PMDA’s Perspectives in Global Clinical Data Evaluation for ... · 7th Annual Conference in Japan...

PMDA’s Perspectives in Global Clinical Data Evaluation for Drug Approval

April 15th, 2013

Yoshiaki Uyama, Ph.D. Pharmaceuticals & Medical Devices Agency (PMDA) Visiting Professor, Graduate School of Advanced Clinical Science, Chiba University Visiting Professor, Graduate School of Medicine, Nagoya University

7th Annual Conference in Japan for Asian New Drug Development April 15-16, 2013 | Nakano Sunplaza, Tokyo, Japan

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Recent trend of Dug-Lag in Japan

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FY2006 FY2007 FY2008 FY2009 FY20100

1

2

3

4

1.2

2.4

1.5 1.5

1

1.21

0.70.5

0.1

2.4

3.4

2.22

1.1

Lag in Development Time

Lag in Review Time

Drug

-Lag

(Yea

r)

Total Lag


Japanese：http://www.pmda.go.jp/operations/notice/2007/file/0928010.pdf

English：http://www.pmda.go.jp/operations/notice/2007/file/0928010-e.pdf

Japanese version English version

Basic principles on Global Clinical Trials

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Trends of Global Clinical Trials including Japan

5

0

5

10

15

20

25

30

0

50

100

150

200

250

300

350

400

% o

f MR

CTs

Num

bers

of C

TN

FY2007(4-9)

FY2008(10-3)

FY2009 FY2010 FY2011(4-9) (10-3) (4-9) (10-3) (4-9) (10-3) (4-9) (10-3) (4-9) (10-12)

FY2012


Operational Area of GCTs

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0

10

20

30

40

50

60

70

EastAsia only

Asia only

Asia+欧米

World wide

No Other Asia

Uncertain


Target Disease of GCTs

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Development Strategy for drug approval in Japan

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FY2007 FY2008 FY2009 FY2010 FY2011 FY20120

25

50

75

100

125

150

Total Bridging GCT

Num

ber

of A

ppro

ved

Dru

gs

Year As of December

0

2

4

6

8

10

12

14

16

18

% of Bridging % of GCT % of Asian GCT

%


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Name of Drug Indication Approval Tolterodine Overactive bladder with symptoms of urge urinary

incontinence, urgency, and frequency Apr. 2006

Insulin glulisine Diabetes mellitus Apr. 2009 Peramivir * Type A and Type B Influenza virus infection Jan. 2010 Temsirolimus Advanced renal cell carcinoma Jul. 2010 Laninamivir * Type A and Type B Influenza virus infection Sep. 2010

Edoxaban* Prevention of venous thromboembolism after major orthopedic surgery Apr. 2011

Indacaterol Chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Jul. 2011

Gefitinib EGFR-Positive unresectable or metastatic non-small cell lung cancer (NSCLC) Nov. 2011

Aripiprazole Manic episodes associated with bipolar disorder Jan. 2012

Exenatide Type II diabetes mellitus (adjunctive to diet, exercise and treatment with SU) Mar. 2012

Esomeprazol Risk reduction of low-dose asprin-induced gastric or duodenal ulcer Jun.2013

Stratera Attention-Deficit/Hyperactivity Disorder in adulthood Aug.2013 Insulin degludec* Diabetes mellitus Sep.2013 Insulin degludec/ Insulin aspart* Diabetes mellitus Dec.2013

Fesoterodine Overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency Dec.2013

Asian GCT-based Drug approval in Japan


New Guidance (Sep 5th 2012): Basic principles on Global Clinical Trials

(Reference Cases)

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日本語：http://www.pmda.go.jp/regulatory/file/guideline/new_drug/GCT_jirei.pdf 英語：http://www.pmda.go.jp/regulatory/file/english_guideline/new_drug/GCT-jirei_en.pdf


• Accumulating new scientific knowledge and regulatory experiences after the publication of the 2007 guideline

• Diversifying a cooperation style between Japan and other countries; e.g. Asian GCT, Large-scale GCT

• Reinforcing the regulatory cooperation among Japan, China and South Korea as well as that among Japan, U.S. and Europe.

