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Risk-based approachon GCP inspectionKazuhiro Matsui, Ph.D.Inspection DirectorOffice of Conformity AuditPMDA

DisclaimerThe views and opinions expressed inthe following PowerPoint slides arethose of the individual presenter andshould not be attributed to MHLW orPMDA. This is not an official PMDAguidance or policy statement.

Contents1. Trends in Improvement of the Efficiencyin Clinical Trials2. Risk-based Approach to GCP Monitoring3. GCP Inspection Procedure in Japan4. EDC Management Sheets

Contents1. Trends in Improvement of the Efficiencyin Clinical Trials2. Risk-based Approach to GCP Monitoring3. GCP Inspection Procedure in Japan4. EDC Management Sheets

Trend in Notified CTs in JapanNo. of initialnotificationInitial CT Notification (NCEs onlｙ）CT notification3-year nation-wide300clinical trialsvitalization plan722250(extended by 1 year)616497 504500463424406 815050800New 5-year clinicaltrials activation planEnactment of new GCP200100No. ofnotification60105107 109119 121132400123563002004310001996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 †† 5-year clinical trials vitalization plan 2012 started in 201205

Trends in Improvement of the efficiencyin clinical trials (1)“5-year Clinical Trials Vitalization Plan 2012”30 March, 2012 Notification 0330 No.33 MHLW/HSB1. The next action forward based on the vitalization plans of the last9 years(1) Enrollment of subjects(2) Procedures for Implementation of Clinical TrialsImprovement in efficiency of monitoring operations considering ofsampling methods to select data for SDV(3) Human resources development (physicians etc.)(4) Dissemination and education for patients and people(5) Appropriate cost(6) Promotion of utilization of IT technologies, etc.2. Approach for Innovative pharmaceuticals and medical devicesdeveloped in Japan6

Trends in Improvement of the efficiencyin clinical trials (2)“Research on the operations of the sponsor-investigator clinical trials”FY2012 Health, Labour and Welfare Scientific Research Grantsfor General Research on Drugs and Medical Devices Regulatory SciencesThe principal researcher, Professor Yuji Watanabe(Faculty of Medicine, Hamamatsu Medical University)Contributor to the research,2012“The application of electromagnetic record to the Clinical Trial-relatedDocuments for the conduct of a clinical trial”“Basic principles of Utilization of Electromagnetic RecordsIn Clinical Trial Documents”MHLW PFSB/ELD Notice, 1 July 2013The advantages of electromagnetic method for recording can be maximizedwhen the characteristics of the method (advantages and/or points of attentioncompared to those of paper documents) is fully understood7

Recent trend on Utilization of Electromagnetic Records Electromagnetic Documentation of Clinical trials1. Notification regarding utilization of electromagnetic record on clinical trialrelated documents† MHLW Administrative Notice(July 01, 2013)2. Project for Trial-related documents delivery by electromagnetic records† Electromagnetic Implement Task Force(JPMA, 2014) Electronic Data Capture (EDC) and Application Data1. Notification regarding inspection method for clinical trials which use EDCsystem† PMDA/CPE Notification No. 0327001(March 27, 2013)2. Electronic Clinical Study Data for Pilot Project† PMDA/CPE Notification No. 0902001(September 02, 2013)3. Project for ‘Remote Data Monitoring’ and ‘EDC- EHR communication’† Health Labour Sciences Research Grant(2013)4. Project for clarifying inspection policy for clinical trials in which CDISCstandard is applied† PMDA the current mid-term target(2014-2019)8

Trends in Improvement of the efficiencyin clinical trials (3)“Research on the operations of the sponsor-investigator clinical trials”FY2012 Health, Labour and Welfare Scientific Research Grantsfor General Research on Drugs and Medical Devices Regulatory SciencesThe principal researcher, Professor Yuji Watanabe(Faculty of Medicine, Hamamatsu Medical University)Contributor to the research, 2012“Research about Risk-Based SDV approaches”“Basic principles of the Risk-Based Approach to Monitoring”MHLW PFSB/ELD Notice, 1 July, 2013Presenting basic principles of risk-based approach for monitoringand SDV9

Contents1. Trends in Improvement of the Efficiencyin Clinical Trials2. Risk-based Approach to GCP Monitoring3. GCP Inspection Procedure in Japan4. EDC Management Sheets

Background To conduct clinical trials, a great volume of operations andcosts are required for monitoring Popularization of EDC (Electronic Data Capture) enablesclinical trial data to be consolidated rapidly and centrally Centralized monitoring is accepted under GCP Ordinance,when the safety of the subjects is secured and the integrityof clinical trial data is assuredConsideration of the risk-based approach to monitoring“Basic principles of the Risk-Based Approach to Monitoring Clinical Trials” MHLW PFSB/ELD Notice, 1 July, 201311

What is Risk-Based SDV approach ? A method to conduct SDV that verifies items selected inaccordance with the pre-determined procedure, taking intoconsideration the impact of the data on the quality of theclinical trials, from the perspective of the safety of thesubjects and importance of the data＊Ministerial Ordinance on GCP Article 21 Paragraph 1 ; GuidanceIf the clinical trials are operated appropriately in the core clinical trialhospitals, etc., not all data are required to be verified with source data“Basic principles of the Risk-Based Approach to Monitoring Clinical Trials” MHLW PFSB/ELD Notice, 1 July, 201312

