and IRB Inspections VA IRB Chairs Meeting August 2012 Janet Donnelly RAC CIP Office of Good Clinical Practice Office of the Commissioner Food and Drug Administration 2 2 Disclaimer The views expressed in this presentation are those of the speaker and is consistent with 21 CFR 1085 ID: 283666
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FDA’s BIMO Inspection Program and IRB Inspections
VA IRB Chairs MeetingAugust 2012Janet Donnelly RAC, CIPOffice of Good Clinical Practice Office of the CommissionerFood and Drug Administration Slide2
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2Disclaimer
The views expressed in this presentation are those of the speaker and is consistent with 21 CFR 10.85 (k) and constitutes an informal communication that represents the presenter's best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed. Slide3
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ObjectivesGeneral Overview of FDA’s Bioresearch Monitoring Program (BIMO)Overview of BIMO IRB Inspection ProgramFDA IRB Inspection Common FindingsHow to Survive an Inspection
Describe What is Expected in Written ResponsesDiscuss Commissioner’s Enforcement Initiative“Preventive Maintenance” SuggestionsSlide4
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Bioresearch Monitoring Program (BIMO) Program DescriptionA comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated researchSlide5
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BIMO Program ObjectivesProtect the rights, safety and welfare of subjects involved in FDA-regulated clinical trialsDetermine the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications
Assess compliance with FDA’s regulations governing the conduct of clinical trials, including those for informed consent and ethical reviewSlide6
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BIMO Program Inspections
Clinical InvestigatorsSponsor/Monitor/CRO Bioequivalence/Good Laboratory PracticeIRBRDRCSlide7
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BIMO Program InspectionsCovers FDA-regulated products Follow FDA Compliance Program Guidance Manual (CPGMs specific to inspected entity)Number of studies inspected limited by available resources
Generally inspect after studies completedFDA shifting more resources to “real-time” inspectionsSelecting sites for inspection becoming increasingly more sophisticatedSlide8
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BIMO Program InspectionsEach FDA Center has oversight of inspections of research related to the product(s) it regulatesInspections are usually conducted by ORA field investigatorsFDA field investigators are NOT specifically assigned to a specific centerAll field investigators are responsible for conducting inspections for all centers Slide9
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BIMO Program - Center ResponsibilitiesSelect entities for inspectionIssue assignments to Office of Regulatory Affairs (ORA)Participate on inspection when expertise is required
Serve as consultants during inspections Evaluate the results of inspections from a scientific, medical, and regulatory perspectiveDetermine final classificationIssue compliance lettersSlide10
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Potential Inspection OutcomesNAI: No Action Indicated - no objectionable conditions or practices were found during the inspectionVAI: Voluntary Action Indicated - objectionable conditions or practices were found during the inspection that represented departures from the regulations
OAI: Official Action Indicated – the objectionable conditions or practices found during the inspection represented significant departures from the regulations and may require the imposition of administrative/regulatory sanctionsSlide11
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IRB InspectionsPurpose: To determine if IRBs are operating in compliance with FDA regulations and IRB Written Procedures
CategoriesRoutine/SurveillanceDirected/For-Cause (generally a result of a complaint)Warning Letter Follow-up* (receiving higher priority than in the past)Slide12
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IRB InspectionsGeneral Inspection ProcessPre-announcementOpening Interview Inspection of records
FDA investigator typically reviews and copies:IRB Membership RostersIRB Written ProceduresIRB Meeting MinutesDocuments related to FDA studies reviewedClosing Meeting/Exit Interview (Issue Form FDA 483 if applicable)Discusses preliminary findingsSlide13
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Form FDA 483List of observations made by the FDA investigator during inspectionObservations do not represent finalAgency determination regarding complianceSlide14
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IRB InspectionsPost-Inspection ActivitiesFDA investigator prepares Establishment Inspection Report (EIR) with exhibits and recommends classificationEIR and exhibits forwarded to the FDA Center that issued the inspection
FDA Center reviews material; determines final classification; issues compliance letterSlide15
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IRB InspectionsIf necessary:Lesser Administrative ActionsFDA withhold approval of new studiesDirect that no new subjects be added to ongoing studies
