advancing roles of japan on global drug development roles of japan on global drug development ethnic...

Advancing Roles of Japan on Global Drug Development

Ethnic factors consideration with a view to International Harmonization

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Dr Yoshiaki UyamaPharmaceuticals & Medical Devices Agency

(PMDA)Visiting Professor, Graduate School of Medicine, Chiba UniversityVisiting Professor, Graduate School of Medicine, Nagoya University

11th Annual Meeting DIA JAPAN 2014 | November 16-18 | Tokyo Big Sight | Ariake

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

2007 GuidelineBasic Principles on MRCTs

3Japanese：http://www.pmda.go.jp/regulatory/file/guideline/new_drug/GCT_jirei.pdf

English：http://www.pmda.go.jp/regulatory/file/english_guideline/new_drug/GCT-jirei_en.pdf

2012 Guideline


FY2007 FY2008 FY2009 FY2010 FY2011 FY2012 FY2013 FY2014

0

5

10

15

20

25

30

% o

f GC

T % of GCT % of Bridging

Total 81 79 107 114 130 134 133 35MRCT 1 0 4 7 12 18 21 9Bridging 4 2 3 6 2 3 1 1

(Year)

As of July

Development strategies for drug approval in Japan

4


MRCTs have contributed to decreasing “Drug Lag”

5

Clinical development strategy

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

Lag

in d

rug

deve

lopm

ent

(day

s)

1111 days

Local

trial

(n = 69)

Local and

foreign trials

(n = 59)

Bridging

study

(n = 19)

Global

clinical

trial

(n = 18)

Foreign

trial

(n = 13)

No

efficacy/safety

trial (n = 5)

***

**

Ueno T et al, Clin Pharmacol Ther, 95, 533-41 (2014)


Regulatory Perspective: PMDA and FDA

Clin Pharmacol Ther. 2013;94:230-42. Clin Pharmacol Ther. 2013;94:195-8.

US FDA PMDA

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US FDA Perspective: Points consider in reviewing global clinical trial data

Points shown here are similar to those in Japanese guideline

7


Activities toward International Harmonization

8

012 | Tokyo, Japan


ICH E17 Guideline

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ICH E17 Guideline: MRCTs

In June 2014, the Steering Committee approved the establishment of the new expert working group (E17 EWG), focusing on “General principle on planning/designing Multi‐Regional Clinical Trials” with MHLW/PMDA as the Rapporteur.

This guideline provide common points to consider in planning/designing MRCTs and minimize conflicting opinions from regulatory bodies.

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Accomplishment in Lisbon

• Sharing regional perspectives as to what topics should be covered in this guideline.

• Reaching a consensus on a table of contents of E17 guideline

• Initiating to draft concrete sentences of some sections in the guideline

• Confirmed that E17 guideline is really important to improve current situation of global drug developemnt and promote simultaneous regulatory submission in multiple countries/regions


Current table of contents (E17)

1. INTRODUCTION1.1 Objective(s) of the Guideline1.2 Background1.3 Scope of the Guideline1.4 General Principles

2. General recommendations in planning/designing MRCT2.1 Strategy-related points

2.1.1 The value of MRCTs in drug development and regulatory approval

2.1.2 The basic requirements to conduct a MRCT2.1.3 Scientific consultation meeting with regulatory

agencies


Current table of contents (E17)

2. General recommendations in planning/designing MRCT2.2 Clinical trial design and protocol-related points

2.2.1 Pre-consideration of regional variability on efficacy/safety2.2.2 Subject selection2.2.3 Selection of doses in MRCTs2.2.4 Choice of endpoint/index2.2.5 Estimation of a sample size and a proportion of each regional

subjects in an MRCT2.2.6 Collecting and handling efficacy/safety information in MRCTs2.2.7 Statistical analysis plans that specifically address the features

of MRCTs2.2.8 Selection of comparator (where applicable)2.2.9 Handling concomitant medications or therapies in a MRCT

3. GLOSSARY


Current Timeline of the E17 guideline

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• First face-to-face EWG Meeting in November 2014 in Lisbon

• Discussion by e-mail and web-based conference: 4Q 2014 -1Q 2015

• Second F2F EWG Meeting in 2Q 2015 for coordinating opinions of all parties and delivering Step 1 document

• Third F2F EWG meeting in 4Q 2015 for adaption of Step 2document

• Public consultation: 4Q 2015 - 2Q 2016

• Revision of the guideline based on comments: 2Q 2016 - 4Q 2016 (depending on contents of comments recieved)

• Fourth face-to-face EWG Meeting for adaption of Step 4 document in 4Q 2016 or 2Q 2017