Background of the New Guidance

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Further promotion of GCTs, especially in East-Asian region, is the key to successful drug development


• Data from well-designed and conducted global clinical trials in East Asia is acceptable for new drug application in Japan.

• To conduct East Asia GCT appropriately and successfully, it is necessary to consider impacts on drug efficacy/safety of ethnic factor among East Asian populations before starting the trial

• Further accumulation and review of scientific data and information on East Asian populations will deepen our understanding of ethnic differences and ensure a smooth and appropriate conduct of global clinical trials in this region.

• It is encouraged to consider to include global clinical trials to be conducted in East Asia as part of drug development plan and accumulate information.

Major points in the new guidance (Special points to consider in East-Asian GCTs: 1/2)

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Major points in the new guidance (Special points to consider in East-Asian GCTs: 2/2)

• East-Asian GCT can be performed in any disease • Proactive planning of East-Asian GCT is encouraged

especially for diseases with high morbidity in East Asia (e.g., gastric cancer and hepatitis)

• Positioning of East-Asian GCT in entire global development plan should be clarified in advance

• All activities in East Asia should be carried out in cooperation with those in the U.S. and Europe.


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Major points in the new guidance (Other points to consider)

• Daily cooperation with foreign partners (Affiliate, HQ, other regulatory agency etc.)

• Optimize a strategy based on collected data • Acceptability of foreign population data on PK/PD • Sample size calculation in case of large-scale GCT • Safety assessment based on GCT, especially describing

an importance of Japanese data on long-term safety evaluation


Classification of development strategies based on PK-profile

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Major difference

No major difference

No major difference

Major difference

PK comparison among East-Asian population

Regional study in East Asia

World wide collaboration

Collaboration study in

Japan/US/EU Local study in Japan

Comparison of PK between Japanese and Caucasian

Major Difference No Major difference

PK comparison among East-Asian population


Future GCTs

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• Effects of ethnic factors on drug efficacy/safety should be more characterized

• Methods for planning/evaluation should be established – Sample size calculation, consistency

evaluation etc. • Regulatory harmonization

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Challenges for better GCTs

Advancing regulatory science


• China/Korea/Japan Tripartite Working Group • MHLW Research group (Kawai study group, Saito study group)

– Examining impacts of ethnic factor on drug efficacy/safety

– Clarifying points to consider in better planning and data evaluation of GCTs

Regulatory Science Research

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Development Strategy

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Japan

Other Asia

US/EU

PK, Safety

Exploratory, Dose-Finding

Confirmatory POC

Japan only

West only



20

Japan

Other Asia

US/EU

PK, Safety


Confirmatory POC

Japan only

West only

J/W GCT

J/W GCT

Japan/West



21

Japan

Other Asia

US/EU

PK, Safety


Confirmatory POC

Japan only

West only

J/W GCT

J/W GCT

Early Japan/West

J/W GCT



22

Japan

Other Asia

US/EU

PK, Safety


Confirmatory POC

Japan only

West only

W/J/EGCT

W/J/EGCT

West/Japan/ Asia



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Japan

Other Asia

US/EU

PK, Safety


Confirmatory POC

Japan only

West only

Asian GCT

Asian GCT Asia



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Japan

Other Asia

US/EU

PK, Safety


Confirmatory POC

Japan only

West only

Asian GCT

Asian GCT Asia

Asian GCT

Asian GCT Early

Asia

Asian GCT



25

Japan

Other Asia

US/EU

PK, Safety


Confirmatory POC

Japan only

West only

W/J/EGCT

W/J/EGCT

W/J/E GCT

W/J/E GCT

Asia Leading East

Asian GCT



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Japan

Other Asia

US/EU

PK, Safety


Confirmatory POC

Japan only

West only

Asian GCT

Asian GCT

Real Asia

Asian GCT

Asian GCT

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EU North America USA

Canada Asia

Drugs from Asia to the world

Cooperation for better drug developments

Pharmaceuticals & Medical Devices Agency

Information

• HOMEPAGE (English) http://www.pmda.go.jp/english/index.html

• Regulatory Science Page http://www.pmda.go.jp/regulatory/index.html

• E-mail: [email protected]

Thank you for your attention

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