. What is ICH E5 for? • For providing good drugs faster to everybody in the world, especially ICH resions. • THEN, is there really many good drugs • which are not approved in Japan, • but approved in the US or EU? • An Illusion of “LEGACY DRUGS” ??

8. Legacy drug ??? • Loratadine ? • Capecitabine ?

9. So many Anti-allergic drugs have been used for asthma patients in Japan Prepared by Y. Fujiwara

10. So many oral fluoropyrimidine Derivatives in Japan ・Tegafur ・Fluorouracil ・Camofur ・UFT ・Doxifluridine ・S-1 Fujiwara Y. J Clin Oncol 17:3362-3365, 1999

11. Almost all of the clinically essential (possible large sales on the market) drugs have already been approved in Japan. The problem is the approved indications do NOT catch up with the scientific progress (the results of high quality clinical trials). In principle, the current Japanese National Heath Insurance System does not cover the drug cost if its indication is not approved (but the drug has other indications).

12. Ann Itern Med 133: 128-135, 2002

13. CONCERN Although the drug is approved faster, drug information to the public and the health professionals may be biased by economical pressure, not by clinical science in Japan. There is no restriction about the content of advertisement to the health professionals.

15. www.astrazeneca.com/mainnav1/s_news/s_press/c_press/idc_press67670/press-release-197.htmlwww.astrazeneca.com/mainnav1/s_news/s_press/c_press/idc_press67670/press-release-197.html

16. In Japanese Homepage the company has not yet refer to the somewhat negative results of the overseas Phase III studies as of October 1, 2002.

17. 「日本では、従来の化学療法で効果が認められなかったり、「日本では、従来の化学療法で効果が認められなかったり、 手術できない症例に対し、単独で投与する薬として 承認されましたし、日本で行なった臨床試験ではなかったので、翻訳掲載していません。」 （ア社日本法人広報） 週間新潮‘０２．９．１２　p39より抜粋

18. Intrinsic/Extrinsic Factors • Food Habits

19. Cumulative incidence rates for breast cancer in selected countries and ethnic groups Source: Parkin, D.M. et al. eds. Cancer Incidence in Five Continents Vol. VII (1997)

20. Tofu Natto (fermented soybean) Soybean may prevent breast cancer ･High consumption in Asian countries ･ low~no consumption in the USA ･Major source of isoflavones, one group of phytoestrogens ･ Experimental studies show anticarcinogenic effects due to its anti-estrogenic effects

21. Comparison of isoflavone levels between countries Serum level Dietary intake Urinary excretion Yamamoto S et al. Journal of Nutrition 131:2741, 2001

22. Epidemiologic study for soybean and breast cancer • 8 case-control studies and 3 prospective studies • Inconsistent results • One example • Horn-Ross (2002) • 111,526 California Teachers • No difference between highest vs. lowest intake quartile • Highest quartile corresponds to lowest quartile in Japan This data provides no suggestion for us Japanese

23. The Future • ・　Sound Infrastructure for Clinical Development • ・　FROM Bridging • TO International Simultaneous Development • ・　FROM Ethnic Difference • TO Genotype Difference

24. INFRASTRUCTURE Non-scientific, but important issues to be recognized by the foreign companies (1) • In the Japanese reviewing and drug price determination process, JMA (Japan Medical Association; mainly composed of private practice physicians) has latent power.

25. FAST TRACK in the United Sates • ・　Multiple meetings (pre-IND through labeling discussions) • ・　Possible Accelerated Approval (surrogate endpoint) • ・　Possible approval under Subpart E (less safety data than normal; P2) • ・　Priority review designation • ・　Portion of an application eligible for early submission Adopted from Dr. Murray M Lumpkin’s slide of 12 June, 2000

27. Non-scientific, but important issues to be recognized by the foreign companies (2) ProfessionalQuality of Regulatory Agency’s Reviewers and Consultants is in crisis. Very few physician reviewers No physician in OPSR (“Kiko”) Only a few consultant physicians (NO oncologists) Very few biostasticians No biostastician in OPSR (“Kiko”) Only two(?) consultant biostasticians

28. Even if the Fast Track System is introduced in Japan, the system will NOT work effectively due to the immature advise system at OPSR (“Kiko”). Neither JPA nor PhRMA does NOT directly point out this system failure. The QUANTITY (the number of reviewers) is imporatnt. But, the QUALITY is MORE important. Have you ever checked CV and Publication List of the reviewers and advisers ?

29. A Weak Point (?) of Multinational Pivotal Trials FROM Bridging TO International Simultaneous Development

30. ACE Inhibitor N Engl J Med 344:1351-1357, 2001

31. Nonpeptide Angiotensin II Receptor Antagonist No subset analysis data has yet been published N Engl J Med 345: 861-869, 2001

32. Pending Reviewer’s Decision • When there occurs the difference between total data sets analysis (all ethnic group, statistically significant) and subset analysis • (Japanese, no significance), • ONE more pivotal study for Japanese population? • OR • Approve it ?

33. FROM Ethnic Difference TO Genotype Difference Ethnicity-neutral approach will prevail in future.

34. Wilson JF, et al. Nature Genetics 29: 265-269, 2001

35. Wilson, Nature Genetics, 2001 • Analyzed SNPs in DNA samples from 354 individuals from 8 different ethnic groups • Genetic data fit to population model (STRUCTURE) • Minimizes number of discrete populations • Assigns each individual (based on SNPs) to a discrete population By courtesy of Dr. Ratain (Univ of Chicago): 2002 ASCO

36. Wilson, Nature Genetics, 2001n=354

38. Conclusions • Interethnic variability is common • Intraethnic variability highest in populations of African descent • Polymorphisms may affect • Pharmacokinetics (metabolism, transport) • Pharmacodynamics (response, toxicity) • More studies are indicated • Genotype more important than ethnicity By courtesy of Dr. Ratain (Univ of Chicago): 2002 ASCO