Efforts on the Japanese side Session 1: Enhancing Review Efficiency of Pharmaceuticals and

Medical Devices

Naoyuki Yasuda

Office Director

Office of International Programs

Pharmaceuticals and Medical Devices Agency

4 October, 2016

1. Introduction

2. Promotion of Regulatory Science to the Global Level

3. Promotion of Developing Innovative Products

Today’s Content

1. Introduction

Today’s Content

As at 2006, new drug marketing in Japan lagged on average 4 years behind the initial

global launch, a gap of around 2.5 years over the US, the country with the smallest lag. *

1,417 days（＝approx. 4 years）

915days

757days

620 days 583 days 538 days 512 days

505 days

（＝approx. 1.5 years）

Japan France Denmark Germany Sweden Switzer- land UK US

* The average of the number of days until marketing in the respective country following initial launch of the global top 100 products. Since the number of the top 100 products available varies with the country, the marketing lag has been calculated using only the number of products marketed in the respective country. For example, for the US where all drugs are available it was calculated using 88 of the 100 best-selling drugs after deduction of duplicate ingredients and those launched prior to 1981. Source: OPIR Research Paper No. 31 (May 2006)

Gap between Japan and the US Approx. 2.5 years

Drug Lag – What did PMDA solve??

4

319

256

648

521

678

605

753

341

426

291

708

1065

PMDA Staff Size

820

0

200

400

600

800

1000

1200

2004.4 2005.4 2006.4 2007.4 2008.4 2009.4 2010.4 2011.4 2012.4 2013.4 2014.4 2015.4 2018

Administrative part Safety Department

Review Department Planned

Enhancement of Consultation from earlier stage

© 2015 DIA, Inc. All rights reserved.

Exploratory Research

Optimization Research

Non-clinical

trial

Development Research Research with specific objectives (disease treatment, etc.) aiming at practical use

Applied Research

Basic Research

Clinical Trial

Application

Review

-> Approval

［Old Model]

Consultation

［New Model]

Consultation

LATER SATGE

EARLIER SATGE

Accelerate the application & approval period

Utilization to Int’ Guideline (e.g. ICH/GL)

© 2014 DIA, Inc. All rights reserved.

http://www.cirsci.org/wp-content/uploads/2016/05/CIRS_RD_-Briefing_59_23052016.pdf

PMDA achieved shorting approval time of new drug

R&D Briefing 59, May 2016, © Centre for Innovation in Regulatory Science, Ltd.

2. Promote Regulatory Science to the Global Level

Today’s Content

Science Board Established in May 2012； to discuss how PMDA can better cope with products with advanced science & technology, in each developmental stage (basic research, development support, product review, and PMS).

Pharmaceutical consultation on R&D

Strategy

Basic Research

Seeds of new

drug / medical devices

Non-clinical tests

Clinical Trial

Quality Tests Practical use

Innovative medical products

Offices of Review (Drugs & Medical Devices), Office of Safety

Clinical Trial Consultation

Review

Review Approve Post Marketing

Post Marketing Safety Measure

Board members

Academia (Knowledge of the Latest Innovative Technologies)

Science Board

9 Communication

Outcome of the Science Board

Summary of discussion on the assessment of the current status of personalized medicine related to development and regulatory review (2014)

Summary of discussion on non-clinical pharmacological studies on anticancer drugs (2013)

Current perspective on evaluation of tumorigenicity of cellular and tissue-based products derived from induced pluripotent stem cells (iPSCs) and iPSCs as their starting materials (2013)

1st term (FY2012 - 2013)

2nd term (FY2014 - 2015)

Discussion on Evaluation of Medical Devices in Pediatric Use (2015) Proposal on Basic Principle to Quality Assurance of Cell Therapy (CT) Products (2015) Report on the use of non-clinical studies in the regulatory evaluation of oncology drugs

(2016) Current Status and Perspectives of Placebo-Controlled Studies (2016) Report on the Use of Numerical Analysis for Evaluating the Strength of Orthopedic

Implants (2016)

3rd term (FY2016 - 2017)

Topics are now in discussion (rare diseases, bottle neck of medical development, and artificial intelligence)

Harmonization to International Guideline/Standards

[Pharmaceutical area]

