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
Mar 28, 2015
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