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Pharmaceuticals and Medical Devices AgencyCurrent statuson Adverse Event Reportingin JapanIku MittaSafety Reports Management Division,Office of Safety IPMDA16th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

AbbreviationPharmaceuticals and Medical Devices AgencyADR: Adverse Drug ReactionDB: DatabaseEPPV：Early Post-Marketing Phase VigilanceHCP: Healthcare ProfessionalICSR: Individual Case Safety ReportMAH: Marketing Approval HolderMHLW: Ministry of Health Labor and WelfareOTC: over-the-counterPBRER: Periodic Benefit Risk Evaluation ReportPMD act: Pharmaceuticals and Medical Devices ActPMDA: Pharmaceuticals and Medical Devices AgencyPMDSI: Pharmaceuticals and Medical Devices Safety InformationPSUR：Periodic Safety Update Reports26th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Today’s AgendaPharmaceuticals and Medical Devices Agency1. Introduction of PMDA andManagement Division, Officeof Safety I2. Reports from MAH（In the case of Drug ICSR）3. Reports from HCPs4. Reports from Patient36th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Pharmaceuticals and Medical Devices Agency1. Introduction of PMDA andManagement Division,Office of Safety I46th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

The role of PMDAPharmaceuticals and Medical Devices AgencySafety TriangleComprehensive risk management through the three function56th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

As of August 1, 201866th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Safety OfficesPharmaceuticals and Medical Devices AgencyAs of August 1, 2018Chief Safety OfficerOffice of Safety IPlanning and Management DivisionSafety Reports Management DivisionRisk Communication DivisionMedical Device Safety DivisionSafety reporting desk, Safety informationprovision, Survey to medical institutes,Pharmaceutical consultation forconsumers etc.Scientific review of safety informationOffice of Safety II13 teamsOffice of Medical Information and EpidemiologyScientific review of safety informationDevelopment of national medicalinformation net work, Epidemiologystudies76th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Pathway and legal base of ADR ReportPharmaceuticals and Medical Devices AgencyHealthcare Professionals (HCPs)(PMD* Act. Article 68-10, 2) Drug Medical device Regenerative medicine(Cellular and Tissue-based Products) Quasi-drugs, cosmeticsMarketing Approval Holders (MAHs)Patients(no legal basis, in trial)(PMD* Act. Article 68-10, 1)8 Drug Medical device Regenerative medicine Drug(Cellular and Tissue-based Products) Vaccination(Preventive Vaccinations Act. Article 12, 1)6th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)8

Cycle of Safety MeasuresPharmaceuticals and Medical Devices AgencyOccurrence of Adverse Drug Reaction (ADR)Provision ofCollection ofinformationinformationDecision of safetymeasuresData analysis96th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Cycle of Safety MeasuresPharmaceuticals and Medical Devices AgencyOccurrence of Adverse Drug Reaction (ADR)Provision ofCollection ofinformationinformationOffice of Safety IDecision of safetymeasuresOffice of Safety IData analysisOffice of Safety IIOffice of Safety II106th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Data processing flow of ICSRPharmaceuticals and Medical Devices AgencyHCPsvia– E-mail– Fax– PostPatientsvia– WebsiteMAHsvia– Electrical transmission– Post– Over-the-counter*Submission of ICSR files is mandatoryCreate ICSR files by PMDAPopulate ICSR into ADR DBPopulate ICSR into ADR DBPMDA s ADRDatabaseData AnalysisOffice of Safety IOffice of Safety II6th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)11

Pharmaceuticals and Medical Devices Agency2. Reports from MAH（In the case of Drug ICSR）12126th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Time Schedule of Surveillance SystemsPharmaceuticals and Medical Devices AgencyADR/AEreportingSpontaneous ADR, infection ReportingRisk Management PlanEPPVPost‐marketcommitmentPeriodic Safety Reports‐‐‐‐use‐results surveysspecified use‐results surveyspost‐marketing clinical studyPSUR, PBRERRe‐examination6 monthsPre‐approvalApproval6‐10 yearsRe‐evaluationIf necessaryPost‐marketing136th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Standards of ADR Reporting by MAHPharmaceuticals and Medical Devices AgencyDomesticForeign15 days15 days15 days (death)-30 ted ADR occurrence trends15 days15 daysCase indicating health hazard bychange of ADR occurrence trends15 days15 daysUnexpectedSeriousNon-seriousExpected* Except for death cases and- ADRs by new drugs (new ingredients) within 2 years after approval- ADRs detected through EPPV14146th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Flow chart of ADRs reporting systemfrom MAHsPharmaceuticals and Medical Devices AgencyProvideinformationInvestigationMAHsHCPsADR reportsInformationsharingData accumulationPMDADatabasePMDAMHLW156th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Numbers of ADR ReportsPharmaceuticals and Medical Devices Agency450,000425,297from MAH (Japanese case)400,000350,000393,825from MAH (Foreign case)345,193from 1296,0477,6240FY2013FY2014FY2015FY2016FY2017166th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Rate of electronic submission in 2017(Drug, Quasi-drug and cosmetics Reports)Pharmaceuticals and Medical Devices Agency1%99%Electoric submissionFD,CD or Paperhttps://www.pmda.go.jp/files/000224626.pdf6th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)17

