FDAs BIMO Inspection Program and IRB Inspections VA

FDA’s BIMO Inspection Program 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 1

Disclaimer 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. 2

Objectives • • General Overview of FDA’s Bioresearch Monitoring Program (BIMO) Overview of BIMO IRB Inspection Program FDA IRB Inspection Common Findings How to Survive an Inspection Describe What is Expected in Written Responses Discuss Commissioner’s Enforcement Initiative “Preventive Maintenance” Suggestions 3

Bioresearch Monitoring Program (BIMO) Program Description • A comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated research 4

BIMO Program Objectives • Protect the rights, safety and welfare of subjects involved in FDA-regulated clinical trials • Determine 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 review 5

BIMO Program Inspections • Clinical Investigators • Sponsor/Monitor/CRO • Bioequivalence/Good Laboratory Practice • IRB • RDRC 6

BIMO Program Inspections • Covers 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 completed – FDA shifting more resources to “real-time” inspections – Selecting sites for inspection becoming increasingly more sophisticated 7

BIMO Program Inspections • Each FDA Center has oversight of inspections of research related to the product(s) it regulates • Inspections are usually conducted by ORA field investigators – FDA field investigators are NOT specifically assigned to a specific center – All field investigators are responsible for conducting inspections for all centers 8

BIMO Program - Center Responsibilities • Select entities for inspection • Issue 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 perspective • Determine final classification • Issue compliance letters 9

Potential Inspection Outcomes NAI: No Action Indicated - no objectionable conditions or practices were found during the inspection VAI: 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 sanctions 10

IRB Inspections • Purpose: – To determine if IRBs are operating in compliance with FDA regulations and IRB Written Procedures • Categories – Routine/Surveillance – Directed/For-Cause (generally a result of a complaint) – Warning Letter Follow-up* (receiving higher priority than in the past) 11

IRB Inspections • General Inspection Process – Pre-announcement – Opening Interview – Inspection of records – FDA investigator typically reviews and copies: üIRB Membership Rosters üIRB Written Procedures üIRB Meeting Minutes üDocuments related to FDA studies reviewed – Closing Meeting/Exit Interview (Issue Form FDA 483 if applicable) üDiscusses preliminary findings 12

Form FDA 483 • List of observations made by the FDA investigator during inspection • Observations do not represent final Agency determination regarding compliance 13

IRB Inspections • Post-Inspection Activities – FDA investigator prepares Establishment Inspection Report (EIR) with exhibits and recommends classification – EIR and exhibits forwarded to the FDA Center that issued the inspection – FDA Center reviews material; determines final classification; issues compliance letter 14

IRB Inspections If necessary: • Lesser Administrative Actions – FDA withhold approval of new studies – Direct that no new subjects be added to ongoing studies – Terminate ongoing studies – Notify interested parties of deficiencies (Sponsors, State Agencies, other Federal Agencies) • Disqualification 15

IRB Compliance Program Guidance Manual (CPGM) 7348. 809 • • • Basic “how to” instructions/inspectional guidelines for FDA investigators for the conduct of IRB inspections Part I – Background Part II – Implementation – – – Objectives Program Management Instructions Types of Inspections Note: CPGMs for BIMO Program are available on the FDA web site 16

CPGM 7348. 809 • Part III – Implementation – – – – – Operations Reporting Establishment Inspections Prior Notification of Intent to Inspect Refusal to Inspect Subsequent Related Sponsor/Investigator Inspections IRB Registration IRB Membership Meetings Written Procedures 17

CPGM 7348. 809 – – – – – Initial IRB Review of Research Continuing IRB Review of Research Adverse Event Reporting IRB Reporting to the Clinical Investigator and the Institution Expedited Review Exception from Informed Consent Pediatric Studies – General Electronic Records and Electronic Signatures 18

CPGM 7348. 809 – Central IRBs/Independent IRBs – Investigational New Drug (IND) Application/Investigational Device Exemption (IDE) Status • Part IV – Analytical – N/A • Part V – Regulatory/Administrative Strategy – Administrative Guidance – Regulatory Guidance – Examples of violations that may warrant OAI classification – Follow-Up Inspections – Post-Inspection Information Sharing 19

CPGM 7348. 809 • Part VI – References, Attachments, and Program Contacts – References – Program Contacts • Part VII – Headquarters Responsibilities – Centers – Division of Compliance Policy/OE/ORA – Division of Compliance Management and Operations/OE/ORA – Division of Domestic Field Investigations/ORO – Office of Good Clinical Practice, Office of the Commissioner 20

CPGM 7348. 809 • Specific 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) 21

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BIMO IRB Inspections How to Survive – – – Have an IRB member present (preferably the Chair) Ensure records available Have all SOPs/Written Procedures available IRB Membership Rosters (current and past) List of completed and ongoing studies Organized study files with documents reviewed, correspondence to CI, AE reports, progress reports – At exit interview don’t miss the opportunity to respond to findings/provide written response 28

In Summary - IRB Inspections • Governed by CPGM 7348. 809 • Federal requirements are minimum requirements • FDA has traditionally viewed IRBs as allies – Common goal: To protect the rights and welfare of human subjects • We stress compliance through cooperation and education • Categories of findings by ORA: – NAI – VAI – OAI IRBs are encouraged to provide written responses to findings 29

