Update on Korea China Japan Tripartite Clinical Trial ... - Apec-ahc.org

<strong>Update</strong> on Korea China Japan
Tripartite Clinical Trial
Collaboration in Japan
Shinobu UZU
International Planning Director,
Ministers’ Secretariat, MHLW

Numbers of All CTN
Trends of MRCTs Including Japan (1/2)
- % of MRCTs in Clinical Trial Notifications -
300
250
200
150
100
50
0
Early
FY2007
(Apr-Sep)
: Total number of Clinical Trial Notification (CTN)
: Number of MRCT CTN
Late Early Late Early
FY2007 FY2008 FY2008 FY2009
(Oct-Mar) (Apr-Sep) (Oct-Mar) (Apr-Sep)
Late
FY2009
(Oct-Mar)
Early
FY2010
(Apr-Jul)
25
20
15
10
5
0
% of MRCTs

Trends of MRCTs including Japan (2/2)
- Operational Regions of MRCTs in FY2009 -
Japan+US/EU
Unknown
15.0%
16.8%
FY2009
12.4%
55.8%
East-Asia Only
World-Wide
3

Ethnic Factors
-Dose Difference by Region-
For 32 % of drugs, US/EU dose was > 2 times higher than Japanese dose
Approved drugs in 2001-2007
Arnold FL et al , Clin Pharmaco Therapeut., 87: 714-720, 2010
4

ILD on Temsirolimus Clinical Trial
Number
of ILD -1
Number
of ILD -2
MRCT Phase II (Japan-Korea- China) MRCT Phase III
North-South America, EU
Japanese Korean Chinese Total IFN
8/20
40.0%
11/20
55.0%
3/30
10.0%
16/29
55.2%
4/32
12.5%
18/28
64.3%
ILD 1 :Reported by investigator
ILD 2 : Reviewed by ILD advisory board
15/82
18.3%
45/77
58.4%
1/200
0.5%
8/138
5.8%
4/208
1.9%
52/178
29.2%
by Japan’s Review Report on Temsirolimus
5

Promotion of MRCT in East-Asia
Background:
- Globalization of Drug Development
- The necessity of evaluation on ethnic factors
- East Asian Advantage
•Ethnic Similarities among East-Asia
(China/Korea/Japan)
•Improvement of clinical trial environment in East-Asia
•Emerging drug market in East-Asia
Better drugs can be rapidly
through promoting MRCT in East-Asia.
Regulatory collaboration among China/Korea/Japan
Development of consideration/guideline to conduct
MRCT in East-Asia

Japan’s Activities on Ethnic Factor
Research
1. Retrospective Literature Study
FY2008: Collecting available PK data of Chinese, Korean and Japan
and review the data
2. Prospective PK study
Clinical
Data
FY2009-2010: Conducting Prospective PK study Including
Chinese, Korean and Japanese in order to compare ethnic
difference more precisely
• Budget: approximately total 400M Yen (=4M $ )
PK Data Clinical
Data
Clinical
Data
• PK for three marketed drugs are measured by validated methods

Ethnic Difference in Pharmacokinetics
Japanese
Intrinsic Factors Extrinsic Factors
Ethnic Difference in PK
Korean
Caucasian
Chinese
8

Summary of PK data analysis
Ethnic Factors in PK from Literature Study
No ethnic difference among 4 populations
No ethnic difference among East Asian populations
Difference between East Asian and Caucasian
Ethnic difference among East Asian populations
Difference between Japanese and Caucasian
No difference between Japanese and Caucasian
Drug Information Association www.diahome.org 9

Clinical Pharmacokinetic Study in East
Asians and Caucasian (Kawai Project)
Moxifloxacin; Japanese East Asians and Caucasians
Simvastatin; Japanese Caucasians
Meloxicam; Japanese Chinese
Same protocol (Practical circumstances)
Standard operation manual
Analytical method for the plasma drug concentration
Analysis site for the plasma drug concentrations
Drug form
Health Labour Sciences Research Grant (Kawai Project)
Drug Information Association www.diahome.org 10

Relative AUC difference
Moxifloxacin Pharmacokinetic Study in East
Asians and Caucasian
Retrospective Study Data
0.2
0
-0.2
-0.4
-0.6
Chinese Caucasian
Compared with Japanese
90%CI
Kawai Project Data
(Relative AUC difference)
Chinese Korean Caucasian
Compared with Japanese
Health Labour Sciences Research Grant (Kawai Project)
Drug Information Association www.diahome.org 11
Relative AUCinf difference
0.4
0.2
0
-0.2
-0.4

