Understanding Adverse Events in Research: Reporting Requirements

1. VHA Handbook 1058.01 Research Compliance Reporting Requirements Revised May 21, 2010 (Presentation prepared for HRPP 101, 01/26/2011)

2. Adverse Events and Unanticipated Problems Based on a presentation by: Karen Jeans, PhD, CCRN, CIP

3. Define “adverse event” Describe “unanticipated problems involving risks to subjects to others” Identify examples of adverse events and unanticipated problems involving risks to subjects to others Understand reporting requirements

4. What is the Difference Between Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others? • AE/UPR

5. Unanticipated Problems Involving Risks to Subjects or Others vs. Adverse Events • Most Adverse Events are not Unanticipated Problems Involving Risks to Subjects or Others • All Unanticipated Problems Involving Risks to Subjects or Others are not Adverse Events • Many Unanticipated Problems Involving Risks to Subjects or Others and Many Adverse Events are not Serious

6. Why Report Adverse Events and Unanticipated Problems? Because it helps ensure the safety of participants in human subject research, by providing information to the IRB and cognizant oversight agencies, and Because it is required

7. Unanticipated Problems Involving Risks to Subjects or Others Under the Common Rule must be reported to the IRB per 38 CFR 16.103(a) Under FDA regulations must be reported to the IRB per 21 CFR 56.108(b) Regulatory Background:

8. Adverse Events – Common Rule The Common Rule (36 CFR 16) does not address “adverse events” and does not require “adverse event reporting” (except when the “adverse event” constitutes an “unanticipated problem involving risks to subjects or others”) VHA Handbook 1058.01 §7 requires that Local, Unanticipated, Serious Adverse Events (SAEs) be reported to the IRB within 5 business days Regulatory Background:

9. Adverse Events – FDA Regulations Investigators must report to the Sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug (must report immediately if alarming) per 21 CFR 312.32(a)&(c) Investigators must report to the Sponsor and the IRB any Unanticipated Adverse Device Effect per 21 CFR 812.150(a) Sponsor must report to FDA and relevant Investigators any Adverse Experience that is both serious and unexpected per 21 CFR 312.32(a)&(c) and 812.159(b)(1) Regulatory Background:

10. What Is An Adverse Event (AE)according to VHA requirements? An AE is any untoward physical or psychological occurrence in a human subject participating in research. Can be unfavorable and unintended event Includes any abnormal laboratory finding, symptom, or disease associated with the research or the use of a medical investigational test article. Does not necessarily have to have a causal relationship with the research. Source: VHA Handbook 1058.01, Paragraph 4(b)

11. Types of Adverse Events • Unanticipated (unexpected) • Local (internal) • Non-local (external) • Related • Not related • Serious • Not Serious

12. Types of Adverse Events: Unanticipated • Unanticipated (unexpected) • Event or problem that is new or greater than previously known in terms of nature, severity, or frequency, given the population described in protocol-related documents and the characteristics of the study population. Source: VHA Handbook 1058.01, Paragraph 4(bb)

13. Types of Adverse Events: Local and Non-Local • Local (internal) • Adverse event occurring at the reporting individual’s own facility Source: VHA Handbook 1058.01, Paragraph 7(c) • Non-local (external) • Adverse events occurring by subjects enrolled by investigators at other institutions

14. Types of Adverse Events: Related • Related • There is a reasonable possibility based upon the available information that the event or outcome may have been caused by or resulted from participation in the research by the subject.

15. Types of Adverse Events: Serious • FDA Regulations • An Adverse Event that • Results in death, a life-threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect; or • Requires, based on a reasonable medical judgment, a medical or surgical intervention to prevent an outcome described above. Source: Section 761(a)(2) of the Food Drug &Cosmetic Act (21 U.S.C. 379aa-1(a)(2))

16. Types of Adverse Events: Serious • VHA Requirements • An Adverse Event in Human Research that • Results in death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect. • Also considered serious when medical, surgical, behavioral, social, or other intervention is needed to prevent such an outcome. Source: VHA Handbook 1058.01, Paragraph 4(w)

17. Serious Adverse Event Definitions FDA Results in death, a life-threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect; or Requires, based on a reasonable medical judgment, a medical or surgical intervention to prevent an outcome described above. VHA • Results in death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect. • Also considered serious when medical, surgical, behavioral, social, or other intervention is needed to prevent such an outcome.

