1. Office of Research Oversight Reporting: Who, What, When, and Why February, 2012

2. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event The Background: A PI became aware of a local unanticipated serious adverse event on January 1, 2012. It was not reported to the IRB by the PI until January 25, 2012, as part of a continuing review submission. The IRB noted the delay in reporting the SAE by the PI at the continuing review, and reminded the PI of the responsibility to report timely in the future. The IRB made no documented determinations about the SAE, or whether serious noncompliance had occurred. 1

3. VETERANS HEALTH ADMINISTRATION Case 1, Question 1: “How soon should the local, serious, unanticipated event have been reported to the IRB?” 2 1.24 hours 2.5 business days 3.As soon as possible 4.In time for the next convened IRB meeting

4. VETERANS HEALTH ADMINISTRATION ORO Resources for Research Compliance Requirements: Tech Assist SharePoint Site 3

5. VETERANS HEALTH ADMINISTRATION ORO Resources for Research Compliance Requirements: Tech Assist SharePoint Site 4

6. VETERANS HEALTH ADMINISTRATION ORO Resources for Research Compliance Requirements: Tech Assist SharePoint Site 5

7. VETERANS HEALTH ADMINISTRATION ORO Resources for Research Compliance Requirements: Tech Assist SharePoint Site 6

8. VETERANS HEALTH ADMINISTRATION ORO Resources for Research Compliance Requirements: Tech Assist SharePoint Site 7

9. VETERANS HEALTH ADMINISTRATION ORO Resources for Research Compliance Requirements: Tech Assist SharePoint Site 8

10. VETERANS HEALTH ADMINISTRATION CASE #1- Reporting apparent serious noncompliance found during an RCO audit 9

11. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event How Soon must an SAE be reported? 10

12. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event The Background: A PI became aware of a local unanticipated serious adverse event on January 1, 2012. It was not reported to the IRB by the PI until January 25, 2012, as part of a continuing review submission. 11

13. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event How Soon must an SAE be reported? VHA Handbook 1058.01: 7. REQUIREMENTS RELATED TO HUMAN RESEARCH – a. Unanticipated Problems Involving Risks to Subjects or Others. Members of the VA research community are required to ensure that unanticipated problems involving risks to subjects or others in research are reported promptly to the IRB in accordance with the time periods established under local SOPs. – b. Serious Unanticipated Problems Involving Risks to Subjects or Others. Within 5 business days of becoming aware of any serious unanticipated problem involving risks to subjects or others in VA research, members of the VA research community are required to ensure that the problem has been reported in writing to the IRB. 12

14. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event The Background: The IRB noted the delay in reporting the SAE by the PI at the continuing review, and reminded the PI of the responsibility to report timely in the future. The IRB made no documented determinations about the SAE, or whether serious noncompliance had occurred. 13

15. VETERANS HEALTH ADMINISTRATION Case 1, Question 2: “Were the actions of the IRB compliant with all VA requirements?” 14 1.Yes 2.No 3.It depends

16. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event The THIRD QUESTION: “What determinations should the IRB have made and documented?” (pause for discussion) 15

17. VETERANS HEALTH ADMINISTRATION Case 1, Question 4: “What determinations should the IRB have made and documented?” 16 1.Whether the event was serious, unanticipated, and related to research 2.Whether the delay in reporting the SAE rose to the level of serious or continuing non- compliance 3.Whether the subject should be compensated financially 4.1+2 5.All of the above

18. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event VHA HANDBOOK 1058.01: 7 (d). IRB Review of Serious Unanticipated Problems and Unanticipated SAEs. – Within 5 business days after a report of a serious unanticipated problem involving risks to subjects or others, or of a local unanticipated SAE, the convened IRB or a qualified IRB member-reviewer must determine and document whether or not the reported incident was serious, unanticipated, and related to the research. NOTE: Per subparagraph 4p, related means the event or problem may reasonably be regarded as caused by, or probably caused by, the research. 17

19. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event Determining whether non-compliance is serious or continuing Therefore, failure by the PI to report an unanticipated SAE within the required time MUST BE REPORTED TO THE IRB and considered as APPARENT serious non-compliance. However, it is extremely important to note that only the IRB has the authority (and the duty) to determine whether the specific facts of a case rise to the level of actual serious or continuing non- compliance. Apparent serious non-compliance may or may not be actual serious non-compliance. The IRB has to decide. 18

20. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event VHA HANDBOOK 1058.01: 7(i). IRB Review of Apparent Serious or Continuing Noncompliance. – (4) An initial report of an IRB determination that serious noncompliance or continuing noncompliance occurred is required, even where the determination is preliminary or disposition of the matter has not been resolved at the time of the report. – NOTE: The IRB must reach a determination that serious or continuing noncompliance did or did not occur within 30-45 days after receiving a report of apparent noncompliance. 19

21. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event The Next Step in the Story: On June 15, 2012, during a regulatory audit, the RCO identified the late report of the local, unanticipated SAE as a compliance concern. The RCO could not find any documentation in the IRB minutes regarding: – Whether the IRB determined that the SAE was serious, unanticipated, and related to research – Whether the IRB determined that the late report by the PI rose to the level of serious non-compliance 20

22. VETERANS HEALTH ADMINISTRATION CASE #1- A Serious Adverse Event The Question Now: “What action(s) does the RCO need to take?” (pause for discussion) 21

23. VETERANS HEALTH ADMINISTRATION Case 1, Question 5: “What action(s) does the RCO need to take?” 22 1.Report to ACOS/R within 5 days 2.Report to IRB within 5 days 3.Report to Director within 5 days 4.1+2 5.All of the above

24. VETERANS HEALTH ADMINISTRATION CASE #2- A Serious Adverse Event The RCO found during a regulatory audit that a local, unanticipated SAE was not evaluated by the IRB as required by VHA Handbook 1058.01 No determination was made whether the SAE was serious, unanticipated, and related to research. The RCO was required to report the SAE back to the IRB within 5 days, this time for the required determination within 5 days by the IRB or designated, qualified member 23

25. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Serious Adverse Event found during an RCO audit 24

26. VETERANS HEALTH ADMINISTRATION CASE #2- A Serious Adverse Event – noncompliance in reporting The RCO found 2 different noncompliance concerns: – The RCO found during a regulatory audit that a local, unanticipated SAE was not reported to the IRB as required by VHA Handbook 1058.01 – In addition, the RCO found during a regulatory audit that the IRB had not reviewed a local SAE and documented their determination as required by VHA Handbook 1058.01 25

27. VETERANS HEALTH ADMINISTRATION CASE #2- A Serious Adverse Event- noncompliance in reporting “ Failure to report one or more unanticipated SAEs or unanticipated serious problems involving risks to subjects or others as required by this (VHA) Handbook (1058.01).” Therefore, the RCO was required to report the finding of late reporting of the local SAE as apparent serious noncompliance found during an audit. Because this was found during an RCO audit, it triggers a special, fast, within-5-day reporting to ORO even while the IRB is still considering the facts 26

28. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting apparent serious noncompliance found during an RCO audit 27

29. VETERANS HEALTH ADMINISTRATION CASE #2- Noncompliance in IRB review of an SAE The IRB had not reviewed a local SAE and documented their determination as required This may represent “serious programmatic noncompliance” – (e) Any programmatic noncompliance involving substantive harm, or a genuine risk of substantive harm, to the safety, rights, or welfare of human research subjects, research staff, or others; and – (f) Any programmatic noncompliance that substantively compromises the effectiveness of the facility’s human research protection or human research oversight programs. If so, the RCO was required to report noncompliant review of the local SAE as apparent serious noncompliance found during an audit. 28

30. VETERANS HEALTH ADMINISTRATION CASE #2- A Serious Adverse Event ORO Common Findings: IRB #7 7. “When reviewing local serious adverse events (SAEs) or unanticipated problems involving risks to subjects or others (UPRs), the IRB (or qualified IRB-member reviewer) did not make proper determinations in a timely manner as required by VHA Handbook 1058.01” 29

