PMDA’s Efforts in Safety Measures

Risk Management- Risk Management Plan(RMP) in Japan -( ) p

Kazuhiko Mori, MSChief Safety OfficerPharmaceuticals and 25th AnnualPharmaceuticals and Medical Devices Agency (PMDA) J

EuroMeeting4-6 March 2013RAI, Amsterdam(PMDA), Japan

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Background conceptBackground concept

Continuous and Comprehensive B/R E l ti th h Lif C l f DEvaluation through Life Cycle of Drugs

RisksBenefits

Risks

ReviewDevelopment Post-ReviewDevelopment(Clinical Trial Consultation)

PostMarketing

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

Volume

Q lit

Evidence of efficacyIncrease

Quality

DiversityPlanning, Planning, Conduct, Conduct,

Unknown Risk,,

Analysis, Analysis, EvaluationEvaluation Convert unknown

risk to known risk

Decrease/

risk to known risk

Risk minimization

Early development Early development PhasePhase

Late development to PostLate development to Post--kk PhPh

Decrease/ Reduction

PhasePhase marketmarket PhasePhase5

Benefit /Risk from Patient View PointsImprove B/R valance

Di Ri kDisease Risk Disease RiskDrug

Drug Efficacy ADRDrug

Efficacy ADR

Elimination of Drug P ti t di d t Disease Risk

only

= Patient disadvantage

6

y

PhV updates in JapanPhV updates in Japan

Pre‐market review Approval Post‐market

Phamacovigilance measures JP, US, EUreview

JPPharmcovigilance plan

Spontaneous ADR, infection ReportingADR/AE reporting

VStreamlined risk 

Pharmacovigilance strategiesi l di Ph i il PlPharmcovigilance plan

For NME

Post‐marketcommitment

Periodic report 6‐10 yearsRe‐examination

Re‐evaluationIf necessary

EPPV（NME 6mo.）

management strategies (pending)

including Pharmacovigilance Planwill be integrated into RMP

US

commitment Re examination If necessary

ADR/AE reporting

Spontaneous ADR, infection Reporting

REMS（high risk NME）

REMS（high risk NME）

Post‐marketPeriodic report

ADR/AE

CommitmentIf necessary

Spontaneous ADR, infection Reporting

EURMP（NME）

RMP（NME）

ADR/AE reporting

Post‐marketCommitmentIf necessary

PSUR8

renewal renewal

The Current Framework for Post-Marketing Safety Measures

Drug Approval

4-10years（8 years)

EPPV（8 years)

ADR and Infection Reporting

PMS

Re-examination

Reporting

Numbers of Adverse Drug Reaction Reports

FY2007

FY2008

FY2009

FY2010

FY20112007 2008 2009 2010 2011

C i 28 500 32 306 30 928 34 677 36 741Companies: Japanese

ADR

28,500 32,306 30,928 34,677 36,741

Companies: foreign

95,036 116,662 141,386 170,021 220,455foreignADR

H l h CHealth Care Professionals

3,891 3,816 6,181 4,809 5,231

Risk Manager systemRisk Manager system

What is the Risk Manager?g

P t(Clinical Trial Consultation)Development Review Post-

marketing

Review Department(Review Team) Safety Department(Safety Team)

Risk Manager(Act as Liaison)

development of early k i h

Advice on D ’ k i evaluation of the resultpost‐marketing phase 

vigilance plan Drug’s post‐marketing 

safety measures 

evaluation of the result of post‐marketing survey 

Risk Manager System in Japan

• For the continuous and comprehensive benefit-risk evaluation– Through life-cycle of productg y p

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

• Integration of information of development and post-marketing stage.

• Enhancement of human resources in the safety department of PMDA began in fiscalsafety department of PMDA began in fiscal 2009 (+100 person) → Risk Manager(RM) was realized!!

Roles and duties of Risk ManagerRoles 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 stageI t ti f i f ti f d l t d t k ti t• Integration of information of development and post-marketing stage

• Advise to developing product– To clarify the safety issuesTo 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)

Li i b t li i l d l t d t k ti f t• Liaison between clinical development and post-marketing safety measures

• 13 Risk Managers in different disease areasg• Risk Managers will be mainly in charge of RMP

Continues Risk Management through Product Life-cycley

Regulatory Tool Person in ChargePhase Regulatory Tool

Clinical Development 

R i T

Development Safety Update Report (ICH E2F)

DSUR

Person in ChargePhase

Phase Review Team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

NDA Review 

Review Team

Risk M

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全ての期RMP

PhaseReview Team anager

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、これまで以上により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となることを目的

RMP

Apr. 2013 - Currently

PSURPost‐Marketing Ph

Review Team

Periodic Benefit-Risk Evaluation Report(ICH E2C(R2))PBRER

PSUR

Phase  Safety Team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、新しい情報又は明らかになりつつある情報の包括的かつ重要な分析を示すことにある

PBRERICH

step4Dec. 2012

Risk Management Plangin Japan

Looking for more efficient t k tipost-marketing survey

• In most of products post-marketing surveys areIn most of products, post marketing surveys are required:

Are they sufficient and minimum?– Are they sufficient and minimum?– Are purposes of data collection clear ?

