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FDA’s BIMO Inspection Program and

IRB Inspections

VA IRB Chairs MeetingAugust 2012

Janet Donnelly RAC, CIPOffice of Good Clinical Practice

Office of the CommissionerFood and Drug Administration

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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.

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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

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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

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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

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BIMO Program Inspections• Clinical Investigators

• Sponsor/Monitor/CRO

• Bioequivalence/Good Laboratory Practice

• IRB

• RDRC

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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

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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

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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

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Potential Inspection OutcomesNAI: 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

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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)

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IRB Inspections• General Inspection Process

– Pre-announcement– Opening Interview – Inspection of records– FDA investigator typically reviews and copies:

IRB Membership RostersIRB Written ProceduresIRB Meeting MinutesDocuments related to FDA studies reviewed

– Closing Meeting/Exit Interview (Issue Form FDA 483 if applicable)Discusses preliminary findings

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Form FDA 483

• List of observations made by

the FDA investigator during inspection

• Observations do not represent final

Agency determination regarding compliance

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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

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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

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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

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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

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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– Informed Consent– Pediatric Studies – General– Electronic Records and Electronic Signatures

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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

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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

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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)

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BIMO IRB InspectionsHow 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

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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

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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

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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

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Example VAI Observations1. Meeting minutes without sufficient details

(attendance, actions)2. Failure to maintain copies of all research proposals

reviewed3. Failure to maintain list of IRB members4. Failure to follow written procedures 5. Quorum related issues6. Subpart D related issues (usually not categorized)7. Inappropriate use of expedited review8. Failure to inform IRB of research approved by

expedited review

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Example OAI Observations1. No written procedures2. ICF consistently lacks required elements3. 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 actions

Occasionally: behavior that results in referral to Office of Criminal Investigation (e.g. falsification of records)

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Final ClassificationVAI 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

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Corrective Action Plans andWritten 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

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Corrective Action Plans andWritten 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

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Corrective Action Plans andWritten 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

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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

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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

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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

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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

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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

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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

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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)

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Resources• Selected FDA GCP/Clinical Trial Guidance

Documents:

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm219433.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/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm118063.htm

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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/ComplianceManuals/ComplianceProgramManual/ucm255614.htm

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Questions?

Thank You!Janet.Donnelly@fda.hhs.gov