2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaPharmacovigilance in Japan.Overview & Specific drug safety issueTomoko Okudaira Office of Safety ,Office of New DrugPharmaceuticals & Medical Devices Agency （PMDA）,JAPAN2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDisclaimerTranslation noteEnglish and Japanese are not a perfect matchThe contents of this presentation represent the view of the speaker only and do not necessarily represent the official positions or policies of the PMDA2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaTodays TopicOrganization of PMDAPillarsCooperation with Ministry of Health, Labour and Welfare (MHLW)Post-marketing activities in JapanGVPADR reportEPPVRe-examinationCurrent situation of PhV plan & Risk ManagementRisk Management Option in JapanNew Risk Management System in Japan2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaPMDAs Three Work AreasRelief Service for SMON, HIV-positive, AIDS and Hepatitis C patientsRelief Service for ADR and Other Infectious DiseaseReview and Audit for Drugs/ Medical Devices Efficacy and SafetyProvision of Medical Expenses, Disability Pensions etc.Clinical Trial ConsultationConformity Audit for Application Materials of GLP,GCP and GMPInformation Provision (via the Internet), Pharmaceutical Consultation for ConsumersPost-marketing Safety Operations for Drugs/ Medical Devices Review of Efficacy and SafetyReinforced Safety Information (Database)Scientific Review and Research for Safety Information2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China Pharmacovigilance Operation Flowchart- MHLW/PMDA Cooperation - Receipt of ADR/ Infection Reports Planning for Safety Measure Information Provision System（via the Internet）Safety Measure ImplementationDATABASEMHLWPMDAReal-time Notification Scientific/ Objective ResearchAnalysis of Accumulative Information Expert ConsultationCompany interviewsExtracting Urgent & Significant Info.Keep Tracking InformationCompiling ReportsAdvisory committee(PFSC)ReportMedical InstitutionsCompaniesMedical Professionals, Public and CompaniesInformation ProvisionReport2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org6Japans Post-marketing ActivitiesPMSSafety reportRe-evaluationAd hocQualityPeriodicPeriodic Safety ReportIncl. PSURRe-examinationDrug Use Investigationof Special Population Post-marketing Clinical TrialDrug Use InvestigationRisk MinimizationRisk CommunicationEPPVPeriodicExpedited2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org7Good Vigilance Practice for Prescription DrugRequirements for Personnel & Organization Creation of Safety Management DepartmentAppointment of Safety Management SupervisorWhat GVP requires MAHs to doCollection & Analysis of Safety InformationPlanning & Execution of Safety MeasuresPlanning & Execution of EPPV* In-house InspectionTraining/Education of Relevant Staff Preparation of SOPs on the above *Early Phase Post-marketing Vigilance2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org8GVP RequirementsPrescription DrugsDrugs other than Prescription onesQuasi Drugs, Cosmetics etc.Organization and Personnela) Creation of Safety Management Departmentb) Qualified Safety Management Supervisor (over 3 yrs experience)a) Not mandatoryb) Safety Management Supervisor (no qualification required)Same as on the leftSOP etc.Preparation of SOPsSame as on the leftNot mandatoryCollection of Information for Safety Management a) Health Care Professionalsb) Scientific Papersc) MHLW, PMDA, etc.d) Foreign authorities, etc.e) Other Companiesf) Others Same as on the leftb) and f) are required for Quasi- Drugs and CosmeticsIn-house Inspection, Education/TrainingRequiredSame as on the leftNot mandatory2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org9Electronic ReportingPaper DocumentsFDICSRData inputPMDADataBasePharmaceutical CompanyADR Reporting by Companies2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org10ADR Reporting by HCPsMHLWMedical InstitutesPharm. CompanyFeedbackInvestigationADR Reporting by Company(Paper and Electronic Reports)Electronic ReportingPostal MailFAXPMDA2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org11ADR Reporting RuleSeriousnessPredictabilityTime frame of report to PMDASeriousNot predictable15 daysPredictable- Death etc.*15 days- Others 30 daysNot seriousNot predictableAnnually(Annual Cumulative Report)Predictable-Reporting time frame depends on seriousness and predictability of the case. (Article 253 of the Ministerial Ordinance on PAL)No timeframe defined for HCP reporting* - Death - ADR caused by new drug ingredient within 2 years after approval - ADR detected by Early Phase Post-marketing Vigilance (EPPV)2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org12Reported ADR Infectious Disease CasesNote :Foreign reports by drug makers are not included in and before FY03. Annual Cumulative Reports are not included.2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaEarly Post-Marketing Phase Vigilance : EPPVEnforced on Oct 1,20011.To ensure necessary information for appropriate use (contraindication, careful administration etc ) is explained to the medical institutions 2 weeks before delivery.2.To request medical institutions to use the drugs carefully and report serious ADRs, if occurred, immediately to pharmaceutical companies3.To request appropriate use and ADR reporting repeatedly to medical institutions for 6 months after delivery.Drug Information Associationwww.diahome.org2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org14Early Post-Marketing Phase Vigilance : EPPVDelivery of new drugs to medical institutionsexplanationevery 2 wks2months6monthsgiving information by visiting, letters, FAX, E-mail etc.Reports of ADRs8monthsSaleonce a month0Report to PMDAPreparation of the protocol of EPPV2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org15Number of reported ADRs of New Active Ingredients before and after the introduction of EPPV (average per month)No. of reportsMonths elapsed since launchingEPPV was introduced in October 2001.Number of before-EPPV is based on 30 new active ingredients launched between Apr. 2000 and Mar. 2001.Number of after-EPPV is based on 22 new active ingredients launched between Oct. 2001 and Oct. 2002.No. of reports before and after the introduction of EPPV024681012141618123456789101112BeforeAfter2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaRe-examinationThe