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Several Years Experience on Bridging Studies
and the Future
National Cancer Center Hospital
Head, Breast and Medical Oncology Group
Yasuhiro Fujiwara MD, PhD
2002/10/02
3rd Kitasato-Harvarad Sympo
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=48)
sumaltriptan : randomized placebo-controlled double-blind
dose-finding study (n=274)
zolmitriptan : randomized placebo-controlled doubleblind 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
US or EU
Japan
PK/PD study
①
PK/PD study
Bridging study
②
Bridging
corresponding study
③
Therapeutic Confirmatory
Long-term administration
Special population
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 ?
So many
Anti-allergic
drugs have
been used for
asthma patients
in Japan
Prepared by Y. Fujiwara
So many
oral
fluoropyrimidine
Derivatives
in Japan
・Tegafur
・Fluorouracil
・Camofur
・UFT
・Doxifluridine
・S-1
Fujiwara Y. J Clin Oncol 17:3362-3365, 1999
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
Cumulative incidence rates for breast cancer in
selected countries and ethnic groups
Japan
US, Hawaii: Japanese
US, San Francisco: Japanese
Korea, Kangwha
China; Shanghai
Singapore: Chinese
US, San Francisco: Chinese
US, SEER: White
US, SEER: Black
Denmark
The Netherlands
Sweden
France
UK
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
%
Source: Parkin, D.M. et al. eds. Cancer Incidence in Five Continents Vol. VII (1997)
Soybean may prevent breast cancer
Tofu
･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
Natto
anti-estrogenic effects
(fermented
soybean)
Comparison of isoflavone levels
between countries
Serum level
Dietary intake
30
FFQ daidzein intake
(mg/day)
200
Serum daidzein
(nmol/l)
Urinary excretion
30
urinary excretion
(μmol/day)
150
20
20
100
10
10
50
0
0
0
male
female
American
male
female
Finnish
male
female
American
Yamamoto S et al. Journal of Nutrition 131:2741, 2001
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
The Future
・ Sound Infrastructure for Clinical Development
・ FROM Bridging
TO International Simultaneous Development
・ FROM Ethnic Difference
TO Genotype Difference
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.
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)
Mathematical
Statistician
N=97 (n=3)
3.5%
Chemistry
11.8%
Pharmacist
1.7%
Nurse
Statistician
0.0%
Computer
specialist
4.1%
Medical
Officer
N=336 (n=12) Toxicology
12.3%
0.5%
Pharmacolog
y
6.7%
Physiology
0.2%
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 ?
FROM Bridging
TO International
Simultaneous Development
A Weak Point (?) of Multinational Pivotal Trials
ACE Inhibitor
N Engl J Med 344:1351-1357, 2001
Nonpeptide Angiotensin II Receptor Antagonist
No subset analysis data has yet been published
N Engl J Med 345: 861-869, 2001
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 ?
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, 2001
n=354
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