Terminate ongoing studiesNotify interested parties of deficiencies (Sponsors, State Agencies, other Federal Agencies)DisqualificationSlide16
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IRB Compliance Program Guidance Manual (CPGM) 7348.809Basic “how to” instructions/inspectional guidelines for FDA investigators for the conduct of IRB inspectionsPart I – BackgroundPart II – Implementation
ObjectivesProgram Management InstructionsTypes of InspectionsNote: CPGMs for BIMO Program are available on the FDA web siteSlide17
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CPGM 7348.809Part III – ImplementationOperationsReporting
Establishment InspectionsPrior Notification of Intent to InspectRefusal to InspectSubsequent Related Sponsor/Investigator InspectionsIRB RegistrationIRB MembershipMeetingsWritten ProceduresSlide18
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CPGM 7348.809Initial IRB Review of ResearchContinuing IRB Review of ResearchAdverse Event ReportingIRB Reporting to the Clinical Investigator and the Institution
Expedited ReviewException from Informed ConsentInformed ConsentPediatric Studies – GeneralElectronic Records and Electronic SignaturesSlide19
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CPGM 7348.809Central IRBs/Independent IRBsInvestigational New Drug (IND) Application/Investigational Device Exemption (IDE) StatusPart IV – Analytical – N/APart V – Regulatory/Administrative Strategy
Administrative GuidanceRegulatory GuidanceExamples of violations that may warrant OAI classificationFollow-Up InspectionsPost-Inspection Information SharingSlide20
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CPGM 7348.809Part VI – References, Attachments, and Program ContactsReferencesProgram ContactsPart VII – Headquarters Responsibilities
CentersDivision of Compliance Policy/OE/ORADivision of Compliance Management and Operations/OE/ORADivision of Domestic Field Investigations/OROOffice of Good Clinical Practice, Office of the CommissionerSlide21
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CPGM 7348.809Specific to VA IRB inspections:Per the September 7, 2010 agreement between VA and FDA, and upon written request by the VA’s ORO, FDA’s Center contacts are authorized to provide ORO redacted copies of FDA-reviewed EIRs and any post-inspection correspondence issued to VA facilities or employees following any inspection (including any 483) Slide22
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BIMO IRB InspectionsHow to SurviveHave an IRB member present (preferably the Chair)Ensure records availableHave all SOPs/Written Procedures available
IRB Membership Rosters (current and past)List of completed and ongoing studiesOrganized study files with documents reviewed, correspondence to CI, AE reports, progress reportsAt exit interview don’t miss the opportunity to respond to findings/provide written response Slide29
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In Summary - IRB InspectionsGoverned by CPGM 7348.809Federal requirements are minimum requirements
FDA has traditionally viewed IRBs as alliesCommon goal: To protect the rights and welfare of human subjectsWe stress compliance through cooperation and educationCategories of findings by ORA:NAIVAI OAIIRBs are encouraged to provide written responses to findingsSlide30
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Potential Problems That Can Lead to Risks for InstitutionInstitution does not invest in the IRBInadequate training for IRB members and staffInsufficient number of IRB staffInstitution has no idea what the IRB is doing or what it is supposed to do
IRB is not given sufficient independenceIO inappropriately meddles in IRB affairsSlide31
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Potential Problems That Can Lead to Risks for InstitutionIRB does not prepare and maintain adequate documentation of IRB activitiesMinutes are inadequateWritten procedures are inadequate, incomplete or out of dateProcedures are okay on paper but not followed
Lack of appropriate expertise on IRBSlide32
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Example VAI ObservationsMeeting minutes without sufficient details (attendance, actions)Failure to maintain copies of all research proposals reviewed
Failure to maintain list of IRB membersFailure to follow written procedures Quorum related issuesSubpart D related issues (usually not categorized)Inappropriate use of expedited reviewFailure to inform IRB of research approved by expedited reviewSlide33
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Example OAI Observations1. No written procedures2. ICF consistently lacks required elements
3. Continuing review dates consistently and substantially not met4. Consistently lack quorum5. Repeatedly allow conflicted IRB member to vote6. Repeatedly failed to maintain adequate records7. Substantially failed to minimize risk8. Failed to implement promised corrective actionsOccasionally:
behavior that results in referral to Office of Criminal Investigation (e.g. falsification of records)Slide34
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Final ClassificationVAI vs. OAI considerations include (not limited to):Impact of the IRB’s actions on subjects’
