early regulatory approval, lesson learned from...

Early Regulatory Approval,lesson learned from Japan

30 August, 2016

Junko Sato, PhD

International Coordination Officer, PMDA

[email protected]

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Today’s Agenda

• Who we are and what we do

• Clinical Trial Notification

• PMDA Consultation

• J-NDA Preparation, Submission, and Approval

• Safety Management

• Key to a successful NDA filing / approval

• Our Future

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“Japan's PMDA and Health Canada may have had the most notable improvements over the past decade.” Regulatory Affairs Professionals Society 14 January 2015

Japan’s Performance on NDA Review

Today’s Agenda







• Our Future

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5

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Kansai Branch

Pharmaceuticals and Medical Devices AgencyDate of Establishment : April 2004

PMDA Homepage:http://www.pmda.go.jp/english/index.html

http://www.pmda.go.jp/english/index.html

PMDA continues to improve the public health and safety of ournation by reviewing applications for marketing approval ofpharmaceuticals and medical devices, conducting safetymeasures, and providing relief to people who have sufferedfrom adverse drug reactions.We conduct our mission in accordance with the following principles:

We pursue the development of medical science while performing our duty withgreater transparency based on our mission to protect public health and the lives ofour citizens.

We will be the bridge between the patients and their wishes for faster access tosafer and more effective drugs and medical devices.

We make science-based judgments on quality, safety, and efficacy of medicalproducts by training personnel to have the latest technical knowledge and wisdom intheir field of expertise.

We play an active role within the international community by promotinginternational harmonization.

We conduct services in a way that is trusted by the public based on our experiencesfrom the past.

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(September, 2008)Our Philosophy

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PMDA’s Three Major ServicesSafety Triangle

- Comprehensive risk management undertaken by three operations -

SafetyContinuous

risk mitigation efforts

ReviewReduction

in risk

Relieffor health

Damage by ADRs

Japanese

Citizens

World-class pharmaceutical regulatory system for

protecting the safety of the people

As the only regulatory authority in the world which plays three roles in an integrated

manner, PMDA contributes to improve the standard of medical care by delivering safer

and higher quality products faster to medical practice based on regulatory science

Key milestones in product lifecycle

Non-clinical

Phase 1

Phase 2

Phase 3

J-NDA prep

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PMS and PhV

PMDA: consultations throughout development stage

PMDA: review/inspections/communication with applicant

MHLW and outside experts: review for final decision

PMDA: construct post-marketing safety measures

CoD = Committee on Drug PAC = Pharmaceutical Affairs Council

Review PACCoDExpDiscussion

PMDA Staff Size

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 2018

Administrative part Safety Department

Review Department Planned

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Today’s Agenda







• Our Future

10

Clinical Trial in Japan

• Clinical trials intended for application for marketing approval under Pharmaceutical Affairs Law (PAL)

• Study must be conducted in compliance with GCP. • Clinical trial notification (CTN) must be submitted per protocol, in

order to start the study.

1st CTN: NCE, new route of administration, trial with a new dose. 1st CTN must be submitted at least more than 30 calendar days beforethe day of planning on contract with the medical institutions.

Nth CTN: any other study with a new protocol. Nth CTN must be submitted at least around 2 weeks before the day of planning on contract with the medical institutions

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Documents for 1st CTN

1. Clinical Trial Notification (CTN)2. Scientific Justification to start the clinical trial3. Protocol4. Informed Consent Document5. Case Report Form6. Investigator’s Brochure

If any are prepared in foreign language, Japanese translation is required, and review is conducted for Japanese translation.