31. VETERANS HEALTH ADMINISTRATION CASE #2- A Serious Adverse Event ORO Common Findings: IRB #7 VHA Handbook 1058.01 §7.d “Within 5 business days after a report of a serious unanticipated problem involving risks to subjects or others, or of a local unanticipated SAE, the convened IRB or a qualified IRB member- reviewer must determine and document whether or not the reported incident was serious, unanticipated, and related to the research.” ORO found that some IRBs, or qualified IRB-member reviewers, did not complete the review of local SAEs or UPRs in a timely manner as required. ORO review of IRB minutes revealed that some IRBs reviewed hundreds of reports of AEs, SAEs, and UPRs during every meeting without separating the reports of local SAEs and UPRs from the reports of external events, or making determinations whether local SAEs and UPRs are serious, unanticipated and related to research. 30

32. VETERANS HEALTH ADMINISTRATION Overview of Handbook 1058.01 “Research Compliance Reporting Requirements” PURPOSE. This Veterans Health Administration Handbook sets forth the requirements for reporting certain research events to facility officials, relevant research review committees, and the Office of Research Oversight (ORO). NOTE: This Handbook does not preempt or otherwise alter any other applicable research reporting requirements, whether within the Department of Veterans Affairs (VA) or involving other Federal or state agencies or commercial sponsors. 31

33. VETERANS HEALTH ADMINISTRATION 4. Definitions 5. General Requirements Serious Adverse Events (SAEs) - Term is limited to Human Subjects Research Serious Non-Compliance: – (1) Involving substantive harm, or a genuine risk of substantive harm, to the safety, rights, or welfare of human research subjects, research staff, or others; or – (2) Substantively compromising the effectiveness of a facility’s human research protection or human research oversight programs. Contents of initial and follow-up reports to ORO. 32

34. VETERANS HEALTH ADMINISTRATION Major Topic Sections in VHA Handbook 1058.01 6. Responsibilities of the Facility Director 7. Requirements Related to Human Research 8. Requirements Related to Animal Research 9. Requirements Related to Research Safety 10. Requirements Related to Research Laboratory Security 11. Requirements Related to Research Information Protection 12. Requirements Related to Research Misconduct Appendix: Table Summarizing Reporting Requirements 33

35. VETERANS HEALTH ADMINISTRATION 6. Responsibilities of the Facility Director a. Ensuring that detailed SOPs are developed and implemented to satisfy all requirements of this Handbook, including requirements affecting the facility’s academic affiliates. b. Ensuring that all persons working in research or performing any research activities have been officially appointed by Human Resources Management. e. Ensuring that the results of all RCO audits are reported to the R&D Committee and all other relevant research review committees f. Reporting to ORO 34

36. VETERANS HEALTH ADMINISTRATION 6. Responsibilities of the Facility Director c. Appointing one or more RCOs to conduct annual research informed consent audits and triennial regulatory audits in accordance with a written audit plan or SOP, and to assist in facility assessments of regulatory compliance – (2) RCO must report directly to the facility Director.. – (3) may serve as a non-voting consultant to oversight committees – (4) may participate in education activities – (5) must report any change in status of the facility RCO 35

37. VETERANS HEALTH ADMINISTRATION 6. Responsibilities of the Facility Director (c) “NOTE: Procedures and materials related to RCO training requirements and RCO audit requirements are updated periodically and posted prominently on ORO’s Web site at: http://www.va.gov/oro/.” 36

38. VETERANS HEALTH ADMINISTRATION 7. Requirements Related to Human Research Review and Reporting local unanticipated SAEs and serious unanticipated problems related to research (UPRs) Definition of apparent serious or continuing noncompliance (SCN), required review and reporting Examples that must be so considered (“the list”) “Fast Track” reporting requirements for apparent SCN found during audits by the RCO Reference to ORO Decision Charts for above matters Reporting to ORO of program and accreditation changes 37

39. VETERANS HEALTH ADMINISTRATION 8, 9, 10: Requirements Related to Animal Research, Research Safety, and Research Laboratory Security Reportable events described Required review Required reporting of oversight committee determinations and actions 38

40. VETERANS HEALTH ADMINISTRATION 11. Requirements Related to Research Information Protection Research Information Protection Incidents defined Reporting requirements to ORO, Information Security Officer (ISO) and Privacy Officer (PO) Immediate (1 hour) reporting to the ACOS for Research, the facility ISO, and the facility PO requirement for any unauthorized use, disclosure, transmission, removal, theft, loss, or destruction of VA research-related protected health information (PHI), individually identifiable private information, or confidential information, as defined by the HIPAA Privacy Rule, the Common Rule, the Privacy Act, or 38 U.S.C. §§5701, 5705, and 7332. 39