Management of Clinical Trial ProcessesAdministration /controllingof electric medical recordsystemcontrol/accountabilityof the IPsRecord keepingSelection of IRB andRequesting of deliberationAssigneddutiesSelection ofsubjects and ICConductinga clinical trialAuditsProtocolCRF etc.Responsibilities formedical careof subjectsImplementing/controlling datacapture systemInformation onADR etc.Clinical trialreportsSelection ofmedical institutionand investigatorMedical recordsReporting ofADRsInformation sharingto involved partiesControl/accountabilityof the IPsSupply of the IPsInvestigator’sBrochureMonitoringRecordkeeping etc.* Regarding risk-based monitoring, it is important to consider not onlyeffectiveness of monitoring, but also process management in medicalinstitutions, etc.13

Risk-based monitoring : Basic principles (1) It is essential for persons in charges in medical institutions to striveto submit data promptly, considering that monitoring could beconducted not by means of SDV It is essential that principal investigator/sub investigators and CRCetc. understand the aim and procedures of risk based monitoringadequatelyIt is a requirement that the involved personnel are aware thatit is their own responsibility to create accurate CRFs in medicalinstitutions Emphasis must be placed on process management of clinical trialsin the medical institution and it is essential that appropriatemeasures are in place to fill out CRFs accurately“Basic principles of the Risk-Based Approach to Monitoring Clinical Trials” MHLW PFSB/ELD Notice, 1 July, 201314

Risk-based monitoring : Basic principles (2) It is important that the sponsors ensure that the clinicaltrials (protocol, CRF, etc.) are designed concisely and clearly;for example, collecting only data those are fit for purpose The following items should be considered: the aim of theclinical trial, the trial design, the endpoints, the studypopulation, and the experience of both the principalinvestigator and the medical institution, and the clinical trialimplementation structure.“Basic principles of the Risk-Based Approach to Monitoring Clinical Trials” MHLW PFSB/ELD Notice, 1 July, 201315

Contents1. Trends in Improvement of the Efficiencyin Clinical Trials2. Risk-based Approach to GCP Monitoring3. GCP Inspection Procedure in Japan4. EDC Management Sheets

GCP Inspection Procedure in Japan Application-based Conducted after the clinical trials (or surveys) havefinished By verifying the implementation status of thefinished clinical trials (or surveys), we aim to securethe quality of ongoing clinical trials (or surveys),and/or trials (or surveys), scheduled in the future. Timing New-drug Application Pre-approval Re-examination Application Post-marketing 17

Selection of Medical InstitutionsCurrent Procedure The drugs with new active pharmaceutical ingredients(Excluding the drugs of quick/priority review, the orphan drugs) OthersPoints to be considered Priority of clinical trials included in the application(ex; pivotal clinical trial) The number of subjects Results of previous inspections * Additional inspections will be conducted if there are problems identifiedduring review/inspection process.18

Conducting GCP On-site Inspection in OverseasCurrent Procedure Points to be considered Pivotal clinical trials conducted in overseas ? Already approved product in overseas ? Already inspected trial/institution by foreignauthorities ? Selection of medical institutions By the same way as in Japan19

Conclusion of GCP On-site InspectionCompliance:Acceptable as application dossier(indicate voluntary action, if necessary)Compliance with condition:Violation of GCP was found in a part ofsubjects Acceptable as application dossierafter excluding the data from NDA packageNon-compliance:Violation of GCP was found generally andsystematically No reliability Not acceptable as application dossier20

Results of GCP On-site InspectionTo sponsors Finding(s) for preparation of clinical trials(preparation of protocol, investigator’s brochure, etc.) Finding(s) for control of clinical trials(monitor’s responsibility, provision of safety information, etc.)To medical institutions General finding(s)(control of investigational products, IRB, etc. ) Finding(s) for individual subjects(informed consent, protocol deviations, etc.)21

Trend in GCP On-site InspectionsFY’ 08FY’ 09FY’ 10FY’ 11FY’ 12Number ofdrugs(NMEs)100(3)84(6)84(7)83(7)99(5)Number ofsponsors100(4)80(6)78(7)87(7)99(5)Number 9(9)(): The number of inspections in overseas22

Detail of Overseas InspectionNumber ofinspection2)Accumulated totalfrom April, 2007 toMarch, umber of Notices of results issuedIncluding the number of CRO23

Conclusion of GCP On-site Inspectionfor New Drugs (FY 2012) 1,2)Compliance(voluntary actions toimprove indicated)12 cases on)87(88%)61casescases(74%)A total of 99 cases 3)1) The products for which the inspection result notification was issuedfrom Apr. 2012 to Mar. 2013.2) There was no “Non-compliance” and ”Compliance with condition” casesin FY 2012.3) Number of inspection result notifications issued (per applicant).24

Findings for Sponsors in JAPAN (FY 2012)Details of findingsfor monitor’s responsibility（N 9 cases）Others4 casesMonitor’sresponsibility9 casesSafetyinformationreporting8 cases（N 21 cases）Protocoldeviation2 casesDiscrepancyof CRF*3 casesRetention ofEssentialdocuments4 cases*CRF: Case Report Form25

Findings for Sponsors in Overseas (FY 2009 - 2011)Details of findingsfor monitor’s responsibility（N 20 cases）Others3 casesOthers2 casesMonitor’sresponsibility20 cases（N 23 cases）Deficiency ofSubinvestigator’sdesignate3 casesProtocol deviation7 casesDiscrepancyof CRF8 cases26

General Findings for Medical Institutions(FY2012 for JAPAN, FY2009 – 2012 for Overseas)OverseasJAPANOthers1 caseContract ofclinical trial1 caseIRB’s review2 casesContract ofoutsourcing5 casesSubinvestigator’sdesignate4 casesInvestigationalproduct control6 cases（N 14 cases）Contract ofoutsourcing1 caseInvestigationalproduct control4 cases（N 10 cases）27