2002/10/02 3rd Kitasato-Harvarad Sympo

Several Years Experience on Bridging Studies

and the Future

National Cancer Center HospitalHead, Breast and Medical Oncology Group

Yasuhiro Fujiwara MD, PhD

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)

Time from NDA Submission to Approval 　note: 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-syrup 　　 5.8 months (priority review)

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=4

8)

sumaltriptan : randomized placebo-controlled double-blind dose-finding study (n=274)

zolmitriptan : randomized placebo-controlled double-blind dose-finding study (n=289)

Type of Bridging Study cont.

palivizumab : single arm open trial (n=31)

oseltamivir dry-syrup : single arm open trial (n=71)

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

①②

③

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” ??

Legacy drug ???

Loratadine ?

Capecitabine ?

Prepared by Y. Fujiwara

So many

Anti-allergic drugs have

been used for asthma patients

in Japan

Fujiwara Y. J Clin Oncol 17:3362-3365, 1999

・ Tegafur・ Fluorouracil・ Camofur・ UFT・ Doxifluridine・ S-1

So many oral fluoropyrimidi

ne Derivatives

in Japan

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).

Ann Itern Med 133: 128-135, 2002

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.

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

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.

「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

Intrinsic/Extrinsic Factors

Food Habits

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

UK

France

Sweden

The Netherlands

Denmark

US, SEER: Black

US, SEER: White

US, San Francisco: Chinese

Singapore: Chinese

China; Shanghai

Korea, Kangwha

US, San Francisco: Japanese

US, Hawaii: Japanese

Japan

%

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)

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)

Comparison of isoflavone levels between countries

FFQ daidzein intake (mg/day)

0

10

20

30

male female American

Serum daidzein (nmol/l)

0

50

100

150

200

male female Finnish

urinary excretion (μmol/day)

0

10

20

30

male female American

Dietary intake Serum level Urinary excretion

Yamamoto S et al. Journal of Nutrition 131:2741, 2001

Epidemiologic study for soybean and breast cancer

8 case-control studies and 3 prospective studiesInconsistent results

One exampleHorn-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

The Future

・　 Sound Infrastructure for Clinical Development

・　 FROM Bridging

　　　　　 TO International Simultaneous Development

・　 FROM Ethnic Difference

　　　　　 TO Genotype Difference

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

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

CD/BER(n=2735)

MedicalOfficer

N=336 (n=12)12.3%

Pharm acist1.7%

Toxicology0.5%

Physiology

0.2%

Pharm acology

6.7%

C om pute rspe cial i st

4.1%

Mathe m aticalS tati sticianN=97 (n=3)

3.5%

C he m istry11.8%

Statistician

0.0%

Nurse

Non-scientific, but important issues to be recognized by the foreign companies (2)

Professional Quality 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

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 ?

A Weak Point (?) of Multinational Pivotal Trials

FROM Bridging

TO International

Simultaneous Development

N Engl J Med 344:1351-1357, 2001

ACE Inhibitor

N Engl J Med 345: 861-869, 2001

Nonpeptide Angiotensin II Receptor AntagonistNo subset analysis data has yet been published

Pending Reviewer’s Decision

When there occurs the difference between total data sets analysis (all ethnic group, statistically sig

nificant) and subset analysis

(Japanese, no significance),

ONE more pivotal study for Japanese population?

OR

Approve it ?

FROM Ethnic Difference

　　　　　 TO Genotype Difference

Ethnicity-neutral approach will prevail in future.

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

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

Wilson, Nature Genetics, 2001n=354

ConclusionsInterethnic 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