rights, safety and welfareSystemic vs. isolated eventSignificance Past inspection history Timeliness of continuing reviewSlide35
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Corrective Action Plans andWritten ResponsesDepends upon nature of violation
Conduct a root cause analysisShould include description of corrective actionsShould include a proposed timeline for correctionsShould track well with the observation(s) in 483 or Warning LetterFor example: “For observation 1 we propose to do the following…”Whenever possible provide documentation of completed corrective actionCopy of new Written Procedure(s)Example of meeting minutes demonstrating new format for documentationSlide36
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Corrective Action Plans andWritten ResponsesExample CAPs
Creating or updating Written ProceduresProviding training to IRB members and staffDeveloping templates for minutes that prompts documentation of required contentDeveloping templates for ICF that prompts required elementsObtaining additional resources to meet the needs of the IRBOccasionally changes in personnelSlide37
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Corrective Action Plans andWritten ResponsesExample CAPs
Hiring Consultants to assist in addressing problemsDeveloping continuing education program for CIDeveloping an Audit System to find problems Expand IRB membership to reflect the nature of the research being reviewedDeveloping electronic systems to track work and datesDeveloping system to alert CI of pending CR dateSlide38
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Commissioner’s InitiativeSet post-inspection deadlinesResponsible steps to speed the warning letter process
Work more closely with FDA’s regulatory partnersPrioritize follow-up on warning lettersBe prepared to take immediate action in response to public health risks
Develop and implement a formal warning letter “close-out” processSlide39
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IRB OAI Follow-Up InspectionsConsistent with Commissioner’s InitiativeNeeded to assess implementation of CAPsThe content of the written response and the nature of the violations will determine the timing of the reinspection
Generally done within 12 months of letterGenerally we want the IRB to have time to demonstrate that the corrective action plan is workingIRB eligible for “Close-out” letter if all corrective actions implemented and working AND no new substantial findings seen on reinspectionRepeat observations may lead to escalating actions up to disqualificationSlide40
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IRB Inspection Site Selection ToolDeveloped to effectively employ limited resources in order to maximally serve the publicUsed to assist in the selection of IRBs for inspectionSlide41
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Preventive Maintenance SuggestionsMonitor FDA Warning Letters (WLs) Sign up for FDA’s free e-mail subscription service to receive an e-mail message each time there is an update on the FDA page(s) you selectUse any of the WL "Browse" functions: Browse Warning Letters by Company
Browse Warning Letters by Issuing Office Browse Warning Letters by Subject Browse Warning Letters with Response Letters Browse Warning Letters with Closeout LettersSlide42
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Preventive Maintenance SuggestionsIRB Warning Letters – lessons learnedMost common deficiencies mentioned earlierIRB failed to adequately assess the qualifications of the CI and site IRB approved research without adequate information on the risks posed to subjectsSlide43
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Preventive Maintenance SuggestionsHave and follow clear Written ProceduresAdequately document the IRB’s findings and actions
Ensure the IRB’s requirements and expectations are clear to your investigatorsMonitor FDA’s guidance documents for new and revised guidance for IRBs, clinical investigators and sponsorsSlide44
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Preventive Maintenance SuggestionsNew GuidanceIRB Continuing Review after Clinical Investigation Approval (February 2012)Q&As on Informed Consent Elements, 21 CFR 50.25(c) (February 2012)Draft GuidanceConsiderations When Transferring Clinical Investigation Oversight to Another IRB (June 2012)
Determining Whether Human Research Studies Can Be Conducted Without an IND (October 2010) Slide45
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ResourcesSelected FDA GCP/Clinical Trial Guidance Documents: http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm219433.htmFDA GCP website for IRB Information Sheet Guidance:
http://www.fda.gov/oc/ohrt/irbs/default.htmSelf Evaluation Checklist for IRBs:http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm118063.htm Slide46
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ResourcesGeneral GCP Information:http://www.fda.gov/oc/gcp/Policy Questions: gcp.questions@fda.hhs.gov
BIMO Inspection Compliance Program Guidance Manuals: http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/ucm255614.htmSlide47
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Questions?
Thank You!Janet.Donnelly@fda.hhs.gov