1. 1 IRB Inspections Melody Lin, Ph.D. Deputy Director, Office for Human Research Protections Director, International Activities Melody.Lin@hhs.gov Santiago, Chile August 2006

2. 2 Objectives Inspections Program Inspections Program – OHRP – FDA Tips for Preparation Tips for Preparation Common Deficiency Common Deficiency Behavioral Guidelines Behavioral Guidelines

3. 3 Jurisdiction OHRP OHRP – 45 CFR 46 – OHRP approved assurance FDA FDA – 21 CFR 56 – 21 CFR 50

4. 4 Inspections Program OHRP OHRP – For cause site visit – Not for cause site visit FDA FDA – Routine surveillance inspection – Directed inspection

5. 5 OHRP Compliance Oversight Investigation Receive allegation of noncompliance Receive allegation of noncompliance Determine OHRP jurisdiction Determine OHRP jurisdiction Written inquiry to appropriate institutional officials Written inquiry to appropriate institutional officials Review of institutions report and relevant IRB documents Review of institutions report and relevant IRB documents Additional correspondence/telephone interview/site visit as needed Additional correspondence/telephone interview/site visit as needed Issue final determinations Issue final determinations

6. 6 OHRP For-Cause Site Visits When does OHRP conduct a site visit? When does OHRP conduct a site visit? Base on: Base on: – Nature and severity of the allegations – Evidence of systemic problems – Appropriateness of any corrective actions taken – Perceived need for more in-depth discussions with institution staff

7. 7 OHRP For-Cause Site Visits Interview with: Interview with: – Institutional administrator(s) – IRB Chairperson(s) – IRB members – IRB staff – Investigators who conduct human subjects research – Others as appropriate

8. 8 OHRP For-Cause Site Visits Record Reviews Record Reviews – Select 50-75 active protocols for review of entire IRB record on-site – Last 25 protocols approved by the IRB under an expedited review procedures – Last 25 amendments approved by the IRB under an expedited review procedure – Protocols determined to be exempt during the past 6 months – Minutes for all IRB meetings for last 4 years

9. 9 OHRP For-Cause Site Visits Findings Findings – Meet with the signatory officials on the Assurance, or their designees on last day to describe OHRPs findings

10. 10 OHRP Not-For-Cause Compliance Oversight Evaluations

11. 11 Purpose of OHRP Not-for Cause Evaluations To assess institutional compliance with 45 CFR 46 To assess institutional compliance with 45 CFR 46 In absence of specific allegations In absence of specific allegations Somewhat proactive Somewhat proactive Some evaluations are partially for cause – previous compliance problems Some evaluations are partially for cause – previous compliance problems

12. 12 OHRP Compliance Oversight Investigation Possible Determinations/Outcomes (1) Protections under an institutions Assurance are Protections under an institutions Assurance are – in compliance – in compliance, but recommended improvements have been identified Noncompliance identified, and Noncompliance identified, and – corrective actions required – Assurance restricted pending required corrective actions – OHRP approval of Assurance withdrawn

13. 13 OHRP may recommend that HHS Officials OHRP may recommend that HHS Officials – suspend – terminate OHRP Compliance Oversight Investigation Possible Determinations/Outcomes (2)

14. 14 OHRP may recommend: OHRP may recommend: – Debarment of Institutions Institutions Investigations Investigations (ineligible for HHS research support) Compliance Oversight Investigation Possible Determinations/Outcomes (3)

15. 15 FDA IRB Inspections Selection Criteria Selection Criteria – Past inspection history Frequency Frequency Compliance status Compliance status – Activity of IRB – New IRBs – Complaints

16. 16 FDA IRB Inspections Routine Routine – Inspections assigned on cyclic basis for surveillance Directed Directed – Complaints to FDA FDA, other agencies FDA, other agencies Sponsor/monitor Sponsor/monitor Subjects/Public Subjects/Public

17. 17 FDA IRB Inspections Inspections are announced and scheduled in advance Inspections are announced and scheduled in advance – Consist of interviews with responsible IRB staff – In-depth review of SOPs, files and records – Active FDA regulated studies

18. 18 Scope of FDA IRB Inspections IRB membership IRB membership Written procedures Written procedures Initial review and approval of studies Initial review and approval of studies Continuing review of research Continuing review of research

19. 19 Scope of FDA IRB Inspections IRB reporting to investigator and institution IRB reporting to investigator and institution Expedited Expedited I.C. I.C. Emergency review Emergency review

