pmda perspective: recent trends in the regulation of ... · regulation of biopharmaceuticals....

1Pharmaceuticals and Medical Devices Agency

Kazuhiko Chikazawa Director

Office of Cellular and Tissue-based Products

Pharmaceuticals and Medical Devices Agency (PMDA)

The views and opinions expressed in this presentation are those of the presenter and should not necessarily represent the views and opinions of the PMDA.

CMC Strategy Forum Japan 2016, December 5-6, 2016, Tokyo Marriot Hotel, Tokyo, Japan

PMDA Perspective: Recent Trends in the

Regulation of Biopharmaceuticals


PMDA Asia Training Center (PMDA-ATC)

SAKIGAKE Designation System

Biosimilars

Japanese Pharmacopoeia (JP)

Post-Approval Changes (ICH Q12)

Outline


PMDA International Strategic Plan 2015

International Pharmaceutical Regulatory Harmonization Strategy



Asian Training Center (PMDA-ATC)


Past and Upcoming Events/Symposia

PMDA-ATC Pharmaceuticals Review Seminar 2016 (Jul 25-29, 2016)

PMDA-ATC Pharmaceuticals Review Seminar 2016 in Bangkok Thailand (Sep 26-29, 2016)

PMDA-ATC Medical Devices Seminar 2016 (Nov 7-11, 2016)

PMDA-ATC GMP Inspection Seminar 2016 (Dec 5-9, 2016)

PMDA-ATC MRCT Seminar 2017 (Jan 23-26, 2017)

PMDA-ATC Pharmacovigilance Seminar 2017 (Feb 6-9, 2017)

Further informationhttps://www.pmda.go.jp/english/symposia/0044.html




Biosimilars



Outline



The MHLW drew up the “Strategy of SAKIGAKE” to lead the world in the practical application of innovative medical products in 2014.

http://www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/140729-01.html

Designation criteria for SAKIGAKE designation system Medical products for diseases in dire need of innovative therapy Development & NDA in Japan being world’s first or simultaneous

with other countries Prominent effectiveness expected on non-clinical and early phase

clinical trials

SAKIGAKE designation system Scheme for rapid authorization of

unapproved drugs


General Timeframe for SAKIGAKE Designation System

Non clinical studies, Clinical studies

Clinical trials I/II

2 m. 12 m.

Practical application of

Innovative medical products

1 m.

6 m.

③ Priority Review

② Prior-review

① Priority Consultations

④Review Partner System

⑤Strengthening Post-Marketing Safety

【Standard】

【SAKIGAKE】

Consultation

on Clinical

trials

phase III study ReviewReim-burse-ment

Post-Marke

ting

Pharmaceutical affairs

consultation for R&D strategy

Non clinical studies, Clinical studies

Clinical trials I/II

Consul-tation

on Clinical trials

phase III study

Fore-runner review assign-ment

Prior review (rolling submission)

Review

Post-Marke

ting

※ In some cases, may acceptphase III data during review

Reim-burse-ment

Pharmaceutical affairs

consultation for R&D strategy


Product name Expected indication company

SirolimusVascular fibroma associated with

tuberous sclerosisNobelpharma

NS-065 / NCNP-01Duchenne muscular dystrophy

(DMD)NihonShinyaku

S-033188 Influenza A or B virus infection Shionogi

BCX7353

Management of angioedema

attacks in patients with hereditary

angioedema (HAE)

Integrated Development

Associates

ASP2215

First-relapse or treatment-resistant

FLT3 gene mutation-positive acute

myeloid leukemia

Astellas Pharma

PembrolizumabUnresectable, advanced and

recurrent gastric cancerMSD

SAKIGAKE designated pharmaceuticals


SAKIGAKE designated

Product name Expected indication company

Titanium Bridge (Hinge-

type plate with Titanium)

Adduction-type spasmodic

dysphoniaNobelpharma

Bioresorbable

adhesion barrier (THN-

01: Trehalose solution)

Postoperative adhesion prevention

Otsuka

Pharmaceutical

Factory

STR01 (Autologous bone

marrow-derived

mesenchymal stem cell)

Nerve syndrome and dysfunction

caused by spinal cord injuryNIPRO

G47△

(Growth-controlled

oncolyticherpes

simplexvirustype 1)

Malignantglioma

Daiichi Sankyo

The University of

Tokyo, Institute of

Medical Sciences

Autologous cardiac

progenitor/stem cells

Pediatric congenital heart disease

(single ventricle physiology)

Japan Regenerative

Medicine

Medical devicesRegenerative medical products


2nd Round of SAKIGAKE Invitation

1st forPharmaceuticals

1st forMedical devices,

In-Vitro Diagnostics, Regenerative medical products

2nd forPharmaceuticals

Announcement 2015. Apr 1 2015. Jul 1 2016. Oct 3

Invitation 2015.May 8 - 29 2015. Sep 14 - Oct 7 2016 Oct 3 – Nov 22

Designation 2015. Oct 27 2016 Feb 10 ????




Biosimilars



Outline


2009 2010 2011 2012

Q&A

Somatropin BS [Sandoz]

Epoetin alfa BS [JCR]

2013

Regulatory History and Status of Biosimilars

Filgrastim BS [F], [MOCHIDA]

Filgrastim BS [NK], [TEVA]

• Application Category for biosimilars• Guideline• Nomenclature rules

Q&ARevision of Nomenclature rules

2014

Filgrastim BS [Sandoz]

Infliximab BS [NK], [CTH]

2015

Insulin glargine

BS [Lilly]

2016

Q&A

Insulin glargine

BS [FFP]


Multidisciplinary Non-Japan approved reference product Data required when submitting first

notification for clinical trials

Quality Comparative bioassays for mAbs Reference standard

Non-clinical Need for toxicity studies

Overview of new Q&As (published on Dec 15 2016)

Clinical Japanese population data Comparative PK studies

– Route– Equivalence margin

Comparative efficacy studies– 95% CI

– Population

Indication extrapolation for mAbs

Post-marketing surveillance Reporting procedure


Is toxicity study (repeat-dose toxicity study) required for biosimilar development?