012 | Tokyo, Japan


ICH E6 Discussion Group

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Training for GCP Inspector

2009.06 Establishment of E6 Discussion Group under the Regulator Forum Regulator Forum=the International Pharmaceutical Regulator Forum

Since then, web‐meeting was regularly held Sharing regulatory experiences on GCP implementation and inspection

Identifying tasks for proper implementation of ICH‐GCP

2011.08 Start to prepare a document regarding general principles of GCP inspector education and training


Members

17

as of Feb 26, 2014

Japan PMDA Yoshiaki Uyama, Group Leader Tomoko Osawa Mari Shirotani Hideaki Ui

Australia TGA Anthony Gill Katherine Clark

Chinese Taipei FDA/CDE Horng-I Yeh Wen-Ting Liu

Korea KFDA Mee-Ryung Ahn Tea-Kyun Nam Hojin Oh

Russia Roszdravnadzor Evgeny Rogov

Singapore HSA Foo Yang Tang

EU Ana Rodriguez (EMA) Alexander Hönel (Austria AGES)

ASEAN Yuppadee Javroongrit (Thai FDA) Akanid Wapeewuttikorn(Thai FDA) Endang Woro (Indonesia BPOM) Ega Febrina (Indonesia BPOM) Farida Anwar (Indonesia BPM) Tan Ann Ling (Malaysia DRA) Joyce Cirunay (Philippines DRA)

GCC Khaled Alshahwan(Saudi FDA) Khalid Almowaizri (Saudi FDA) Ahmad M. Al-Ghamdi (Saudi FDA) Abdullah H AL-Hatareshah (Saudi FDA) Haitham A.Al-Hassan (Saudi FDA)

PANDRH Ileana Herrera Gallegos (Costa Rica DRA)

SADC Joseph Mthetwa (SADC Secretariat) Fortunate Fakudze (MoH Swaziland)

11th Annual Meeting DIA JAPAN 2014 | November 16-18 | Tokyo Big Sight | Ariake 18

• 15 page document• Introduction• Purpose• General steps for

training GCP inspector– step 1- step4

• Appendix 1- Appendix 3

General Principles for Training/Education of GCP Inspectors FINAL (May 23, 2013)

Uyama, Y. et al. Therapeutic Innovation & Regulatory Science, (2014)


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Possible strategies of future drug development


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Case 1：phase I study in Japanese population before initiating MRCTs

Is there any cases that conduct of phase I study in Japanese population is not necessary before joining a MRCT?

Japan

US/EUJ/WGCT

J/WGCT

Too late for joining


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• ３rd guideline specifically focusing on MRCTs

• Provides several cases for which phase I study is required or not required.

• Useful for planning an early phase of global drug development

Just Published:Basic principles on conduct of phase I study in Japanese

population before initiating MRCTs（October 27th 2014)


PMDA Workshop on MRCTs

22http://www.pmda.go.jp/operations/shonin/info/report/workshop20141215.html


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Case 2: Asia-leading drug development

• In some therapeutic area whose prevalence is higher in Asia (e.g.; gastric cancer, hepatitis etc.), can early phase of drug development (PI, POC, ePII etc.) be initiated in Asia?

• If yes, can later phase clinical trials be conducted globally, based on a hypothesis established by Asian data?


Japan

Other Asia

US/EU

PK, Safety

Exploratory, Dose‐Finding ConfirmatoryPOC

Japan only

West only

W/J/EGCT

W/J/EGCTAsian

GCT

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• PROS：

– More appropriately design a confirmatory trial based on Asian data

• Dose selection, Target population etc.– Provide more scientific evidences in Asian population

• CONS (Challenges)– Uncertainty about effects of extrinsic ethnic factors– How to define Asia? How much Japanese data are

required?– Acceptability of a hypothesis based on Asian data in

non-Asian countries


Pros/Cons


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Case 3: Genome-defined population

Can we define a population based on a specific genotype relating to drug responses rather than an ethnicity/race?

e.g.; molecular-target drug EGFR (+)

EGFR (-)Gefitinib

Calboplastin+Paclitaxel


Gefitinib


Gefitinib

Gefitinib: IPASS study


Case 3: Genome-defined population

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• PROS：

– Maybe not necessary to consider strictly about subject number from a country in a clinical trial

– Can select more objectively a target population based on genomic test results

• CONS (Challenges):– Need to develop CDx simultaneously– Uncertainty about effects of extrinsic ethnic factors– How much Japanese data are required?

Pros/Cons


Conclusion

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• Prepare for various strategies of drug development

• More scientific data and experiences facilitate activities of the international harmonization

More MRCTs with more international cooperation for providing more drugs earlier to patients


Information

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

• E-mail:[email protected]

Thank you for your attention

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