20. 20 Discuss IRB administration and procedures Discuss IRB administration and procedures – Individual responsibility and authority – Membership – Operations – Record keeping requirements – Review and approval of informed consent FDA IRB Inspections

21. 21 FDA IRB Inspections Record Review Record Review – SOPs Must have written procedures as required by 21 CFR 58.108 Must have written procedures as required by 21 CFR 58.108 Should agree with procedures described during interview Should agree with procedures described during interview

22. 22 FDA IRB Inspections Inspection of IRB files-FDA regulated study files Inspection of IRB files-FDA regulated study files – Minutes of meetings – List of IRB members – Documents submitted to IRB to obtain study approval – Correspondence between IRB and investigator – Records of continuing review – Any other records

23. 23 Conclusion of FDA IRB Inspection Exit interview with management Exit interview with management – Discussion of inspection findings – Issuance of an FDA 483

24. 24 Post FDA IRB Inspection Detailed Narrative Report Prepared Detailed Narrative Report Prepared Submitted to HQ BIMO Staff for Evaluation Submitted to HQ BIMO Staff for Evaluation

25. 25 FDA Compliance Inspection Classification (1) NAI – No Action Indicated NAI – No Action Indicated VAI – Voluntary Action Indicate VAI – Voluntary Action Indicate – Objectionable conditions or practices were found, but FDA is not prepared to take or recommend any administrative of regulatory action

26. 26 FDA Compliance Inspection Classification (2) OAI – Official Action Indicated OAI – Official Action Indicated – Regulatory and/or Administrative actions will be recommended due to significant objectionable observations

27. 27 Tips Prior to Inspection (1) Know what the regulatory requirements are for your operations Know what the regulatory requirements are for your operations – 21 CFR 50 and 56 IRBs and informed consent – 21 CFR 312 Clinical Investigators and Sponsors of Drugs and biologics – 21 CFR 812 Clinical Investigators of Medical Devices

28. 28 Tips Prior to Inspection (2) Obtain and be familiar with the Compliance Program covering your operation Obtain and be familiar with the Compliance Program covering your operation Retain all records necessary to completely reconstruct activities and findings Retain all records necessary to completely reconstruct activities and findings

29. 29 Tips During the Inspection (1) Have the most responsible personnel available Have the most responsible personnel available – IRB Chair – IRB administrator/Exec. Sec. – Institutional official

30. 30 Tips During the Inspection (2) Have all records readily available and organized Have all records readily available and organized Be available throughout the inspection to answer questions Be available throughout the inspection to answer questions

31. 31 Tips During Inspection (3) Update records, organized and be available Update records, organized and be available – Inventory of ongoing research and current status – IRB SOPs covering current practices – IRB membership rosters, current and past – IRB meeting minutes – Records of tracked studies Protocol, consent forms, IRB correspondence, etc. Protocol, consent forms, IRB correspondence, etc.

32. 32 Post FDA IRB Inspection Correspondence Correspondence – Sent to IRB Chair – Describes which practices or conditions, were determined to be objectionable – Letters are sent for serious noncompliance and require a response

33. 33 Recurrent Compliance Problems (1) IRB failure to review grant applications IRB failure to review grant applications IRB lacks sufficient information to make determinations IRB lacks sufficient information to make determinations Inadequate continuing review, or longer than 1 year Inadequate continuing review, or longer than 1 year Inadequate IRB review at convened meetings Inadequate IRB review at convened meetings IRB failure to review grant applications IRB failure to review grant applications IRB lacks sufficient information to make determinations IRB lacks sufficient information to make determinations Inadequate continuing review, or longer than 1 year Inadequate continuing review, or longer than 1 year Inadequate IRB review at convened meetings Inadequate IRB review at convened meetings

34. 34 Contingent approval without subsequent re-review Contingent approval without subsequent re-review IRB meetings without a quorum IRB meetings without a quorum IRB members with conflicts of interest IRB members with conflicts of interest Inadequate records, minutes, files, documentation, policies and procedures Inadequate records, minutes, files, documentation, policies and procedures Contingent approval without subsequent re-review Contingent approval without subsequent re-review IRB meetings without a quorum IRB meetings without a quorum IRB members with conflicts of interest IRB members with conflicts of interest Inadequate records, minutes, files, documentation, policies and procedures Inadequate records, minutes, files, documentation, policies and procedures Recurrent Compliance Problems (2)