Basically, a company should evaluate the non-clinical safety of biosimilar candidate itself prior to entering into clinical studies, in accordance with ICH S6 (R1).

However, in cases where there is no concern on non-clinical safety based on characterization studies and comparative comparison of the physicochemical and pharmacological properties, in vivo toxicity studies may be not required.

This approach should be on a case-by-case basis. PMDA recommends to use our consultations


Consultation for Biosimilars

Fiscal year

No

. of

con

sult

atio

ns

2006 2007 20082009 2010 20112012 20130

5

10

15

20

25

Based on date of application

(from April 1 to March 31)

2014

<Number> <Product type>

(66%)2015

mAbs & Fc-fusion proteins, 42

Hormones, 3

ESAs, 7

Insulins(incl. analogues), 5

G-CSFs, 4

FSHs, 2

Enzymes, 1

30

2016

As of October 31


Recent Trends of Biosimilars in Japan

Biosimilar･･･

@ National Diet in March 2015


Challenge in Biosimilar Development in Japan

non-Japan sourced RP

….

Biosimilar Japan sourced RP

Reference Product (RP)

Biosimilar company should confirm the comparability to the RP which is approved (and used by healthcare providers and patients) in Japan.

However, if the company needs to use non Japan-sourced RP in comparability exercise, it is required to explain that the non- Japan sourced RP is the representative of the Japan sourced RP by analytical assays and publicly available information.




Biosimilars



Outline


History and Legal Status of JP

Under the Article 41.1 of PMD. Act, the MHLW establishes and publishes the JP.

Article 41.1:To standardize and control the properties and quality of drugs, the Minister shall establish and publish the JP, after hearing the opinion of the Pharmaceutical Affairs and Food Sanitation Council.

JP was first published in June,1886 and implemented in July, 1887. => 130th Anniversary!

JP has been revised periodically.

The 17th edition came into effect on April 1, 2016 under the Ministerial Notification No.64.

JP English electric ver. can be downloaded free of charge from the JP English website; http://www.pmda.go.jp/english/rs-sb-std/standards-development/jp/0010.html

http://www.pmda.go.jp/english/rs-sb-std/standards-development/jp/0010.html


JP17 at a Glance

1. Notification of MHLW2. Contents3. Preface4. General Notices5. General Rules for Crude Drugs6. General Rules for Preparations7. General Tests (78 General Tests)8. Official Monographs (1962 Monographs)9. Ultraviolet-visible Reference Spectra10. Infrared Reference Spectra11. General Information (50 General Information)12. Table of Atomic Mass as an appendix13. Cumulative Index

Official Monographs<Scope> Chemical Substances/Products Biological Substances/Products Vaccines and Blood Products, whose

specifications are referred to another official standard: “Minimum requirement for biological products”

Herbals<Out of scope> Gene Therapy Products Cellular and Tissue-based Products


Challenge for biotherapeutic products in JP

Establishment of general rules regarding quality assurance of biotherapeutics

Listing test methods to be applied for biotherapeutics

Listing official monographs for biotherapeutics




Biosimilars



Outline


From Richard Lit, 2013 APEC Harmonization Center Biotherapeutics Workshop

Complex Lifecycle Management in the World

From Susanne Ausborn, CMC Strategy Forum Europe 2014

From Stefanie Pluschkell, WHO/MFDS Implementation Workshop: Evaluation of biotherapeutic products 2014


Issues to be addressed in ICH Q12 Regulatory Dossier Explore the development of a harmonised approach to “regulatory commitments” for inclusion in the

guideline. Such approaches could enable post approval changes that facilitate continual improvement and encourage the adoption of innovative technologies.

Delineate the appropriate level of detail and information necessary for regulatory assessment and inspection in the dossier, in order to create a more enabling post approval change management system.

Pharmaceutical Quality System (PQS) aspect Establish criteria for a harmonised risk-based change management system based on product, process

and/or clinical knowledge that effectively evaluates the impact of change on quality, and, as applicable to safety and efficacy.

Clarify expectations and reinforce the need to maintain a knowledge management system that ensures continuity of product and process information over the product lifecycle.

Post-Approval Change Management Plans and Protocols Introduce the concept of a post-approval management plan that can be used to proactively identify

post-approval changes and the mechanism to submit and assess these changes by regulatory authorities (Assessors and Inspectors)

Establish criteria for post-approval change management protocols that can be adopted by the ICH regions (enabling a harmonised proactive approach for lifecycle management)

Encourage enhanced product development and control strategy approaches (Quality by Design (QbD)) providing opportunities for scientific and risk based foundations for post-approval change management plans.

From ICH Q12 Concept Paper


PMDA ICH Q12 WG

PMDA Q12WG

AMED* research group

Industries

• Academia: from scientific viewpoint• Industry: from manufacturing experience• PMDA: from regulatory viewpoint, review experience

ICH Q12

MHLW

Research report/ Proposal

*: Japan Agency for Medical Research and Development


Investigation of Application Form

In 22,297/32,466 (69%), a discrepancy was found b/w Application Form and SOP.


Approved Matters = Established Conditions??

Module 2 (QOS)

Module 3

Module 1(AF)

Summarized

Japan

Extracted

Established Conditions

ICH

Module 3

?Approved Matters


Thank you for your attention!

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