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2002/10/02 3rd Kitasato-Harvarad Sympo Several Years Experience on Bridging Studies and the Future National Cancer Center Hospital Head, Breast and Medical.

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Presentation on theme: "2002/10/02 3rd Kitasato-Harvarad Sympo Several Years Experience on Bridging Studies and the Future National Cancer Center Hospital Head, Breast and Medical."— Presentation transcript:

1 2002/10/02 3rd Kitasato-Harvarad Sympo Several Years Experience on Bridging Studies and the Future National Cancer Center Hospital Head, Breast and Medical Oncology Group Yasuhiro Fujiwara MD, PhD

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 palivizumab approved on Jan 17, 2002 oseltamivir dry-syrup approved on Jan 17, 2002 And 4 other drugs (Review reports are not open to public)

3 Time from NDA Submission to Approval note: Not TIME CLOCK ! fexofenadine14.0 months oseltamivir 4.7 months (priority review) anastrozole13.3 months sumaltriptan10.7 months zolmitriptan15.5 months palivizumab12.9 months (priority review) oseltamivir dry-syrup 5.8 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 PK/PD study Japan US or EU PK/PD study Bridging study Bridging corresponding study Therapeutic Confirmatory Long-term administration Special population

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

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

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: , 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.

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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 p39

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

21 Comparison of isoflavone levels between countries Dietary intake Serum level 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 In the Japanese reviewing and drug price determination process, JMA (Japan Medical Association; mainly composed of private practice physicians) has latent power. Non-scientific, but important issues to be recognized by the foreign companies (1) INFRASTRUCTURE

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 Lumpkins slide of 12 June, 2000

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27 Non-scientific, but important issues to be recognized by the foreign companies (2) Professional Quality of Regulatory Agencys 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 N Engl J Med 344: , 2001 ACE Inhibitor

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

32 Pending Reviewers 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: , 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, 2001 n=354

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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


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