Potential Problems That Can Lead to Risks for Institution • Institution does not invest in the IRB – Inadequate training for IRB members and staff – Insufficient number of IRB staff • Institution has no idea what the IRB is doing or what it is supposed to do • IRB is not given sufficient independence – IO inappropriately meddles in IRB affairs 30

Potential Problems That Can Lead to Risks for Institution • IRB does not prepare and maintain adequate documentation of IRB activities – Minutes are inadequate – Written procedures are inadequate, incomplete or out of date – Procedures are okay on paper but not followed • Lack of appropriate expertise on IRB 31

Example VAI Observations 1. Meeting minutes without sufficient details (attendance, actions) 2. Failure to maintain copies of all research proposals reviewed 3. Failure to maintain list of IRB members 4. Failure to follow written procedures 5. Quorum related issues 6. Subpart D related issues (usually not categorized) 7. Inappropriate use of expedited review 8. Failure to inform IRB of research approved by expedited review 32

Example OAI Observations 1. No written procedures 2. ICF consistently lacks required elements 3. Continuing review dates consistently and substantially not met 4. Consistently lack quorum 5. Repeatedly allow conflicted IRB member to vote 6. Repeatedly failed to maintain adequate records 7. Substantially failed to minimize risk 8. Failed to implement promised corrective actions Occasionally: behavior that results in referral to Office of Criminal Investigation (e. g. falsification of records) 33

Final Classification VAI vs. OAI considerations include (not limited to): – Impact of the IRB’s actions on subjects’ rights, safety and welfare – Systemic vs. isolated event – Significance – Past inspection history – Timeliness of continuing review 34

Corrective Action Plans and Written Responses • • • Depends upon nature of violation Conduct a root cause analysis Should include description of corrective actions Should include a proposed timeline for corrections Should track well with the observation(s) in 483 or Warning Letter – For example: “For observation 1 we propose to do the following…” • Whenever possible provide documentation of completed corrective action – Copy of new Written Procedure(s) – Example of meeting minutes demonstrating new format for documentation 35

Corrective Action Plans and Written Responses • Example CAPs – Creating or updating Written Procedures – Providing training to IRB members and staff – Developing templates for minutes that prompts documentation of required content – Developing templates for ICF that prompts required elements – Obtaining additional resources to meet the needs of the IRB – Occasionally changes in personnel 36

Corrective Action Plans and Written Responses • Example CAPs – Hiring Consultants to assist in addressing problems – Developing continuing education program for CI – Developing an Audit System to find problems – Expand IRB membership to reflect the nature of the research being reviewed – Developing electronic systems to track work and dates – Developing system to alert CI of pending CR date 37

Commissioner’s Initiative 1. Set post-inspection deadlines 2. Responsible steps to speed the warning letter process 3. Work more closely with FDA’s regulatory partners 4. Prioritize follow-up on warning letters 5. Be prepared to take immediate action in response to public health risks 6. Develop and implement a formal warning letter “close-out” process 38

IRB OAI Follow-Up Inspections • • • Consistent with Commissioner’s Initiative Needed to assess implementation of CAPs The content of the written response and the nature of the violations will determine the timing of the reinspection – Generally done within 12 months of letter – Generally we want the IRB to have time to demonstrate that the corrective action plan is working IRB eligible for “Close-out” letter if all corrective actions implemented and working AND no new substantial findings seen on reinspection Repeat observations may lead to escalating actions up to disqualification 39

IRB Inspection Site Selection Tool • Developed to effectively employ limited resources in order to maximally serve the public • Used to assist in the selection of IRBs for inspection 40

Preventive Maintenance Suggestions • Monitor 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 select • Use 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 Letters 41

Preventive Maintenance Suggestions • IRB Warning Letters – lessons learned – Most common deficiencies mentioned earlier – IRB failed to adequately assess the qualifications of the CI and site – IRB approved research without adequate information on the risks posed to subjects 42

Preventive Maintenance Suggestions • Have and follow clear Written Procedures • Adequately document the IRB’s findings and actions • Ensure the IRB’s requirements and expectations are clear to your investigators • Monitor FDA’s guidance documents for new and revised guidance for IRBs, clinical investigators and sponsors 43

Preventive Maintenance Suggestions • New Guidance – IRB Continuing Review after Clinical Investigation Approval (February 2012) – Q&As on Informed Consent Elements, 21 CFR 50. 25(c) (February 2012) • Draft Guidance – Considerations When Transferring Clinical Investigation Oversight to Another IRB (June 2012) – Determining Whether Human Research Studies Can Be Conducted Without an IND (October 2010) 44

Resources • Selected FDA GCP/Clinical Trial Guidance Documents: http: //www. fda. gov/Science. Research/Special. Topics/ Running. Clinical. Trials/Guidances. Information. Sheetsa nd. Notices/ucm 219433. htm • FDA GCP website for IRB Information Sheet Guidance: http: //www. fda. gov/oc/ohrt/irbs/default. htm • Self Evaluation Checklist for IRBs: http: //www. fda. gov/Science. Research/Special. Topics/ Running. Clinical. Trials/Guidances. Information. Sheet sand. Notices/ucm 118063. htm 45

Resources • • General 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/Compliance. Manuals/Compli ance. Program. Manual/ucm 255614. htm 46

Questions? Thank You! Janet. Donnelly@fda. hhs. gov 47