18. Types of Adverse Events: Unanticipated • Unanticipated (unexpected) • Event or problem that is new or greater than previously known in terms of nature, severity, or frequency, given the population described in protocol-related documents and the characteristics of the study population. Source: VHA Handbook 1058.01, Paragraph 4(bb)

19. Common Rule Undefined FDA Regulations Undefined Definition: Unanticipated Problem Involving Risks to Subjects or Others

20. Unanticipated Problems Involving Risks to Subjects or Others OHRP Guidance: Any incident, experience, or outcomes that meets all three criteria: • Unexpected • Related or possibly related to participation in research • Suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized • Harm may be physical, psychological, economic, or social Source: OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events – January 15, 2007

21. PI-initiated changes in protocol Study amendments, for example: revision of the Consent Form; revision of inclusion/exclusion criteria; addition/deletion of study procedures; etc. Suspension of enrollment New Information (e.g., DSMB reports, publications, sponsor alerts, etc.) Research-related Events or Problems Which Could Be (Or Could Reveal) Unanticipated Problems Involving Risks to Subjects or Others

22. Study sponsors (if multisite study) make reports to PIs, who, in turn, report them to the IRB. Members of the VA research community are responsible for reporting to the IRB per local IRB Standard Operating Policies and Procedures Local IRB Standard Operating Policies and Procedures can exceed but not be less stringent than federal requirements Reporting Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others

23. The IRB determines when events, incidents, or outcomes are Unanticipated Problems Involving Risks to Subjects or Others, or Adverse Events that are serious, unanticipated, and probably related to research, and reports to Institutional Officials accordingly Reporting Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others

24. Require study modification Providing additional information to subjects Modify informed consent process/document Educational plan Assignment of Mentor Require additional monitoring Suspension or termination of IRB approval Other actions as determined by the IRB Possible IRB Actionsmay include:

25. When the IRB determines that a study-related event is an Unanticipated Problem involving Risk to subjects or others, it must be reported to Institutional Official Institutional Official reports to Oversight Agencies and entities as applicable Office of Research Oversight Office for Human Research Protections U.S. Food and Drug Administration Sponsors Other entities Reporting By The IRB And Institutional Officials

26. Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others are not synonymous However, reporting of Serious, Unanticipated Adverse Events probably related to research, and Unanticipated Problems Involving Risks to Subjects or others is the same. Policies and procedures must describe when and how adverse events and possible unanticipated problems involving risks to subjects or others are reported to the IRB. The IRB reviews determines which are unanticipated problems involving risks to subjects or others, and reports as required by VHA Handbook 1058.01 Summary

27. QUESTIONS

28. Highlights (New Requirements in Red – Previous Requirements in Blue) Requirements for Designation of Facility RCO [1058.01 §6c] Requirements to Conduct Annual and Triennial Audits as Specified by ORO [1058.01 §6c] Facility Director Reporting Requirements [1058.01 §6f] Annual Facility Director Certification of Research Oversight [1058.01 §6g] RCO Roles as Consultant to Review Committees [1058.01 §4t] Requires Reporting of All RCO Audit Findings to Relevant Review Committees and R&DC [1058.01 §§6d, 6e] Time Periods for Implementing Remedial Actions [1058.01 §5d] Requires Providing ORO Compliance Reports to ACOS/R, RCO, Relevant Review Committees and R&DC [1058.01 §6g]