• Participation to ICH

• Participation to PIC/S

• Bilateral talking with US/Europe on each area & GCP inspection

[Medical Devices area]

• Participation to IMDRF (GHTF)

• Participation to ISO/IEC standard setting (horizontal)

11

Can avoid duplicative works and seek common data utilization

Under the harmonization

3. Promotion of Developing Innovative Products

- Pharmaceutical Affairs Consultation on R&D Strategy

- SAKIGAKE Designation

- Conditional and Time-limited Authorization of Regenerative Medical Products

- Utilization to International Standards on Medical Devices

Today’s Content

(1) Pharmaceutical Affairs Consultation on R&D Strategy

© 2015 DIA, Inc. All rights reserved.

Exploratory Research

Optimization Research

Non-clinical

trial

Development Research Research with specific objectives (disease treatment, etc.) aiming at practical use

Applied Research

Basic Research

Clinical Trial

Application

Review

-> Approval

［Old Model]

Consultation

［New Model]

Consultation

LATER SATGE

EARLIER SATGE

Communication from the early development

Seamless Activity from Research to Approval - Collaboration PMDA & AMED -

© 2015 DIA, Inc. All rights reserved.

Exploratory Research

Optimization Research

Non-clinical

trial

Development Research Research with specific objectives (disease treatment, etc.) aiming at practical use

Applied Research

Basic Research

Clinical Trial

Application

Review

-> Approval

Drug Discovery Support Network

AMED*

Pharmaceutical Affairs Consultation

On R&D Strategy (Scientific Advice)

PMDA

Close Collaboration • Japan Agency for Medical

Research and Development

1.Utilizing Pharmaceutical Affairs Consultations on R&D

Strategy

3. Mutual cooperation to improve clinical research

infrastructures

4. Sharing information

2. Support AMED to evaluate projects

Partnership Agreement with AMED (August 19, 2015)

1. Research and Development on Medical issues

2. Foundation of Clinical Study

3. Support towards commercialization

4. Promotion of International Strategy

Japan Agency for Medical Research and Development (AMED) was established on 1 April, 2015, with following missions

Collaboration with other Organizations

Comprehensive Partnership Agreements since FY 2015

NCC (National Cancer Center) (February 2, 2016)

Hiroshima University (March 4, 2016)

Keio University (March 11, 2016)

• Joint Research

• Human Resources Development

• Information Dissemination

Joint Graduate School Agreement （December 2009- ）

with 19 graduate schools in medicine: Personnel Exchanges

Expansion and

Improvement

University of Tsukuba (March 30, 2016)

National Center of Neurology and Psychiatry (July 11, 2016)

Designation Criteria

- New mechanisms compared to existing approved products

- Medical products for diseases in dire need of innovative therapy

- Applied for approval firstly or simultaneously in Japan

- Prominent effectiveness can be expected based on non-clinical study and early

phase of clinical trials

Advantage for Designated Products

Prioritized Consultation

[Waiting time:

2 →1 month]

Review Partner

[PMDA manager

as concierge]

Post Market Measures

[Extension of re-examination

period considered]

Prior-Review

Consul.

(Rolling Review)

Prioritized Review

[12 → 6 months]

(2) SAKIGAKE Designation

SAKIGAKE - General Timeframe

18

Designated:

6 Pharmaceuticals, 2Medical Devices, 3 Regenerative Products

Progress of SAKIGAKE Designation System Comprehensive Evaluation Consultations in SAKIGAKE System

Approval NDA

Submission

Review

1. CMC

2. Non-Clinical

3. Clinical

4. GCP/GLP

Compliance

5. GMP

Compliance

ca. 4 months

First

submission

I/A

(on-site Inspection) Preparation

On-site Inspection Phase

III

Preparation

On-site Inspection (on-site inspection)

= Permission to

submit

I/A

Inquiry/Answer

6 months

Monthly

Consultation

with Concierge

SAKIGAKE Designated Products (Drugs, as of Oct. 2015)

Name of drug Proposed indication Name of applicant

Sirolimus (NPC-12G) Angiofibroma associated with tuberous sclerosis Nobelpharma Co., Ltd.

