Latest Trend of Pharmaceutical and Medical Device Regulation in Japan

Takao Yamori, Ph.D.Executive Director

Pharmaceuticals and Medical Devices Agency (PMDA)

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Regulatory Authority in JAPAN

Scientific Review for Drugs & Medical Devices

GCP, GMP Inspection

Consultation on Clinical Trials etc.

Final Authorisation of applications

Administering laws, publishing legislations

Publishing Guidelines

Advisory committee

Supervising PMDA Activities

PMDAMHLW – PSEH BureauPharmaceutical Safety and Environmental Health Bureau,

Ministry of Health Labour and WelfarePharmaceuticals and Medical Devices Agency

Today’s topics

1. Review Process

2. International Collaboration

3. Summary

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New active substance (NAS) median approval time for six regulatory authorities in 2008-2017 (Pharmaceuticals)

Centre for Innovation in Regulatory Science (CIRS) , 2018, R&D Briefing 67

PMDA

333

EMA

419

FDA

243

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NAS median approval time by review type for six regulatory authorities in 2013-1017

Centre for Innovation in Regulatory Science (CIRS) , 2018, R&D Briefing 67

PMDA was the agency with the smallest difference

between expedited review median approval time and standard review median approval time in 2017.

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Reform to rational and efficient structure based on Regulatory Science

Lead the World in Regulatory Innovation

Stage Agendas for MHLW/PMDA Activity

Development Support for promising seeds to forward the

development

Regulatory Sceince Consultation(from July 2011)

Review Approaches to cutting-edge technologies

(including iPS Cells by collaboration with Academia)

Encourage Japan-first development and approvals

Improve efficiency of development and review process by utilizing electric data

Science Board(from June 2012)

SAKIGAKE Designation System(from 2015)

Conditional Early Approval System for Pharmaceuticals(from October 2017)

Post-marketing

○ Utilize medical information database to develop more

sophisticated safety measures

○ Predictability & Transparency in post-marketing change

control

MIHARI project (from 2009)

MID-NET project (from April 2018)

PACMP pilot (from April 2018)

Establishment of Regulatory Science Center (from April 2018)

*PACMP: Post-Approval Change Management Protocol

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SAKIGAKE Designation System

ConsultationClinical

Trial PhIII

Clinical Trial

Ph I/II

【Ordinal Review】

【SAKIGAKE 】

Review

Clinical

Trial PhIII

Clinical Trial

Ph I/IIPrior

Review

Priority Consultation

2 months

12 months

Priority Review

6 months

1 month

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Name of product

(Applicant)Summary of product Product indications

XOFLUZA Tablets 10mg/20mg

(baloxavir marboxil)

by Shionogi & Co., Ltd.

- an antiviral drug indicated for influenza

- novel mechanism

(suppresses influenza viral replication via inhibition of cap-

independent endonuclease enzymes required for viral mRNA

synthesis in host cells)

Influenza

Types A and B

図2 塩野義製薬株式会社プレスリリース資料から引用、一部改変

< Timeline of SAKIGAKE-designation >

Oct. 2015: Designated for SAKIGAKE

Novel mechanism of action developed in Japan (Shionogi & Co., Ltd)

Influenza Virus

Figure Excerpted with partial revisions from Shionogi’s original press release

Attachment

Released

from cell

Particle formation

Invasion

Membrane fusion Duplication of genome RNA

mRNA elongation

Polymerase inhibitor

(favipiravir)

Start of mRNA synthesis

(Cap endonuclease)

Neuraminidase inhibitor

(e.g. oseltamivir, laninamivir,

peramivir)

Cap-dependent endonuclease inhibitor

(baloxavir marboxil)

Viral genome

RNA

Feb. 2018: Regulatory approval

4 months

Oct. 2017: Submission

for marketing approval

Details of the product approved with SAKIGAKE-designation (Drug)

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Name of product

(Applicant)Summary of product Product indications

TITANBRIDGETM

(device for thyroid cartilage

fixation)

by Nobelpharma Co., Ltd.