29. Highlights (New Requirements in Red – Codification of Previous Guidance in Blue) Distinguishes Rapid Reporting Requirements for Serious Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others from Reporting Requirements Under Local SOPs Clarifies Definitions of Serious or Continuing Noncompliance [1058.01 §§4e, 4x] Limits Special Rapid Reporting Requirements for Serious or Continuing Noncompliance to Human Research [1058.01 §§4e, 4x] Distinguishes Apparent Serious or Continuing Noncompliance from IRB-Determined Serious/Continuing Noncompliance and Provides Specific Examples[1058.01 §7i] Defines “Reportable Events” for Non-Human of Research [1058.01 §§8-11]

30. Role of the RCO RCO’s primary responsibility = auditing and reviewing research projects relative to VA research requirements RCO may also serve as a nonvoting consultant, as needed, to the facility’s R&D Committee, IRB, IACUC, Subcommittee on Research Safety (SRS), and other research review committees The RCO may not serve as a voting or nonvoting member of these committees -- may attend meetings of these committees when requested by the committee or as specified in local committee SOPs [1058.01 §4t]

31. Non-Voting Consultant vs Non-Voting Member • Real or Apparent Conflict of Interest • RCO audits entail review of IRB actions – the RCO’s perceived independence is compromised if the RCO is a member of the committee under review • Flexibility of RCO time and resource commitments • Multiple mandatory committee memberships decrease optimal use of RCO time and resources • Flexibility in developing working relationship that meet facility research protection and oversight needs [1058.01 §4t]

32. The IRB is responsible for determining: Whether or not apparent noncompliance is serious or continuing Remedial action(s) in response to identified noncompliance Verifying that the remediation is implemented as required. [1058.01 §7i]

33. Remedial Actions Remedial actions related to specific research projects should typically be completed within 90-120 days of the research review committee’s determination of noncompliance. Except where remediation requires substantial renovation, fiscal expenditure, hiring, legal negotiations, or other extenuating circumstances, remedial actions related to programmatic noncompliance should typically be completed within 120-180 daysof the noncompliance determination. Where completion of remedial actions extends beyond the periods described in the preceding subparagraphs, the facility must provide ORO with a written justification for the delay and an acceptable timeline for completion. [1058.01 §5d]

34. Serious or Continuing Noncompliance vs Apparent Serious or Continuing Noncompliance Serious Noncompliance: Involves substantive harm (or genuine risk of substantive harm) to the safety, rights, welfare of human subjects, research staff or others in human research Substantively compromises the effectiveness of the facility’s human research protection/oversight programs Continuing Noncompliance: Reflects a persistent failure to adhere to the laws, regulations, or policies governing VA human research [1058.01 §§4e,4x,7e, 7f, 7g]

35. Serious or Continuing Noncompliance vs Apparent Serious or Continuing Noncompliance Apparent Serious or Continuing Noncompliance = a situation that, in the judgment of the individual observing it: Satisfies the Handbook’s definition of Serious Noncompliance Satisfies the Handbook’s definition of Continuing Noncompliance Reflects one or more of the examples provided in the Handbook [1058.01 §§4e,4x,7e, 7f, 7g]

36. Apparent Serious or Continuing Noncompliance Observed by an RCO in an Informed Consent, Regulatory, or Other Systematic Audit of Human Subjects Research Must be reported to the Facility Director, IRB, ACOS/R, R&D Committee, etc. within 5 business days Facility Director must report to ORO Regional Office within 5 business days of being notified (even if disposition complete) Facility Director must provide follow-up reports as specified by ORO Regional Office Convened IRB determines whether: Serious or Continuing Noncompliance occurred Remedial Actions are warranted [1058.01 §7h]

37. Apparent Serious or Continuing Noncompliance in Human Subject Research Observed by anyone in the Research Community (including RCO in context other than audit) Must be reported to the IRB within 5 business days Convened IRB determines whether: Serious or Continuing Noncompliance occurred Remedial Actions are warranted If Serious or Continuing Noncompliance, IRB must report to Facility Director, ACOS/R, R&D Committee, etc, within 5 business days Facility Director must report to ORO Regional Office within 5 business days of being notified [1058.01 §7i]

38. Note Change in Reporting Requirements Involving • UNANTICIPATEDAdverse Events • UNANTICIPATED Problems Involving Risks to Subjects/Others The 5-day requirement for reporting Adverse Events (AEs) and Problems Involving Risks to Subjects or Others TO THE IRB Now applies only to AEs and Problems that are UNANTICIPATED and SERIOUS