reexamination system is aimed at reconfirmation of the clinical usefulness of drugs by performing GPSP or GVP as one aspect of PMS, through collecting information on the efficacy and safety of the drug during a specified period of time after approval. The surveillance and studies required for reexamination applications must be performed in compliance with the GPMSP (GPSP), GCP or GLP depending on their objective.The timing when these drugs should be reexamined is designated by the MHLW at the time of their approval as new drugs. Reexamination period of drugs containing new active ingredients: 8 years (maximum 10 years) 0Drug Information Associationwww.diahome.org162nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaRiskCommunicationManagedDistributionProductRecall etcInformedConsentsRisk Management Options in JapanRisk Communication ToolsFor HCPsPackage insertDear Dr LetterLeafletWeb site etcFor PatientsMedication GuideLeafletWeb site etcRecall, Withdrawal, Suspension of the saleRegistration of HCPs, Patients etcDrug Information Associationwww.diahome.org2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaGoalTo minimize the risk of Thalidomide exposure during pregnancy in womenElementsEducation Managed Distribution Registration of Physicians, Pharmacists, PatientsPeriodic Pregnancy TestPeriodic Confirmation of Understanding etcDrug Information Associationwww.diahome.org18Example . Thalidomide T.E.R.M.S : Thalidomide Educations and Risk Management System2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaRisk Management on ReviewBrand name To avoid misusePackage To avoid misuseRisk communication tool For healthcare professionals & patientsPackage insert, leaflet, website etc.Other Risk Management OptionInformed ConsentsManaged DistributionDrug Information Associationwww.diahome.org192nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaPhV Plan and J-NDAPharmacovigilance plan is a component of CTD ( if the plan has been prepared)PMDA recommend to prepare PhV plan until NDA submission through consultation PhV is an important discussion point under reviewDescription on review reportMonitor and review the data Submission of a local periodic report with PSURDrug Information Associationwww.diahome.org20REVIEWAPPROVALPOST APPROVALJAPANUSEUPLAN OF POST APPROVAL SURVEYS AND STUDIESAPPROVAL CONDITIONEPPV（6MONTH）PSURRE-EXAMINATION4-10 Y AFTERRE-EVALUTATIONAD HOCPOST APR. STUDY ETCIF REQUIRED APPROVAL RENEWAL5 YEARS ADR AND INFECTION REPORTINGADR AND INFECTION REPORTINGADR AND INFECTION REPORTINGADR AND INFECTION REPORTINGADR AND INFECTION REPORTINGADR AND INFECTION REPORTINGPOST APR. STUDY ETCIF REQUIRED Comparison of Regulation on Safety : Japan, US and EU2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org22New Risk Management System in JapanSeamless evaluation of risk & benefit balance from FIH to post-approvalThrough lifecycle of a drugEarly detection of safety signalAccumulation of informationSeamless assessmentDevelopment of New MethodsMake Timely and Appropriate Safety Actions to Minimize Risks2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaRisk Manager SystemPurpose of RM System PMDA will collect, compile, evaluate and manage all the safety information on new drugs from development to post approval stages to give guidance and advice to companies on PMS at early stage and in a timely manner.PMDA RM System will help the life cycle management of drugs in safety aspectIdentification of safety profile from development stageGuidance and advice on designing post-approval surveys, studies and other activities at review stageEvaluation and advice on outcome and problems of post-approval surveys, studies and other activities etc Drug Information Associationwww.diahome.org232nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org24Collection, compilation, assessment and follow up of all the safety information related to a drug Non-clinical and clinical data (pre- and post-approval )ADR DB + epidemiologal dataHistory of safety actions (pre-caution revision, Dear HCP letters etc.)Related literaturesMore scientific and active interaction and discussion with review teamCreation of safety assessment team corresponding to review team(s)Team of different expertiseDiscussions based on scientific evidence (epidemiology data, ADR DB analysisParticipation of Safety Team in Review Process under New Risk Management System (Future)2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org25Active participation in review processParticipation in review process from clinical trial consultation to make contribution to clinical safety assessmentMore responsibility for assessment of post approval survey and studies includingPSUR and re-examination Non-clinical and clinical data (pre- and post-approval )Identification of safety profile of new drug and its incorporation in review reportIdentified risks that require further evaluationPotential risks that require further evaluationParticipation of Safety Team in Review Process under New Risk Management System (Future)(contd)2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaDrug Information Associationwww.diahome.org26Guidance and advice on drafting PMS plan attached to CTDStarting discussion at early stage of review process (even at clinical trial consultation)Concrete design of post approval surveys/studies and PMS plan at approvalFollow up of PMS plan at post approval stageAssessment of results of post approval surveys and studiesAssisting evaluation and decision on result of approval conditions More involvement in EPPV, PSUR, Re-examinationParticipation of Safety Team in Review Process under New Risk Management System (Future)(contd)Pilot study of new system is starting in selected stages of review process from 2009.72nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaPossible Benefits of New Risk Management SystemEfficient preparation of effective PMS planConsistent safety management throughout lifecycle both in PMDA and companiesPreventing withdrawal of new drugs (at early stage)Completion of lifecycle of a drugProtection of patients especially at early stage of marketingDrug Information Associationwww.diahome.org272nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, ChinaThank you for your kind attention!Drug Information Associationwww.diahome.org28Thank you for your kind attention!