- A medical device to be used for the treatment of adductor

spasmodic dysphonia

- novel mechanism

(preventing excessively tight closure of the glottis and maintaining

the glottis opening)

Type Ⅱ thyroplasty

< Timeline of SAKIGAKE-designation >

Feb. 2016: Designated for SAKIGAKE

Dec. 15, 2017: Regulatory approval

6 months

Jun. 30, 2017: Submission

for marketing approval

Novel mechanism of action developed in Japan

(Nobelpharma Co., Ltd)

Developed by Dr. Nobuhiko Isshiki, Prof. of Kyoto Univ.

Kumamoto Univ.

etc., cooperated to

conduct research

Manufactured by

Wakayoshi

Seisakusho Co.,

Ltd. (Fukui pref.)

Nobelpharma,

venture capital,

led them to

practical use

*There AMED research funding support of MHLW

Improvement of

dysphonia

Over-closing

prevention of glottis

Details of the product approved with SAKIGAKE-designation (MD)

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<Implemented on 20 Oct, 2017>

To realize early access to innovative treatments that are:

For severe diseases with limited choice of treatments

Difficult to conduct confirmatory clinical trials due to small number of patients or prolonged follow-up period

Conditional Early Approval System for Pharmaceuticals

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Accepted Pharmaceuticals for Conditional Early Approval scheme

Product Expected indication Marketing Authorization Applicant

Granted Date

Lorlatinib The treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on 1 or more ALK tyrosine kinases inhibitors (TKIs).

Pfizer 8 June 2018

Pembrolizumab(KEYTRUDA)

The treatment of patients with unresectable or metastatic, microsatellite instability-high(MSI-H) Cancer

MSD 22 June 2018

https://www.pfizer.co.jp/pfizer/company/press/2018/2018_06_12.htmlhttp://www.msd.co.jp/newsroom/msd-archive/2018/product_news_0627.xhtml

All medical technologies using processed cells

whose safety and efficacy have not yet been

established

The Act on Pharmaceuticals and

Medical Devices (PMD Act)

Production and marketing of regenerative

and cellular therapeutic products by firms

The Act on the Safety of

Regenerative Medicine

Commercial IND and

product approval

MHLW process PMDA process

At hospital

Regenerative

Medicine Products

Two acts regulating cellular-, tissue- and gene therapies(Regenerative medicine products)

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Clinical Trial Clinical research

Mar

keti

ng

Approval

Clinical Trial

First Approval

Marketing&

Clinical Trial

Permanent Approval

or Revocation

Clinical Research

↑Re-application

Conventional Pathway

E.g. Autologous skeletal myoblast

New scheme

Conditional & time-limited approval for cellular-, tissue-,

and gene-therapy products (Regenerative medicine products)

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Today’s topics

1. Review Process

2. International Collaboration

3. Summary

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:Cooperative Arrangement has been signed between the Interchange Association of Japan and East Asia Relations of Taiwan

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PMDA staff stationed at the agency

Joint symposium held Cooperative Arrangement signed

As of 23 Oct. 2017

Health Canada,Canada

FDA, the United

StatesUSP, the United

States

ANVISA, Brazil

Japan

Taiwan FDA,Taiwan

NPRA,Malaysia

NADFC,Indonesia

TGA,Australia

HSA,Singapore

Thai FDA,Thailand

CDSCO,India

ChP,China

MFDS,Korea

CFDA,China

MHRA,the UnitedKingdom

CBG-MDB,the Netherlands

Swissmedic,SwitzerlandAIF

A,Italy

ANSM,France

HPRA,Ireland

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MPA,Sweden

EMA, the European Union

EDQM, the Council of

EuropeWHO

EC, the European Union

URPL, Poland

Bilateral cooperation

Cooperative Arrangement on cooperation of pharmacopoeia signed

Confidentiality Arrangement signed

DKMA,Denmark

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FY 2018 Planned symposium

Month Country Contents (Location)