• Discussion & Agreement of Post-marketing survey between PMDA and MAH before approval– Healthcare professional’s opinion have been

involved in the review process, however,p– Are the results of current post-marketing surveys

useful for Healthcare professionals?useful for Healthcare professionals?

Concept of J-RMP

Risk Minimization Action PlanPh i il Pl

Safety Specification

Important Identified Risk Risk Minimization Action PlanPharmacovigilance Plan

Routine

Important Identified RiskImportant Potential RiskImportant Missing Data

Spontaneous reporting Package InsertNeed

Additional measures？(Evaluation)※ No

Yes

Spontaneous reportingResearch ReportForeign actions report

Package InsertBooklet of Precaution for Use

Additional

Yes

Info Dissemination by EPPVInfo for Health ProfessionalsDrug Guide for patientsAccess restriction

PvPand / or

RiskMAP？ Additional RiskMAP

（Perio

Reporti

Risk E

val

Enhancement of spontaneous reporting by EPPV

Access restrictionetc

RiskMAP？(Evaluation)※

Additional P P

Additional RiskMAP odic ng

）

luation

※Burden on HCPs should

Drug use –results surveySpecified drug use surveyPost Marketing Clinical Study（I l d Ph E i S d )

Additional PvP

be taken into consideration. （Includes PharmacoEpi Study) etc

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Development andrevision of RMP

NDA li tiAdvisory

l l hNDA application committee approval launch

30 60d300d

Discuss between review teamconsultation

30～60days～300days

Revision as necessary

Submit draft RMP as MAH Confirmed RMP version

as necessary

Submit draft RMP as MAH Confirmed RMP versionagreed with review team

Ver.1.0（finalized RMP）（ 1 month before launch ）

Information about the RMP• About drug risk management plan (in Japanese)

Information about the RMPAbout drug risk management plan (in Japanese)– Objective– Conceptual diagramConceptual 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)Risk Management Plan Guidance (in English)http://www.pmda.go.jp/english/service/pdf/mhlw/PFSB-SD_Notification120411-1.pdf

• We are now preparing for providing information of RMPto HCPs and general public including patients

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

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PMDA English website

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http://www.pmda.go.jp/english/service/safety_info_mhlw.html

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Current RMP in JapanCurrent RMP in Japan

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

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

• Is RMP made based product’s character ?• Is purpose of RM/data collection clear ?Is purpose of RM/data collection clear ?

Table of Contents of RMP GuidanceTable of Contents of RMP Guidance

1 Introduction1. Introduction2. Risk Management Plang3. Safety Specification4 Ph i il Pl4. Pharmacovigilance Plan5. Plan for Survey/Study on Efficacyy y y6. Risk Minimization Plan

E l i f Ri k M Pl d7. Evaluation of Risk Management Plan and Report to PMDA

Characteristics of Japanese RMPCharacteristics of Japanese RMP

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

• Start to discussion at the submission of NDA• Start to discussion at the submission of NDA• Set up milestones

– Obvious goal of surveillance– Revision of RMP by new information if ecessaryRevision of RMP by new information, if ecessary.

• Transparency among stakeholders– Comprehensive information collection & risk

management thorough life-cycle of the product

Please Visit PMDA English website htt // d j / li h/i d ht lhttp://www.pmda.go.jp/english/index.html

RMP & B/R evaluationRMP & B/R evaluation

Coming era of PBRER from PSUR

Just reached the step4 !

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B/R Evaluation

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

Drug Information Association www.diahome.org30

B/R Balance becomes inevitably worse after Approval?

IND NDA Approval

ClinicalSafety data

Pre-market Post-market

Cli i lClinicalEfficacy data

Questions from seven years ago

Conventional drug → Little difference between i di id l b bindividuals or between subgroups

Targeted therapy drug→ Large difference between individuals or between subgroups

Even though they show a similar average value, then g y g ,do you consider that B / R balance is the same?

Average level

C ti l D T t d th D32

Conventional Drug Targeted therapy Drug

For reliable quantitative assessment

• Randomized controlled trials are essential• Placebo vs. Active comparator • Data Quality Management• Data Quality Management• Standardization of method, data format,

etc.• Validity of the weighting of each elementValidity of the weighting of each element• Generalizability of evaluation results• Individual optimization vs. average data• Continuous reassessment is essentialContinuous reassessment is essentialDrug Information Association www.diahome.org

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All the players in good harmony

Thank you for your attention