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PMDA’s Efforts in Safety Measures- Risk Management Plan(RMP)

in Japan -

Kazuhiko Mori, MSChief Safety OfficerPharmaceuticals and Medical Devices Agency (PMDA), Japan

Disclaimer

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Background concept

Continuous and Comprehensive B/R Evaluation through Life Cycle of Drugs

ReviewDevelopment(Clinical Trial Consultation)

BenefitsRisks

Post-Marketing

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Early development Phase

Late development to Post-market Phase

Volume

Quality

Diversity

Evidence of efficacy

Unknown Risk

Decrease/ Reduction

Increase

Continuous Improvement of B/R valance Through Life-Cycle of Product

Planning, Conduct, Analysis, Evaluation Convert unknown

risk to known risk

Risk minimization

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Benefit /Risk from Patient View Points

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Disease Risk

Drug Efficacy ADR

Disease Risk

Drug Efficacy

ADR

Disease Riskonly

Improve B/R valance

Elimination of Drug = Patient disadvantage

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PhV updates in Japan

Pre‐market review Approval Post‐market

JP

US

EU

Phamacovigilance measures JP, US, EU

Pharmcovigilance planFor NME

Post‐marketcommitment

Periodic report 6‐10 yearsRe‐examination

Re‐evaluationIf necessary

REMS（high risk NME）

Periodic report

REMS（high risk NME）

RMP（NME）

Post‐marketCommitmentIf necessary

PSUR

RMP（NME）

Spontaneous ADR, infection ReportingADR/AE reporting

ADR/AE reporting

ADR/AE reporting

Post‐marketCommitmentIf necessary

Spontaneous ADR, infection Reporting

Spontaneous ADR, infection Reporting

EPPV（NME 6mo.）

Streamlined risk management strategies (pending)

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renewal renewal

Pharmacovigilance strategiesincluding Pharmacovigilance Planwill be integrated into RMP

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Re-examination

Drug Approval

4-10years（8 years)

The Current Framework for Post-Marketing Safety Measures

ADR and Infection

ReportingPMS

EPPV

Numbers of ADR Case Reports

0

50000

100000

150000

200000

250000

300000

FY2007 FY2008 FY2009 FY2010 FY2011 FY2012

domesticreportforeignreportphysicianreport

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Risk Manager system

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

What is the Risk Manager?

Review Department(Review Team) ( y )Safety Department

(Safety Team)

(Act as Liaison)

Development Review Post-marketing

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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

Continues Risk Management through Product Life-cycle

Regulatory Tool

Clinical Development Phase

NDA Review Phase

Post‐Marketing Phase 

Review Team(consultation)

Review Team(NDA review)

Review Team(Re‐examination)

&Safety Team

Risk  M

anage

r

Periodic Benefit‐Risk Evaluation Report(ICH E2C(R2))製品の全体的なベネフィット・リスクプロファイル評価を可能にす

るために医薬品のリスクに関して及び該当する場合には、承認された適応症に対するベネフィットに関して、新しい情報または明らかになりつつある情報の重要な分析を示すことにある。

Risk Management Plan(ICH E2E+α)医薬品の開発段階、承認審査時から製造販売後のすべての期間において、ベネフィットとリスクの評価・見直しが行われ、これまで以上に明確な見通しを持った製造販売後の安全対策の実施が可能になることを目的.

Development  Safety Update Report (ICH E2F)治験薬に関して調査対象期間中に収集された関連する安全性情報の包括的かつ十分に検討された年次レビューと評価を提示する

DSUR

PBRER

RMP

Apr. 2013 ‐

ICH step5May. 2013

Currently PSUR

Person in ChargePhase

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Risk Management Planin Japan

※Burden on HCPs should be taken into consideration.

Concept of J-RMP

Risk Minimization Action PlanPharmacovigilance Plan

Routine

Additional

Safety Specification

Important Identified RiskImportant Potential RiskImportant Missing Data

Need Additional measures？

(Evaluation)※ No

Yes

Spontaneous reportingResearch ReportForeign actions report

Package InsertBooklet of Precaution for Use

Enhancement of spontaneous reporting by EPPVDrug use –results surveySpecified drug use surveyPost Marketing Clinical Study（Includes PharmacoEpi Study) etc

Info Dissemination by EPPVInfo for Health ProfessionalsDrug Guide for patientsAccess restrictionetc

PvPand / or

RiskMAP？(Evaluation)※

Additional PvP

Additional RiskMAP

（Periodic

Reporting

）

Risk E

valuation

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• About drug risk management plan (in Japanese)– Objective– Conceptual diagram– Relevant documents– Case Described of drug risk management plan

http://www.info.pmda.go.jp/rmp/to_company.html

• Risk Management Plan Guidance (in English)http://www.pmda.go.jp/english/service/pdf/mhlw/PFSB-SD_Notification120411-1.pdf

• Information page of RMP for company (in Japanese)http://www.info.pmda.go.jp/rmp/to_company.html

Information about the RMP

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http://www.info.pmda.go.jp/rmp/to_company.html

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Please Visit PMDA English website http://www.pmda.go.jp/english/index.html

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Risk Management Plan Guidance

http://www.pmda.go.jp/english/service/pdf/mhlw/PFSB-SD-0411-1_PFSB-ELD-0411-1.pdf

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Publication of Risk Management Plan

http://www.pmda.go.jp/english/service/pdf/mhlw/PFSB-ELD-0304-1_PFSB-SD-0304-1.pdf

Current RMP in Japan

• Discussion & Agreement of RMP between PMDA and MAH before approval– Are Healthcare professionals involved?

• Most of products are required PMS.– Are they sufficient and minimum?

• Is RMP made based product’s character ?

• Is purpose of RM/data collection clear ?

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Table of Contents of RMP Guidance

1. Introduction

2. Risk Management Plan

3. Safety Specification

4. Pharmacovigilance Plan

5. Plan for Survey/Study on Efficacy

6. Risk Minimization Plan

7. Evaluation of Risk Management Plan and Report to PMDA

Characteristics of Japanese RMP

• Optimal risk management and data collection– Incl. generic drug

• Start to discussion at the submission of NDA

• Set up milestones– Obvious goal of surveillance

– Revision of RMP by new information, if ecessary.

• Transparency among stakeholders– Comprehensive information collection & risk

management thorough life-cycle of the product

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RMP & B/R evaluation

Coming era of PBRER from PSUR

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Just reached the step4 !

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Published Japanese step5 document

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Dated 17 May 2013

• As new information about the drug emerges during marketing experience, benefit-risk evaluation should be carried out to determine whether benefits continue to outweigh risks ….

B/R Evaluation

Drug Information Association www.diahome.org28

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ClinicalEfficacy data

ClinicalSafety data

IND NDA Approval

Pre-market Post-market

Our effort to improve B/R Balance is endless!!

All the players in good harmony

Thank you for your attention