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Image of what happens during 1st CTNSunday Monday Tuesday Wednesday Thursday Friday Saturday

1 2 3 4 5 6

7 8 9 10 11 12 13

14 15 16 17 18 19 20

21 22 23 24 25 26 27

28 29 30

P: review contents of the 1st CTN package

P: send inquiry to sponsor

P: receive response by

sponsor

S: sponsor submit revised documents

★End of 30-day review

Administrative period at MHLW

S: prepare response

P: review response/ confirm the contents via phone, send another inquiry, etc

P: prepare report to MHLW

P: forward result to MHLW

P&S: agree on responses

S: 1st CTN submitted by sponsor

S: Sponsor, P: PMDA

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Today’s Agenda







• Our Future

14

PMDA Consultations: what we do

PMDA offers consultations to give guidance and advice on clinical trials of drugs, medical devices, and cellular and tissue-based products as well as on data for regulatory submissions.

In clinical trial consultations for new drugs, PMDA checks whether a proposed clinical trial complies with the requirements for regulatory submission, taking into consideration the ethical and scientific aspects and reliability of the clinical trial as well as the safety of

trial subjects, and also gives advice to facilitate the improvement of the clinical trial.

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PMDA Profile of Services (2014-2015) http://www.pmda.go.jp/files/000151997.pdf

http://www.pmda.go.jp/files/000151997.pdf

Synthesis,

isolation

Pharmacology

Toxicology

Pre-P1 Consul

Clinical Trial

2 – 10 years (average of 5 years)

Phase 1

Phase 2

End of P2Consul

Phase 3

Pre J-NDA Consul

CT

N

Su

bm

issio

n

SD / MD study

Pre Late P2 Consul

30 days

Drug Development and PMDA Consultation

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Non-clinical

Review

Pre-early P2

Consul

Would the rationale for bridging strategy be

acceptable for approval?

Is the endpoint acceptable for the

planned indication?

Is it appropriate to make J-NDA submission with

this data?

Would the data support bioequivalence for this formulation change?

Can we start Ph 1 with this non-clinical data?

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Would the rationale for bridging strategy be

acceptable for approval?

Is the endpoint acceptable for the

planned indication?

Can we start Ph 1 with this non-clinical data?

Is it appropriate to make J-NDA submission with

this data?

Would the data support bioequivalence for this formulation change?

End of Phase 2 consultation

Pre J-NDA submission

consultationBioequivalence

consultation

Pre-Phase 1 consultation

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Consultation Category

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NOTE: The list shown here is only on drugs. Another list available for medical devices

So many categories to support a drug development -

a sponsor can consult basically on ANYTHING,

ANYTIME!

Consultations that meet many needs…

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Q: This product is innovative! Can PMDA review the already available data in advance of the submission??

A: Prior-Assessment Consultation (parts of CTD of a innovative product can be submitted in advance of the J-NDA submission)

Q: We are using a new additive. I wonder if this additive was ever used in Japan.A: Simple consultation (PMDA would provide information based on accumulated experience)

Q: We plan to make J-NDA submission in 2 months. I wonder what the timeline would be after J-NDA submission.

A: Pre-submission pre-consultation meeting for review schedule (informal consultation, free of charge, no minutes, small group discussion)

Q: We want to have a PMDA consultation. I wonder what data they would like to see at the consultation.

A: Pre-consultation meeting (informal consultation, free of charge, no minutes, small group discussion)

PMDA consultation process (example)

PMDA consultation

PMDAPre-

InquiriesResponse

Pre-Inquiry

Submit

FAX

Monday -5 wks Sponsor submit consultation questions and materials

PMDA’s Opinion

Sponsor’s response to PMDA’s opinion View

- 4 weeks

Sept 9

Oct

-2 weeks Oct 11

-1 week Oct 17

0 day Oct 24

Sponsor Submit Request for Consultation2 mo. in advance of the request

month, on the 1st working day

Date arrangedApprox 1 week from request

submission

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Aug 1

Aug 8

Draft minutes

Minutes finalizedBy Nov 24Within 1 month

Consultation on Clinical Trial

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1：Pharmaceutical Affairs Consultation on R&D Strategy has been conducted since 2011, July 1st. 2：Conducted since 2013, October 1st. 3：Conducted since 2014, November 25th (conducted as Consultation on R&D Strategy for Drugs/Medical Devices)4：Including Consultation on R&D Strategy for Drugs conducted since 2014, November 24th. The numerical values in [ ] are values

added up from individual consultations conducted over a period of days (to an extent necessary for thorough evaluation on thequality and efficacy of the product) before clinical trial notification for cellular and tissue-based products.