35. 35 Inappropriate use of expedited review for new, continuing, and changes Inappropriate use of expedited review for new, continuing, and changes Failure to report unanticipated problems to IRB, IO, OHRP Failure to report unanticipated problems to IRB, IO, OHRP Failure or inadequate review of protocol changes Failure or inadequate review of protocol changes Inappropriate use of exempt categories Inappropriate use of exempt categories Inappropriate use of expedited review for new, continuing, and changes Inappropriate use of expedited review for new, continuing, and changes Failure to report unanticipated problems to IRB, IO, OHRP Failure to report unanticipated problems to IRB, IO, OHRP Failure or inadequate review of protocol changes Failure or inadequate review of protocol changes Inappropriate use of exempt categories Inappropriate use of exempt categories Recurrent Compliance Problems (3)

36. 36 Deficient or inadequate informed consent documents Lack of diversity, expertise of IRB membership Overburdened IRB Inadequate IRB resources Recurrent Compliance Problems (4)

37. 37 Common IRB Deficiencies (FDA) Written procedures Written procedures – Incomplete – inadequate – not followed – Expedited review – Device SR/NSR – Inadequate continuing reviews – Minutes insufficient – Vote not recorded by number of votes – Adverse events not adequately reviewed

38. 38 Majority of members not at meeting Majority of members not at meeting Majority of members not present for vote Majority of members not present for vote Non-scientific member not present Non-scientific member not present Fail to report to FDA when study is suspended or terminated Fail to report to FDA when study is suspended or terminated Common IRB Deficiencies (FDA)

39. 39 Behavioral Guidelines

40. 40 Rules to Follow During Inspection Know the contents of your job description Know the contents of your job description Be aware of your body language Be aware of your body language Never remain in the room to chat with a inspector after you have answered all inspection related questions. Never remain in the room to chat with a inspector after you have answered all inspection related questions.

41. 41 More to dos… Be yourself Be yourself Remain focused Remain focused Answer only the question asked Answer only the question asked

42. 42 More to dos… Think before you answer. There are no bonus points for being fast Think before you answer. There are no bonus points for being fast Remain calm, remember you do your job every day, and no one knows your job as well as you Remain calm, remember you do your job every day, and no one knows your job as well as you

43. 43 What is Redacting? Redacting is the act of selecting or adapting for publication or release Redacting is the act of selecting or adapting for publication or release Remove all information that the inspector is not legally entitled to see Remove all information that the inspector is not legally entitled to see

44. 44 Use Caution During Inspection Dont fill in the silences Dont fill in the silences Dont allow yourself to become irritated. Maintain a professional demeanor at all times Dont allow yourself to become irritated. Maintain a professional demeanor at all times

45. 45 Answer all yes or no questions with yes" or no Answer all yes or no questions with yes" or no Do not editorialize or volunteer information Do not editorialize or volunteer information More cautions…

46. 46 More cautions… Never hand a document directly to a inspector - - - always pass documents to the inspection team leaders Never hand a document directly to a inspector - - - always pass documents to the inspection team leaders

47. 47 More cautions… Never volunteer information on any subject Never volunteer information on any subject Never refer to another topic, area, or procedure when answering a question Never refer to another topic, area, or procedure when answering a question

48. 48 Body Language Do not sit on the edge of your chair, Do not sit on the edge of your chair, Make eye contact Make eye contact Do not play with your hair, twirl your thumbs, click your ink pin, or tap your fingers Do not play with your hair, twirl your thumbs, click your ink pin, or tap your fingers

49. 49 Body Language Do not watch the door Do not watch the door Never cross your arms over your chest or slouch in your chair Never cross your arms over your chest or slouch in your chair

50. 50 Statement to Avoid… Its supposed to do (fill in the blank). Its supposed to do (fill in the blank). Wow, it usually never does it right the first time! Wow, it usually never does it right the first time! Do you want to know how it is supposed to happen or how it really happens? Do you want to know how it is supposed to happen or how it really happens?

51. 51 Statement to Avoid… I didnt even know we had an SOP for that! I didnt even know we had an SOP for that! I didnt even know the SOP said that. I didnt even know the SOP said that. I dont know (with no follow-up). I dont know (with no follow-up).

52. 52 Statement to Avoid… Let me show you what we do for Pfizer (or any other client). Let me show you what we do for Pfizer (or any other client). Would you like to see all our metrics? Would you like to see all our metrics? Well, I can try to do that for you, but Ive never really been trained. Well, I can try to do that for you, but Ive never really been trained.