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