5：Conducted since 2014, November 25th

Consultation FY2011１ FY2012 FY2013 FY2014 Total

Consultation on R&D Strategy for drugs 20 28 66 48 162

Consultation on R&D Strategy for

medical devices6 5 38 16 65

Consultation on R&D strategy for

Cellular and Tissue-based Products３- - - 2 2

Consultation on Quality and Safety for

Cellular and Tissue-based Products４5 [7] 7 [13] 19 [32] 18 [44] 49 [96]

Consultation on Roadmap for

Development５- - - 1 1

Total 31 [33] 40 [46] 123 [136] 85 [111] 279 [326]

Number of Pharmaceutical Affairs Consultationon R&D Strategy

Introductory consultation／pre-

consultationFY2011１ FY2012 FY2013 FY2014 Total

Introductory consultation

(conducted at Kansai branch２)118 302 237 (20) 271 (63) 928 (83)

Pre-consultation

(conducted at Kansai branch２)153 254 346 (26) 325 (57) 1,078 (83)

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Today’s Agenda







• Our Future

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Overall organization of CTD

M3

CMC data

M5

Clinical Study

Report (CSR)

M1

Regional

CMC

M2

Clinical

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M1 (must be written in Japanese)

- J-NDA application form- Japan labeling- Risk Management Plan

Basically “common” as US/EU dossier(English documents acceptable)

M2 (must be written in Japanese)

- Clinical overview including rationale to extrapolate overseas data to Japanese per ICH-E5 (generic difference, weight, medical settings, etc.)Non-clinical

(overviews and

summaries)

M4

Non-clinical Study report

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BEFOREPaper submission

CURRENTeCTD submission

• Required in J-NDA filing after 2016• Will allow PMDA to conduct data analysis,

leading to more efficient review • Accumulation of data across products

Clinical Data Interchange Standards Consortium

Team Reviewing at the PMDA

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Office Director

Review Director

Team Leader

Risk Manager

Reviewers are required to have a high level of expertise

Pharmacology

BiostatisticsToxicology

ADMECMC

Clinical

Flow of J-NDA review

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CoD = Committee on Drug PAC = Pharmaceutical Affairs Council

• Conduct review of J-NDA• Conduct GCP, GMP inspections• Prepare review report

• Obtain input from outside expert• Discuss J-labeling contents• Discuss approvability

• MHLW and outside expert make final decision on approvability

Target review period: 9 mo. for priority, 12 mo. for standard review

PMS and PhVReview PACCoDExpDiscussion

Accelerating Review Period

Target Period

Percentile Total

Review

Period2013 2014 2015 2016 2017 2018

Standard 50 60 70 70 80 80 12mo.

Priority 50 60 60 70 70 80 9 mo.

6.7 6.4 5.1 4.2 4.6

10.57.6

6.35.7 6.7

19

16

12 12 12

92 9280 81

96

0

20

40

60

80

100

0

5

10

15

20

6.4

3.4 2 1.53.8

3.6

4.94.2 3.8

3.6

1110

9 9 9

15

20

50 53

42

0

10

20

30

40

50

60

0

2

4

6

8

10

12

Total Review Period New Drug

(Standard) (Priority)(mo.) (mo.)(No.) (No.)

