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1 IRB IRB Inspections Inspections Melody Lin, Ph.D. Melody Lin, Ph.D. Deputy Director, Office for Human Research Deputy Director, Office for Human Research Protections Protections Director, International Activities Director, International Activities [email protected] [email protected] Santiago, Chile Santiago, Chile August 2006 August 2006

IRB Inspections

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IRB Inspections. Melody Lin, Ph.D. Deputy Director, Office for Human Research Protections Director, International Activities [email protected] Santiago, Chile August 2006. Objectives. Inspections Program OHRP FDA Tips for Preparation Common Deficiency Behavioral Guidelines. - PowerPoint PPT Presentation

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IRB IRB InspectionsInspections

Melody Lin, Ph.D.Melody Lin, Ph.D.Deputy Director, Office for Human Research ProtectionsDeputy Director, Office for Human Research ProtectionsDirector, International ActivitiesDirector, International [email protected]@hhs.gov

Santiago, ChileSantiago, Chile

August 2006August 2006

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ObjectivesObjectives

Inspections ProgramInspections Program– OHRPOHRP

– FDAFDATips for PreparationTips for PreparationCommon DeficiencyCommon DeficiencyBehavioral GuidelinesBehavioral Guidelines

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JurisdictionJurisdiction

OHRPOHRP– 45 CFR 4645 CFR 46

– OHRP approved assuranceOHRP approved assuranceFDAFDA

– 21 CFR 5621 CFR 56

– 21 CFR 5021 CFR 50

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Inspections ProgramInspections Program

OHRPOHRP– For cause site visitFor cause site visit

– Not for cause site visitNot for cause site visitFDAFDA

– Routine surveillance inspectionRoutine surveillance inspection

– Directed inspectionDirected inspection

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OHRP Compliance Oversight OHRP Compliance Oversight InvestigationInvestigation

Receive allegation of noncomplianceReceive allegation of noncompliance Determine OHRP jurisdiction Determine OHRP jurisdiction Written inquiry to appropriate Written inquiry to appropriate

institutional officialsinstitutional officials Review of institution’s report and Review of institution’s report and

relevant IRB documentsrelevant IRB documents Additional correspondence/telephone Additional correspondence/telephone

interview/site visit as neededinterview/site visit as needed Issue final determinationsIssue final determinations

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OHRP For-Cause Site OHRP For-Cause Site VisitsVisits

When does OHRP conduct a site visit?When does OHRP conduct a site visit? Base on:Base on:

– Nature and severity of the allegationsNature and severity of the allegations

– Evidence of systemic problemsEvidence of systemic problems

– Appropriateness of any corrective actions Appropriateness of any corrective actions takentaken

– Perceived need for more in-depth Perceived need for more in-depth discussions with institution staffdiscussions with institution staff

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OHRP For-Cause Site OHRP For-Cause Site VisitsVisits

Interview with:Interview with:– Institutional administrator(s)Institutional administrator(s)

– IRB Chairperson(s)IRB Chairperson(s)

– IRB membersIRB members

– IRB staffIRB staff

– Investigators who conduct human Investigators who conduct human subjects researchsubjects research

– Others as appropriateOthers as appropriate

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OHRP For-Cause Site OHRP For-Cause Site VisitsVisits

Record ReviewsRecord Reviews– Select 50-75 active protocols for review of Select 50-75 active protocols for review of

entire IRB record on-siteentire IRB record on-site

– Last 25 protocols approved by the IRB under Last 25 protocols approved by the IRB under an expedited review proceduresan expedited review procedures

– Last 25 amendments approved by the IRB Last 25 amendments approved by the IRB under an expedited review procedureunder an expedited review procedure

– Protocols determined to be exempt during Protocols determined to be exempt during the past 6 monthsthe past 6 months

– Minutes for all IRB meetings for last 4 yearsMinutes for all IRB meetings for last 4 years

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OHRP For-Cause Site OHRP For-Cause Site VisitsVisits

FindingsFindings– Meet with the signatory officials on Meet with the signatory officials on

the Assurance, or their designees on the Assurance, or their designees on last day to describe OHRP’s findings last day to describe OHRP’s findings

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OHRP Not-For-Cause OHRP Not-For-Cause Compliance Oversight Compliance Oversight

EvaluationsEvaluations

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Purpose of OHRP Not-for Purpose of OHRP Not-for Cause EvaluationsCause Evaluations

To assess institutional compliance To assess institutional compliance with 45 CFR 46with 45 CFR 46

In absence of specific allegationsIn absence of specific allegations Somewhat proactiveSomewhat proactive Some evaluations are partially “for Some evaluations are partially “for

cause” – previous compliance cause” – previous compliance problemsproblems

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OHRP Compliance Oversight OHRP Compliance Oversight Investigation Possible Investigation Possible Determinations/Outcomes Determinations/Outcomes (1)(1)