ICH guidelines for ICSRPharmaceuticals and Medical Devices AgencyICH E2B (R2):Data Elements for Transmission of IndividualCase Safety .pdfICH M2:Electronic Transmission of Individual CaseSafety Reports Message .pdfICH E2B (R3): Since April 2016Implementation Guide for ElectronicTransmission of Individual Case Safety Reports(ICSRs) E2B(R3) Data Elements and 0219341.pdf18186th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Start of E2B(R3) implementation in JapanPharmaceuticals and Medical Devices Agency ICH E2B (R3) Step 4: 2012/11 Start of implementation：2016/4/1 Transitional period：until 2019/3/31 Parallel implementation of R2 and R3 Complete conversion to R3：starting 2019/4/1196th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Major discussion points concerningconversion to R3Pharmaceuticals and Medical Devices Agency Issuance of a notice regarding R3 implementation (includingrevisions of existing notifications, etc.) Review of Japan-only items (J items) to be added to ICH E2B data items Determine whether the reporting companies can comply (R3remodeling, schedule) Determine system vendors availability (R3 remodeling,schedule) Establish a working group (MHLW, PMDA, industry) and consider Determine whether R2 and R3 will be applied together orR2 will be integrated into R3 Based on opinions from industry at the above working group, determinewhether R3 compliance is possible for all reporting companies Review of R3 reporting tools and reporting procedures (EDI,uploading to dedicated website, mailing paper reports andelectronic media) We decided to enhance the R3 reporting tool and reportingprocess such that SMEs without a side effect reporting systemcan easily comply with R3206th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Related notifications for R3 implementationPharmaceuticals and Medical Devices Agencya. ICH E2B(R3) Implementation Guide (IG)(Notification for translated IG issued by MHLW)b. Q&As for ICH E2B(R3) IG(Notification for translated Q&As issued byMHLW)c. Reporting Form (Notification issued by MHLW)d. MHLW IG (Notification issued by MHLW)e. Q&As for MHLW IG (Notification issued byMHLW)f. PMDA User Guide (Notification issued byPMDA)g. Supplemental Information216th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Timeline for E2B(R3) implementationPharmaceuticals and Medical Devices Agency4Q/2012WGformed2013 to 2014Develop IG/UG andQ&A, and revise3Q/4Q 2015Test Working group was formed from 4Q/20121Q 2016April 1, 2016IssuerevisedIG/UGE2B(R3)start Members: MHLW, PMDA and Industries Work Items: Draft implementation guides (IG), user guide (UG) and Q&As MHLW/PMDA Review these documents – Industries Test E2B(R3) reporting using PMDA provided tools to evaluate feasibilityof the IG/UG and the tool – Industries Develop E2B(R3) reporting user manual (generally called “green book” )– Industries E2B(R3) Complete enforcementApril 1, 2019226th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Coordination with industry re: R3implementationPharmaceuticals and Medical Devices Agency Version 1 of R3 implementation will be announced 3 years prior to the start ofimplementation in consideration of the preparatory period for R3correspondence by companies and system vendors Subsequently, multiple notice revisions will be carried out before R3implementation Publish a beta version of the R3 reporting tool developed by PMDA andprovide opportunities for reporting companies to test Provide comments from participating companies to PMDA Representatives from industry associations will participating in the Workinggroup and provide industry opinions as working groups Industry members of the working groups will survey participating companiesand accumulate industry opinions as necessary Industry associations will set up R3 briefing sessions for participatingcompanies, MHLW, PMDA, and industry representatives will explained thecontents of R3 Main briefing session will be described in the next slide236th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Presentations of E2B(R3)implementationPharmaceuticals and Medical Devices Agency Major presentations A full-day seminar (July 2011): Introduction of ICHE2B(R3) IG ICH symposium in Japan (December 2012):Report of achieving Step 4 and explanation of theICH E2B(R3) IG package A half-day seminar (September 2013):Introduction of MHLW/PMDA IG/UG A half-day seminar (May 2015): Introduction ofrevised MHLW/PMDA IG/UG A half-day seminar (July 2016): Summary ofE2B(R3) implementation246th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)

Advantages of R3 over R2Pharmaceuticals and Medical Devices AgencyR2R3SGMLXML（HL7 format）The following 2 SGML files: ICH items (ICSR) J itemsReport formatNo versatility (static nature ofinformation)Character code used s-JISCharacteristics1 XML file also including J itemsHigh versatility of informationAll possible if UTF8File attachmentsSubmitted via postal mail or inperson submissionAll electronic attachments can beencoded as XMLBatch* reporting?NoYesReporting methodElectronicsubmission protocolElectronic reporting, CD reporting, paper reportingAS1AS1、AS2、Web site* Batch reporting is a reporting method in which multiple individual case reports, etc. are submitted as a single report256th Joint Conference of Taiwan and Japan on Medical Products Regulation (October 11, 2018)