39. “UNANTICIPATED” refers to an event/problem that is new or greater than previously known in terms of nature, severity, or frequency, given the procedures described in protocol-related documents and the characteristics of the study population. • “SERIOUS” refers to: • Events that qualify as Serious Adverse Events (SAEs) as defined by FDA;or • Problems/events that involve: • Substantive harm, or a genuine risk of substantive harm to the safety, rights, or welfare of research subjects, staff, or others; or • Substantively compromise the effectiveness of the facility’s human research protection or human research oversight programs

40. This change is meant to improve oversight by: • Decreasing the overload experienced by IRBs from rapidly reviewing large numbers of clinical events that are unlikely to reflect substantive, unconsidered risks • Allowing timely expert peer review focused on events that are more likely to reflect substantive concerns • All SAEs and Problems Involving Risks to Subjects or Others still require review by the IRB as described in local Standard Operating Procedures consistent with: • VHA Handbook 1200.05, • The Common Rule at 28 CFR 16, and • Applicable FDA regulations

41. Serious Adverse Event (SAE) Reporting Investigator (or other person) must report any localAE that is SERIOUS andUNANTICIPATED to the IRB within 5 business days: Serious = untoward physical or psychological occurrence in a human subject resulting in death, life-threatening experience, impatient hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, or that requires medical, surgical, behavioral, social, or other intervention to prevent such an outcome Unanticipated = reflects a risk that is new or greater than previously known Special review by IRB (or qualified IRB member) within 5 business day after the report to categorize the event [1058.01 §§ 4b,4p,4x,4y,4bb,7c, 7d]

42. Serious Adverse Event (SAE) Reporting IRB must report any Unanticipated, Related, Local SAE to the Facility Director within 5 business days of categorization Related = event may reasonably be regarded as caused by, or as probably caused by, the research Facility Director must report to ORO Regional Office within 5 business days of being notified IRB (or qualified IRB member) must also document whether or not action is needed to prevent immediate hazard to subjects If consent or protocol modifications are required, convened IRB must determine whether previously enrolled subjects must be notified, and if so when, how, and how documented [1058.01 §§ 4b,4p,4x,4y,4bb,7c,7d]

43. Unanticipated Problem Reporting Investigator (or other person) must report any Unanticipated Problem Involving Risks to Subjects or Others in human research to the IRB within 5 business days if it: May reasonably be regarded to involve substantive harm, or a genuine risk of substantive, to safety, rights, or welfare, or Substantively compromises the effectiveness of the facility’s human research protection or human research oversight programs Special review by IRB (or qualified IRB member) required within 5 business days after the report to categorize the event Investigator (or other person) must report any other unanticipated problems involving risks to subjects or others in human research to the IRB promptly per local SOPs [1058.01 §§ 4y,4bb,7a,7b,7d]

44. Unanticipated Problem Reporting IRB must report Related, Serious, Unanticipated Problem Involving Risk to Subjects or Others to Facility Director within 5 business days of categorization Related = event may reasonably regarded as caused by, or as probably caused by, the research Facility Director must report to ORO Regional Office within 5 business days of being notified IRB (or qualified IRB member) must also document whether or not action is needed to prevent immediate hazard to subjects If consent or protocol modifications are required, convened IRB must determine whether previously enrolled subjects must be notified, and if so when, how, and how documented [1058.01 §§ 4b,4p,4x,4y,4bb,7c,7d]

45. Animal Research, Research Safety, Research Lab Security, Research Information Protection, Research Misconduct Reporting not based on “Serious or Continuing Noncompliance” as defined in human research Reportable Events defined for each type of research No special requirements for Rapid Review / Rapid Reporting to ORO 5-day standard for reporting: Reportable Event to Research Review Committee Review Committee Determination to Facility Director To ORO by Facility Director [1058.01 §§ 8, 9, 10, 11, 12]

46. QUESTIONS