41. VETERANS HEALTH ADMINISTRATION 12. Requirements Related to Research Misconduct Research Misconduct is defined as fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results. For any allegation of Research Misconduct, ORO CO (Peter Poon) must be notified as soon as possible, preferably by telephone or email. Formal written notification may come later. Appendix B of this Handbook summarizes reporting procedures for allegations of Research Misconduct. Reference VHA Handbook 1058.2 “Research Misconduct” (May 4, 2005) 40

42. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE The Background: Foxtrot VAMC used their Medical Affiliate as their IRB of record. The IRB reviewed a local, unanticipated serious adverse event, and determined that it might reasonably be regarded as caused by the research. 41

43. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE The Situation Now: The IRB Chair sent a letter the same day to the ACOS for Research and the Chair of the R&D Committee at the Foxtrot VAMC, notifying them of the IRB’s determination. 42

44. VETERANS HEALTH ADMINISTRATION Case 2, Question 1: “Is this method of reporting the determination of the IRB compliant with VA requirements?” 43 1.Yes 2.No 3.It depends

45. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE ORO Common Findings: IRB #12 12. “The IRB did not report reportable unanticipated problems involving risks to subjects or others (UPRs), local serious adverse events (SAEs),or serious or continuing noncompliance to the Medical Center Director (only reported to ACOS/R&D and R&DC)” 44

46. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE ORO Common Findings: IRB #12 VHA Handbook 1058.01 §7.d(1) “If the convened IRB or the qualified IRB member-reviewer determines that the problem or event is serious and unanticipated and related to the research, the IRB Chair or designee must notify ORO via telephone or e-mail within 48 hours and report the problem or event directly (without intermediaries) to the facility Director within 5 business days after the determination.” ORO found that some IRBs, particularly IRBs at affiliate universities, reported these reportable research events to the ACOS/R&D and/or the R&DC, but not directly to the Medical Center Director as required. 45

47. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE Follow-Up QUESTION: “In addition to notification of ORO and the Facility Director, what further actions must the IRB take when a local adverse event is found to be serious, unanticipated, and related to research?” (pause for discussion) 46

48. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE “Further IRB actions needed:” 1.A simultaneous determination is required regarding the need for any action (e.g., suspension of activities; notification of subjects) necessary to prevent an immediate hazard to subjects in accordance with VA regulations in 38 CFR 16.103(b)(4)(iii). 47

49. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE “Further IRB actions needed:” 2.The convened IRB must determine and document whether or not a protocol or informed consent modification is warranted. 3.If informed consent modification is warranted, the IRB must also determine and document the following: (a) Whether or not previously enrolled subjects must be notified of the modification and, if (b) When such notification must take place and how such notification must be documented. 48

50. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE “Further IRB actions needed:” Are there other actions required? (pause for discussion) 49

51. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE “Further IRB actions needed:” Who else may need to be notified when a local adverse event is found to be serious, unanticipated, and related to research? (pause for discussion) 50

52. VETERANS HEALTH ADMINISTRATION CASE #2- Reporting a Local SAE “Further IRB actions needed:” The Common Rule 38 CFR 16.103(b)(5) “Procedures for reporting” (OHRP) FDA regs at 21 CFR 56.108(b) The PI may also have a responsibility to report to the study sponsor 51

53. VETERANS HEALTH ADMINISTRATION CASE #3-Complex SAE Decisions The Background: Alpha VAMC had many oncology research protocols, with frequent adverse events that may or may not have been related to research depending on complex fact patterns. In their experience, the Alpha VAMC IRB found that often more than 5 days were needed to gather and evaluate all the facts, in order to best determine whether the adverse event was serious, unanticipated, and probably related to research 52

54. VETERANS HEALTH ADMINISTRATION CASE # 3-Complex SAE Decisions The Situation Now: The Alpha VAMC IRB SOPs required the IRB Chair to forward the report to the convened IRB when more time was needed to reasonably make a determination whether a reported UPR or local SAE was serious, unanticipated, and related to research. 53