Feb. Thailand The 4th Joint Symposium (Bangkok)

Apr. India The 2nd Joint Symposium (Tokyo)

May. Korea The 2nd Joint Symposium (Seoul)

May. Indonesia The 3rd Joint Symposium (Jakarta)

Dec. Taiwan The 5th Joint Conference (Taipei)

FY 2017 Completed symposium （As of August, 2018）

Bilateral Symposium

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Month Country Contents (Location)

Apr. Thailand The 5th Joint Symposium (Bangkok)

Jul. Korea The 3nd Joint Symposium (Tokyo)

Aug. India The 3nd Joint Symposium (India)

Oct. Taiwan The 6rd Joint Symposium (Tokyo)

Dec. Brazil The 4th Joint Conference (Tokyo)

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Bilateral cooperation with India

11th April,2018; PMDA(Tokyo)

Information sharing on the

latest issues

Discussions toward the 3rd

India-Japan Symposium

Bilateral Meeting between PMDA/MHLW and MHFW/CDSCO

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Asian sites

PMDA Asia Training Center for Pharmaceuticals and Medical Devices Regulatory Affairs(ATC)

Japan

APEC

(1)Help raise the level of regulations in Asia as a whole

(2)Training seminar at PMDA, local prefectures in Japan and Asian with manufacturing site

visits

(3)APEC Center of Excellence (COE) for Training (Multi-Regional Clinical Trials and Pharmacovigilance)

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International Reputation of Asia Training Center

Attendance (FY 2017)

Nine training seminars and 235 attendees from 27countries/regions

More than 70% of attendees rated as “Very good” according to the

questionnaire

Official certificate of APEC LSIF RHSC Training Centers of

Excellence for Regulatory Science from APEC

Area: Global clinical trials/GCP inspection, pharmacovigilance

Stipulate utilization of ATC in the Joint Statement of ASEAN-

JAPAN Health Ministers (July 15th in 2017)

PMDA contributes to mutual understanding and cooperation in Asia 19

Contents Date Location

1 Pediatric Review June 11-14, 2018 Tokyo (PMDA)

2 Pharmaceuticals Review June 18-22, 2018 Tokyo (PMDA) and Toyama Prefecture

3 Good Registration Management(GRM)*

September 26-28, 2018

Taipei

4 Pharmaceuticals Review October 15-16, 2018 Naypyidaw, Myanmar

5 Medical Devices Review November 12-16, 2018 Tokyo (PMDA)

6 Good Manufacturing Practice(GMP) **

November 26-30, 2018 Utsunomiya, Tochigi Prefecture

7 Pharmaceuticals Review December 10-13, 2018 Jakarta, Indonesia

8 Multi-Regional Clinical Trial (MRCT)* January 21-24, 2019 Tokyo (PMDA)

9 Pharmacovigilance* February 4-7, 2019 Tokyo (PMDA)*APEC-LSIF-RHSC CoE Workshop **With the support of PIC/S

Asia Training Center: Training Seminar 2018

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Today’s topics

1. Review Process

2. International Collaboration

3. Summary

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Summary 1

1. Adapt for innovative science technology

Through innovative science and technology, it will become possible to treat hard-to-treat diseases.

It will become necessary to be more cautious in development/approval/post-marketing safety measures

To start the new initiative, it will be necessary to improve and make existing work more efficient.

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Summary 2

2. Cooperation between reliable regulatory agencies

Using the review results and the outcomes of reliable regulatory authorities

Using the resources freed through operational streamlining for adapting to new technology such as regenerative medicine.

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Summary 3

3. International harmonization activities

International harmonization is important

Active participation in international harmonization activities such as ICH and PIC/S.

Thank you for your attention25

Work Together for patients!!