NS-065/NCNP-01 Duchenne muscular dystrophy (DMD) Nippon Shinyaku Co., Ltd

S-033188 Influenza A or B virus infection Shionogi & Co., Ltd.

BCX7353 Management of angioedema attacks in patients with hereditary angioedema (HAE)

Integrated Development Associates Co., Ltd.

ASP2215 First-relapsed or treatment-resistant FLT3 mutation-positive acute myeloid leukaemia Astellas Pharma Inc.

Pembrolizumab (genetical recombination)

Unresectable, advanced and recurrent gastric cancer MSD K.K.

SAKIGAKE Designated Products (Medical Devices and Regenerative Medical Products, as of Feb. 2016)

Name of medical products Proposed indication Name of applicant

Titanium Bridge

(Hinge-type plate with titanium) Adduction-type spasmodic dysphonia Nobelpharma Co., Ltd.

Bioresorbable adhesion barrier

(THN-01: Trehalose solution) Postoperative adhesion prevention

Otsuka Pharmaceutical Factory,

Inc.

STR01

(Autologous bone marrow-derived

mesenchymal stem cell)

Nerve syndrome and dysfunction caused by spinal

cord injury NIPRO Medical Co., Ltd.

G47△

(Growth-controlled oncolytic

herpes simplex virus type 1)

Malignant glioma Daiichi Sankyo Co., Ltd. The University of Tokyo, Institute of Medical Sciences

Autologous cardiac

progenitor/stem cells

Pediatric congenital heart disease (single ventricle physiology)

Japan Regenerative Medicine Co.,

Ltd.

(3) Conditional and Time-limited Authorization of Regenerative Medical Products

Re-Application (or Expiration) within max. 7yrs

Conventional Regulatory Approval Process

Clinical trial (likely to

predict efficacy,

confirmation of

safety)

Marketing further confirmation of efficacy

and Safety

Clinical

research

Marketing

Authorization or

Revocation of the

conditional approval

Conditional

and time-

limited

authorization

Continued

marketing

Clinical trial (Confirmation of efficacy and safety)

Clinical

research

Mark

eti

ng

Approval

Regulatory System that Facilitate Early Patient Access

Regenerative Medical Products Approval

HeartSheet ® for serious heart failure due to ischemic heart disease

(conditional and time-limited authorization – 5 years, conducting post-

marketing efficacy studies)

1 Product approved on 18 September 2015 Note: application in September/in October 2014

Conditional approval requirement (part)

I. Confirmation of efficacy (survival) with 60 HeartSheet

cases vs 120 existing treatment cases

II. Time limitation of approval: 5 years

・ Target: Serious heart failure due to Ischemic Heart Disease

・ Product: Autologous skeletal myoblast

・ Manufacturing Process - Biopsy from Quadriceps -> manufactured at company CPF -> sheet culture in hospital CPF

[Conditional and time-limited authorization(HeartSheet ®)]

Conditional approval requirement (part)

I. Confirmation of efficacy (survival) with 60 HeartSheet cases vs 120 existing treatment cases

II. Time limitation of approval: 5 years

Figures quoted from the company

press release docs

Demonstrating Conformity Assessment

25

Essentia

l Prin

cip

les

Test1

Test5 Test4

Test3

Test2

Test1 Test4

(Standards) Test3

Test2

Test1

Test2

(Standards) Test3

(Standards)

Merits of Standards

Enhance transparency

Reduce duplication

Reduce Oversight

26

Time saving

Cost saving

Enhancing Safety and Efficacy

Technologies beyond Standards

27

Exis

ting t

echnolo

gie

s

MD1 MD2 MD3

Innovative T

echnolo

gie

s

Sta

ndard

s

Com

pete

ncy o

f Revie

ws

IMDRF Strategic Priority

The MC will select further New Work Items (NWIs) to improve

the effectiveness and efficiency of premarket review. These may

include assuring the reliability of data submitted to regulatory

bodies, improving quantity and quality of clinical data, developing

Good Review Practices for premarket reviews/evaluations which

includes competence and training for pre-market reviewers,

developing guidance on benefit-risk determinations, and

improving the suitability of international standards for

regulatory authorities and effective regulatory authority

involvement at each stage in standards development.

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Thank you for your attention!!