55. VETERANS HEALTH ADMINISTRATION Case 3, Question 1: “Is this policy for taking more time in order to make a complex determination about a local SAE compliant with VA requirements?” 54 1.Yes 2.No 3.It depends

56. VETERANS HEALTH ADMINISTRATION CASE # 3-Complex SAE Decisions ORO Common Findings: IRB #5 5. IRB policies and procedures contained information that was outdated or inconsistent with current VHA policies : b. IRB SOPs required the IRB Chair/Designee to forward the report to the convened IRB when he/she cannot make determinations whether a reported UPR or local SAE is serious, unanticipated, and related to research. This policy is derived from VHA Handbook 1058.01 dated February 27, 2009. 55

57. VETERANS HEALTH ADMINISTRATION CASE # 3-Complex SAE Decisions ORO Common Findings: IRB #5 The current effective VHA Handbook 1058.01 dated November 15, 2011, stipulates that: “Within 5 business days after a report of a serious unanticipated problem involving risks to subjects or others, or of a local unanticipated SAE, the convened IRB or a qualified IRB member-reviewer must determine and document whether or not the reported incident was serious, unanticipated, and related to the research.” (§7.d) 56

58. VETERANS HEALTH ADMINISTRATION CASE # 3-Complex SAE Decisions What is best compliant practice? An initial determination MUST be made within 5 days, based on the best facts available. If that determination is that YES, the local SAE was serious, unanticipated, and probably related to research, then ORO must be notified within 48 hours and formally through the Medical Center Director within 5 days plus 5 days 57

59. VETERANS HEALTH ADMINISTRATION CASE # 3-Complex SAE Decisions What is best compliant practice? Regardless of the initial determination of the designated qualified member, if more time is needed for fact-finding and analysis, that time may be taken by the IRB. A final determination can be made later based on a more complete analysis. This final determination may uphold or reverse the initial determination. 58

60. VETERANS HEALTH ADMINISTRATION CASE #4-Reporting Anticipated Adverse Events-The Background: Foxtrot VAMC IRB is reviewing a protocol that is an oncology trial for Stage 4 cancer. The primary outcome measure for the trial is death, and death is listed in the protocol as the expected outcome. 59

61. VETERANS HEALTH ADMINISTRATION CASE # 4-Anticipated SAEs The QUESTION: “Does every death that occurs in subjects during this study have to be reported within 5 days to the IRB and a determination made within 5 days whether the SAE was unanticipated and related to research?” (pause for discussion) 60

62. VETERANS HEALTH ADMINISTRATION Case 4, Question 1: “Do anticipated serious adverse events need to be reported to the IRB within 5 days?” 61 1.Yes 2.No 3.It depends

63. VETERANS HEALTH ADMINISTRATION CASE # 4 Reporting Anticipated SAEs: Only SAEs judged by the PI to be unanticipated require reporting to within 5 days to the IRB for a determination. Anticipated SAEs are reported to the IRB as described in the protocol and/or local SOPs 62

64. VETERANS HEALTH ADMINISTRATION CASE # 4 Reporting Anticipated SAEs: In the example given, death from cancer would be an anticipated SAE However, if the PI suspected death occurred for some other reason, for example allergic reaction, that death might be unanticipated and require reporting 63

65. VETERANS HEALTH ADMINISTRATION CASE # 5: Anticipating SAEs in protocol design and description: A study is proposed to measure hearing acuity over time in human subjects who are on renal dialysis and IV gentamycin therapy Every subject will be followed with repeated hearing tests for at least 12 months Hospitalizations are anticipated to occur in this patient population during the follow-up period, unrelated to the study or the hearing tests. 64

66. VETERANS HEALTH ADMINISTRATION CASE # 5: Anticipating SAEs in protocol design and description: Hospitalizations are defined in local SOPs as serious adverse events. How can the PI avoid reporting every hospitalization to the IRB for a determination of whether the hospitalization is related to the research study? 65

67. VETERANS HEALTH ADMINISTRATION VHA Handbook 1058.01 “Research Compliance Reporting Requirements” WHAT ARE YOUR MOST COMMON ISSUES RELATED TO THE REQUIREMENTS OF THIS HANDBOOK? (pause for discussion) 66