China, Japan, Korea Tripartite Cooperation
- Related Activities in This Year -
1. China, Japan, Korea Tripartite Meeting, Oct. 2011
Research Group for ethnic factors
Director General Meeting
2. MRCT Tokyo Symposium, Nov.2011
Key issues to be identified in “Seoul Symposium 2010” will be
discussed further.
To Develop recommendation for next step
3. Develop Japan’s “consideration” for MRCT among East Asia,
considering Ethnic Factors
Drug Information Association www.diahome.org 12

APEC LSIF (Life Science Innovation Forum)
Source: APEC
Leaders Meeting
Ministerial Meeting
Senior Officials Meeting
Committee on
Trade and Investment
LSIF
Regulatory Harmonization
Steering Committee (RHSC)
Regulatory Members: Canada, China, Japan,
Korea, Peru, Chinese Taipei, Thailand, US

APEC Multi-Regional Clinical Trial Workshop
(Sep. 13-15, 2010, Seoul, Korea)
写真
Major issues
• Study Design
• Operational
Aspects
• Korea-China-Japan
Cooperation
• Case Studies on
Oncology
• Panel Discussion
14

1. Overall
Recommendations
A) MRCTWS should be continued on MRCT
Roadmap
B) China-Japan-Korea Cooperation: valuable effort
for entire APEC Region
2. Study Design (statistical point of view)
A) In order to reduce variance of data, involvement of
the region in question in early stage is important.
3. Operational Aspects
A) Trainings for CRCs, principal investigators and
support staff are urgently needed 15

Roadmap to promote MRCT
Goal:To facilitate MRCTs and acceptance of MRCT results for
drug review by regulatory authorities in APEC regions
Overview:
Evaluate current practices relative to international best practices
Establish common understanding regarding the following key issues
and other issues within APEC region under the auspices of LSIF.
[Key Issues]
- Implementation of ICH E5 guideline
- Study design of MRCT
- Operational/Regulatory procedure to facilitate MRCT efficiently
- Cooperative regulatory approach to facilitate MRCTs on diseases prevalent in subregions
of APEC.
Implement training for those involved in MRCT
Develop necessary items for Training/Workshop to promote MRCT
- APEC economies share best practices
- MRCTWS as well as each economy considers developing training curricula
Issue recommendation on regulatory harmonization regarding MRCT
RHSC will support the activities and development of recommendation
for next step.

Asia’s Role in Global Drug Development
EU
East Asia
Japan
ASIA
ASEAN
APEC
North America
USA
Canada

Back up
Drug Information Association www.diahome.org 18

国際共同試験での日本人の情報
【エベロリムス(審査報告書より)】
• 日本人を含む国際共同第Ⅲ相試験(試験番号2240)

Consideration of Ethnic Factors
Intrinsic Factors
Body weight (Rosiglitazone)
Genotype of drug metabolizing enzymes (Omeprazole and
Tolterodine etc.)
Genotype of drug transporter (Statins)
Metabolized by CYP3A4/5 (Nifedipiene and Simvastatin etc.)
Renal function (Fluconazole)
Extrinsic Factors (Practical circumstances)
Protocol (subjects, operation, meal, etc.)
Analytical method and sites
Ethnic Factors in PK from Literature Study
Drug Information Association www.diahome.org 20

Ethnic Difference in Pharmacokinetics
Caffeine (CYP1A2)
Pioglitazone (CYP2C8)
Tolbutamide (CYP2C9)
Omeprazole (CYP2C19)
Lansoprazole (CYP2C19)
Nortriptyline (CYP2D6)
Retrospective Literature Study
Nifedipine (CYP3A4/5)
Nicotine (CYP2A6) Amlodipine (CYP3A4/5)
Rosiglitazone (CYP2C8)
Meloxicam (CYP2C9)
Tolterodine (CYP2D6)
Sorafenib (CYP3A4, UGT1A9)
Rosuvastatin (OATP1B1)
Simvastatin (CYP3A4/5, OATP1B1)
Moxfloxacin (UGT1A1, SULT2A1)
Ranitidene (Renal excretion)
Fluconazole (Renal excretion)
21

Globalization of Clinical Trials
Japan
15.7; 10.3%
Nature Rev Drug Discovery, 7: 13, 2008

Difference among East
Asian populations
PK Data of Japanese, Koreans, Chinese, and Caucasians
Difference between Japanese
and Caucasians
Comparing Japanese and Caucasians
No difference among East
Asian populations
No difference between Japanese
and Caucasians
Comparing among East Asians Comparing among East Asians
Difference among East
Asian populations
No difference among
East Asian populations
23