Protections under an institution’s Assurance Protections under an institution’s Assurance are are – in compliancein compliance

– in compliance, but recommended improvements in compliance, but recommended improvements have been identifiedhave been identified

Noncompliance identified, and Noncompliance identified, and – corrective actions required corrective actions required

– Assurance restricted pending required corrective Assurance restricted pending required corrective actionsactions

– OHRP approval of Assurance withdrawnOHRP approval of Assurance withdrawn

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OHRP may recommend that HHS OHRP may recommend that HHS Officials Officials – suspend suspend

– terminateterminate

OHRP Compliance Oversight OHRP Compliance Oversight Investigation Possible Investigation Possible Determinations/Outcomes Determinations/Outcomes (2)(2)

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OHRP may recommend:OHRP may recommend:– Debarment ofDebarment of

InstitutionsInstitutions InvestigationsInvestigations

(ineligible for HHS research support)(ineligible for HHS research support)

Compliance Oversight Compliance Oversight Investigation Possible Investigation Possible Determinations/Outcomes Determinations/Outcomes (3)(3)

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FDA IRB InspectionsFDA IRB Inspections

Selection CriteriaSelection Criteria– Past inspection historyPast inspection history

Frequency Frequency Compliance statusCompliance status

– Activity of IRBActivity of IRB

– New IRBsNew IRBs

– ComplaintsComplaints

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FDA IRB InspectionsFDA IRB Inspections

RoutineRoutine– Inspections assigned on cyclic Inspections assigned on cyclic

basis for surveillancebasis for surveillanceDirectedDirected

– Complaints to FDAComplaints to FDA FDA, other agenciesFDA, other agencies Sponsor/monitorSponsor/monitor Subjects/PublicSubjects/Public

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FDA IRB InspectionsFDA IRB Inspections

Inspections are announced and Inspections are announced and scheduled in advancescheduled in advance– Consist of interviews with responsible Consist of interviews with responsible

IRB staffIRB staff

– In-depth review of SOPs , files and In-depth review of SOPs , files and records records

– Active Active FDA regulated studiesFDA regulated studies

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Scope of FDA IRB Scope of FDA IRB InspectionsInspections

IRB membershipIRB membershipWritten procedures Written procedures Initial review and approval of Initial review and approval of

studiesstudiesContinuing review of researchContinuing review of research

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Scope of FDA IRB Scope of FDA IRB InspectionsInspections

IRB reporting to investigator and IRB reporting to investigator and institutioninstitution

ExpeditedExpedited I.C.I.C. Emergency reviewEmergency review

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Discuss IRB administration and Discuss IRB administration and proceduresprocedures– Individual responsibility and authorityIndividual responsibility and authority

– MembershipMembership

– OperationsOperations

– Record keeping requirementsRecord keeping requirements

– Review and approval of informed Review and approval of informed consentconsent

FDA IRB InspectionsFDA IRB Inspections

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FDA IRB InspectionsFDA IRB Inspections

Record ReviewRecord Review– SOPsSOPs

Must have written procedures as Must have written procedures as required by 21 CFR 58.108required by 21 CFR 58.108

Should agree with procedures Should agree with procedures described during interviewdescribed during interview

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FDA IRB InspectionsFDA IRB Inspections

Inspection of IRB files-FDA regulated Inspection of IRB files-FDA regulated study filesstudy files– Minutes of meetingsMinutes of meetings– List of IRB members List of IRB members – Documents submitted to IRB to obtain Documents submitted to IRB to obtain

study approvalstudy approval– Correspondence between IRB and Correspondence between IRB and

investigatorinvestigator– Records of continuing reviewRecords of continuing review– Any other recordsAny other records

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Conclusion of FDA IRB Conclusion of FDA IRB InspectionInspection

Exit interview with managementExit interview with management– Discussion of inspection findingsDiscussion of inspection findings

– Issuance of an FDA 483Issuance of an FDA 483

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Post FDA IRB InspectionPost FDA IRB Inspection

Detailed Narrative Report PreparedDetailed Narrative Report PreparedSubmitted to HQ BIMO Staff for Submitted to HQ BIMO Staff for

EvaluationEvaluation

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FDA Compliance Inspection FDA Compliance Inspection ClassificationClassification(1)(1)

NAI – No Action IndicatedNAI – No Action Indicated VAI – Voluntary Action IndicateVAI – Voluntary Action Indicate

– Objectionable conditions or practices were Objectionable conditions or practices were found, but FDA is not prepared to take or found, but FDA is not prepared to take or recommend any administrative of recommend any administrative of regulatory actionregulatory action