Number of applicant

Regulatory

Applicant

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PMDA’s Performance - Internationally Highly Evaluated

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Comparison of the approval time among six regulatory authorities: 2004-2013

“Japan's PMDA and Health Canada may have had the most notable improvements over the past decade.” Regulatory Affairs Professionals Society 14 January 2015

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English translation of the review reports are publicly available at PMDA website

http://www.pmda.go.jp/english/review-services/reviews/approved-information/drugs/0001.html

Today’s Agenda







• Our Future

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Continuous and Comprehensive B/R Evaluation through Lifecycle of Drug

ReviewDevelopment(Clinical Trial Consultation)

BenefitsRisks

Post-

Marketing

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New Risk management

system

AnalysisCollection of Information

Planning and Implementation of Safety measures

Hypothesis

Evaluation of hypothesis

• Prevention of serious drug safety-related crisis from Japan• Effective encouragement of proper drug use.• Ensuring credibility to post-market safety management system

Goal

Assessment of Safety measure effects

Improvement of Safety Measures

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Crisis management

development of early post-marketing phase

vigilance plan

Advice on Drug’s post-marketing

safety measures

evaluation of the result of post-marketing survey

(Clinical Trial Consultation)

Risk

Manager

Throughout Drug Life Cycle

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Review Department Safety Department

Development Review

Post-marketing

(Act as Liaison)

Roles and duties of Risk Manager• For the continuous and comprehensive benefit-risk evaluation

• Through life-cycle of product

• From development stage to review period and post-approval stage

• Integration of information of development and post-marketing stage

• Advise to developing product

• To clarify the safety issues

• To make safety measure before approval

• To identify issues to collect post-marketing data

• To avoid misuse

• To make user friendly information (incl. labeling)

• Liaison between clinical development and post-marketing safety measures

• 13 Risk Managers in different disease areas

• Risk Managers will be mainly in charge of RMP

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development of early post-marketing phase

vigilance plan

Advice on Drug’s post-marketing

safety measures

evaluation of the result of post-marketing survey

(Clinical Trial Consultation)

Risk

Manager

Throughout Drug Life Cycle

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Review Department Safety Department

Development Review

Post-marketing

(Act as Liaison)

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MIHARI Project and MID-NET Project

MIHARI Project “MIHARI” means “guard” or “monitor” in Japanese

Establishment of a framework in PMDA to utilize

pharmacoepidemiological methods for safety assessment

of a drug

MID-NET Project （Medical Information Databese NETwork）

Establishment of a new medical information database in

Japanese patients for safety assessment of a drug

Medical RecordsDB

ADR reportsDB

SafetyMeasure

*DPC, etc.(inpatient)

DB

TransmitTo

medical institutio

ns

MHLW Medical institutions

Literatures

OverseasRegulatoryinformation

Presentationsat AcademicConference

Etc.

Health insurance societies’ claims

Claim Data

Safety assessment based onElectronic Health InformationDatabases ＝MIHARI Project

PMDA

Safety assessment based onconventional data sources

Sophistication of Safety measures1. Medical Information for Risk Assessment Initiative(MIHARI Project)2. Project for developing the medical information database infrastructure (MID-NET)

*Diagnosis procedure combination Development of

New DB＝MID-NET

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MID-NET Project A project initiated by MHLW / PMDA to establish the network of

electronic medical record database in Japan for a real-time

assessment of drug safety

PMDA

Hospital

Hospital

HospitalHospital

HIS dataDB

DB

DBDB

23 hospitals

In closed network

Hospital

Database

Claims data

DPC data

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Analytical system of MID-NET

Central data center

PMDA access and analyzes the data using exclusive PC Review results provided by

hospitals Combine all results into 1 Conduct additional analysis

by using these results

①PMDA sends analytical programs to 23 hospitals

②Each hospital sends anonymized individual level data

(w/o ID) and/or result of analysis to data center.