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FDA Compliance Inspection FDA Compliance Inspection ClassificationClassification(2)(2)

OAI – Official Action IndicatedOAI – Official Action Indicated– Regulatory and/or Administrative Regulatory and/or Administrative

actions will be recommended due to actions will be recommended due to significant objectionable observationssignificant objectionable observations

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Tips Tips Prior to InspectionPrior to Inspection(1)(1)

Know what the regulatory Know what the regulatory requirements are for your requirements are for your operationsoperations– 21 CFR 50 and 56 IRBs and informed 21 CFR 50 and 56 IRBs and informed

consentconsent

– 21 CFR 312 Clinical Investigators and 21 CFR 312 Clinical Investigators and Sponsors of Drugs and biologicsSponsors of Drugs and biologics

– 21 CFR 812 Clinical Investigators of 21 CFR 812 Clinical Investigators of Medical DevicesMedical Devices

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Tips Prior to InspectionTips Prior to Inspection(2)(2)

Obtain and be familiar with the Obtain and be familiar with the Compliance Program covering your Compliance Program covering your operationoperation

Retain all records necessary to Retain all records necessary to completely reconstruct activities completely reconstruct activities and findingsand findings

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Tips During the Tips During the Inspection Inspection (1) (1)

Have the most responsible Have the most responsible personnel available personnel available – IRB ChairIRB Chair

– IRB administrator/Exec. Sec.IRB administrator/Exec. Sec.

– Institutional officialInstitutional official

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Tips During the Tips During the InspectionInspection(2)(2)

Have all records readily available Have all records readily available and organizedand organized

Be available throughout the Be available throughout the inspection to answer questionsinspection to answer questions

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Tips During Inspection Tips During Inspection (3)(3)

Update records, organized and be Update records, organized and be availableavailable– Inventory of ongoing research and current Inventory of ongoing research and current

statusstatus– IRB SOPs covering current practicesIRB SOPs covering current practices– IRB membership rosters, current and pastIRB membership rosters, current and past– IRB meeting minutesIRB meeting minutes– Records of tracked studiesRecords of tracked studies

Protocol, consent forms, IRB Protocol, consent forms, IRB correspondence, etc.correspondence, etc.

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Post FDA IRB InspectionPost FDA IRB Inspection

CorrespondenceCorrespondence– Sent to IRB Chair Sent to IRB Chair

– Describes which practices or Describes which practices or conditions, were determined to be conditions, were determined to be objectionableobjectionable

– Letters are sent for serious Letters are sent for serious noncompliance and require a response noncompliance and require a response

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Recurrent Compliance ProblemsRecurrent Compliance Problems(1)(1)

• IRB failure to review grant applicationsIRB failure to review grant applications• IRB lacks sufficient information to IRB lacks sufficient information to

make determinations make determinations • Inadequate continuing review, or Inadequate continuing review, or

longer than 1 yearlonger than 1 year• Inadequate IRB review at convened Inadequate IRB review at convened

meetingsmeetings

• IRB failure to review grant applicationsIRB failure to review grant applications• IRB lacks sufficient information to IRB lacks sufficient information to

make determinations make determinations • Inadequate continuing review, or Inadequate continuing review, or

longer than 1 yearlonger than 1 year• Inadequate IRB review at convened Inadequate IRB review at convened

meetingsmeetings

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• Contingent approval without Contingent approval without subsequent re-reviewsubsequent re-review

• IRB meetings without a quorumIRB meetings without a quorum• IRB members with conflicts of interestIRB members with conflicts of interest• Inadequate records, minutes, files, Inadequate records, minutes, files,

documentation, policies and documentation, policies and proceduresprocedures

• Contingent approval without Contingent approval without subsequent re-reviewsubsequent re-review

• IRB meetings without a quorumIRB meetings without a quorum• IRB members with conflicts of interestIRB members with conflicts of interest• Inadequate records, minutes, files, Inadequate records, minutes, files,

documentation, policies and documentation, policies and proceduresprocedures

Recurrent Compliance ProblemsRecurrent Compliance Problems(2)(2)

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• Inappropriate use of expedited review Inappropriate use of expedited review for new, continuing, and changesfor new, continuing, and changes

• Failure to report unanticipated problems Failure to report unanticipated problems to IRB, IO, OHRPto IRB, IO, OHRP

• Failure or inadequate review of protocol Failure or inadequate review of protocol changeschanges

• Inappropriate use of exempt categoriesInappropriate use of exempt categories

• Inappropriate use of expedited review Inappropriate use of expedited review for new, continuing, and changesfor new, continuing, and changes

• Failure to report unanticipated problems Failure to report unanticipated problems to IRB, IO, OHRPto IRB, IO, OHRP

• Failure or inadequate review of protocol Failure or inadequate review of protocol changeschanges

• Inappropriate use of exempt categoriesInappropriate use of exempt categories

Recurrent Compliance Problems(3)

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• Deficient or inadequate informed consent documents

• Lack of diversity, expertise of IRB membership

• Overburdened IRB• Inadequate IRB resources

Recurrent Compliance ProblemsRecurrent Compliance Problems(4)(4)

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Common IRB Deficiencies Common IRB Deficiencies (FDA)(FDA)

Written proceduresWritten procedures– Incomplete – inadequate – not followedIncomplete – inadequate – not followed

– Expedited reviewExpedited review

– Device SR/NSRDevice SR/NSR

– Inadequate continuing reviewsInadequate continuing reviews

– Minutes insufficientMinutes insufficient

– Vote not recorded by number of votesVote not recorded by number of votes

– Adverse events not adequately reviewedAdverse events not adequately reviewed

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Majority of members not at Majority of members not at meeting meeting

Majority of members not present Majority of members not present for votefor vote

Non-scientific member not presentNon-scientific member not presentFail to report to FDA when study is Fail to report to FDA when study is

suspended or terminatedsuspended or terminated

Common IRB Deficiencies Common IRB Deficiencies (FDA)(FDA)

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Behavioral Behavioral GuidelinesGuidelines

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Rules to Follow During Rules to Follow During InspectionInspection

Know the contents of your job Know the contents of your job descriptiondescription

Be aware of your body languageBe aware of your body languageNever remain in the room to chat Never remain in the room to chat

with a inspector after you have with a inspector after you have answered all inspection related answered all inspection related questions.questions.

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More to do’s…More to do’s…

Be yourselfBe yourselfRemain focusedRemain focusedAnswer only the question askedAnswer only the question asked

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More to do’s…More to do’s…

Think before you answer. There Think before you answer. There are no bonus points for being fastare no bonus points for being fast

Remain calm, remember you do Remain calm, remember you do your job every day, and no one your job every day, and no one knows your job as well as youknows your job as well as you

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What is Redacting?What is Redacting?

Redacting is the act of selecting Redacting is the act of selecting or adapting for publication or or adapting for publication or releaserelease

Remove all information that the Remove all information that the inspector is not legally entitled to inspector is not legally entitled to seesee

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Use Caution During Use Caution During InspectionInspection

Don’t fill in the silencesDon’t fill in the silencesDon’t allow yourself to become Don’t allow yourself to become

irritated. Maintain a professional irritated. Maintain a professional demeanor at all timesdemeanor at all times

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Answer all “yes” or “no” Answer all “yes” or “no” questions with “yes" or “no”questions with “yes" or “no”

Do not editorialize or volunteer Do not editorialize or volunteer informationinformation

More cautions…More cautions…

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More cautions…More cautions…

Never hand a document directly Never hand a document directly to a inspector - - - always pass to a inspector - - - always pass documents to the inspection documents to the inspection team leadersteam leaders

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More cautions…More cautions…

Never volunteer information on Never volunteer information on any subjectany subject

Never refer to another topic, Never refer to another topic, area, or procedure when area, or procedure when answering a questionanswering a question

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Body LanguageBody Language

Do not sit on the edge of your Do not sit on the edge of your chair, chair,

Make eye contactMake eye contactDo not play with your hair, twirl Do not play with your hair, twirl

your thumbs, click your ink pin, your thumbs, click your ink pin, or tap your fingersor tap your fingers

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Body LanguageBody Language

Do not watch the doorDo not watch the doorNever cross your arms over your Never cross your arms over your

chest or slouch in your chairchest or slouch in your chair

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Statement to Avoid…Statement to Avoid…

““It’s supposed to do (fill in the It’s supposed to do (fill in the blank).”blank).”

““Wow, it usually never does it right Wow, it usually never does it right the first time!”the first time!”

““Do you want to know how it is Do you want to know how it is supposed to happen or how it supposed to happen or how it really happens?”really happens?”

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Statement to Avoid…Statement to Avoid…

““I didn’t even know we had an SOP I didn’t even know we had an SOP for that!”for that!”

““I didn’t even know the SOP said I didn’t even know the SOP said that.”that.”

““I don’t know (with no follow-up).”I don’t know (with no follow-up).”

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Statement to Avoid…Statement to Avoid…

““Let me show you what we do for Let me show you what we do for Pfizer (or any other client).”Pfizer (or any other client).”

““Would you like to see all our Would you like to see all our metrics?”metrics?”

““Well, I can try to do that for you, Well, I can try to do that for you, but I’ve never really been trained.”but I’ve never really been trained.”