Standardization & transformation

Hospital A

PMDA

Programs for

data extraction

and analysis①

①②

②

③

HIS data

Claims data

DPC data

DB for

MID-NET

Project

41Standardization & transformation

Hospital B

HIS data

Claims data

DPC data

DB for

MID-NET

Project

Today’s Agenda







• Our Future

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PMDA’s activities for successful NDA filing / approval

• Discussion on drug development through consultations

• Continuity in PMDA’s side : same reviewer involved from CTN, consultation, J-NDA review

• Close communication with the applicant for better development

• Decision making based on “Regulatory Science” based on following

• Information provided by applicant (worldwide experience on a product)

• Experience from past reviews (accumulated knowledge of other products)

• Information from latest science

• Information exchange / discussion with overseas regulatory authorities

• Discussion with outside experts

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Tips for successful NDA filing / approval

Think ahead while conducting clinical trials !

• What data will be needed to support the labeling ?

• What are the signs of post marketing safety measures ?

• How do you define clinical importance of the product ?

Be open and consult the regulators on questions !

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Today’s Agenda







• Our Future

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JUST ANNOUNCED ON JUNE 26, 2015!

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Vision I: To contribute to the world through regulatory innovation

PMDA will, based on regulatory science, promote public health globallyby communicating the outcomes of its first-in-the-world product reviews,safety measures, and relief services

Vision II: To maximize the common health benefits to other

countries/regionsPMDA will, in order to realize quicker access to more effective and safermedical products for patients around the globe, communicate moreclosely with countries around the world to promote regulatoryharmonization and collaboration

Vision III: To share the wisdom with other countries/regions

PMDA will, by fully utilizing the accumulated knowledge and experience,contribute to the public health of partner countries/regions throughprovision of information and training that are essential for buildingregulatory capacity in those countries

PMDA International Strategic Plan 2015

Establishment of “Regulatory Science Center”

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Data from industry

Data from MID-NET, etc

• Utilized to conduct pharmacoepidemiologicinvestigation Risk/benefit evaluation Investigate new method for

pharmacoepidemiologic study, etc

• Utilized to conduct simulation and model building based on clinical trial data, etc Disease model-building Development new drug evaluation endpoints, etc

Promote regulatory science based• Decision makings• Product reviews• Implementation of

safety measures etc.

BIG DATA to • Create new guidelines• Create recommendations

for development

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Trainings at PMDA, visits to prefectures such as Toyama, industry with innovative technology, etc

Enable more staffs to attend the trainingTraining can be arranged according to the needs

Design and conduct tailored training programs that meet the needs of regulators in Asia

Images of Asian Training Center

* To be established within PMDA

Training programs in partner countries

Expand training programs in Japan

Establish APEC MRCT CoE

Take the leadership as APEC MRCT project champion to set Center of Excellence (CoE) in Asia

PMDATokyo & Osaka, Japan

FDA and USP, US CFDA,

China

Confidentiality Arrangement

Resident Staff Joint SymposiumMemorandum of Understanding (MOU)

Health Canada,Canada

ANVISA, Brazil

EMA(EU)

TGA, Australia

NADFC, Indonesia

ThaiFDA, Thailand

Swissmedic, Switzerland

* MOU between the Chinese SFDA (present CFDA) and the Japanese MHLW, under which PMDA supports cooperative activities** MOU concluded between Interchange Association and East Asia Relations Commission, but is being implemented through

cooperation of related organizations.

*

HSA, Singapore

TFDA, **Taiwan

HPRA,Ireland MHRA,

UK

ANSM, France

AIFA, Italy

CBG-MEB,Netherlands

NPCB, Malaysia

PMDA and the World

PMDA will continue to contribute

• To the product development throughout the product lifecycle

• To the health and healthy life expectancy of the people in Japan, and globally

• To the world through close communication with the Science Board, academia, overseas regulatory authorities

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Find out more about PMDA• English Website


• PMDA International Strategic Plan 2015

http://www.pmda.go.jp/english/int-activities/outline/0017.html

• PMDA Updates (monthly news on PMDA activity)


• Profile of Services


• Annual reports

http://www.pmda.go.jp/english/about-pmda/annual-reports/0001.html

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http://www.pmda.go.jp/english/about-pmda/annual-reports/0001.html

Thank you !

For additional questions please click on “Contact us” on our English website

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