1. IRB-Investigator/ Research Coordinator Mtg. “CUMC’s New Progressive Policy For Adverse Event Reporting” April 13, 2004 George Gasparis Andrew Wit, Ph.D. Professor of Pharmacology Columbia University Medical Center IRB

2. Objectives 1)Present Columbia’s new adverse event reporting policy 2)Provide an understanding of how to comply with the policy. 3)Improve human subjects protection through monitoring.

3. 45 CFR 46 Reporting Requirements To the IRB, institutional officials, the relevant Department or Agency Head, and applicable regulatory body, and OHRP

4. 45 CFR 46 Reporting Requirements 1) Unanticipated problems involving risks to subjects or others in any covered research;

5. 45 CFR 46 Reporting Requirements 2) Serious or continuing noncompliance with Federal, institutional or IRB requirements;

6. 45 CFR 46 Reporting Requirements 3) Suspension or termination of IRB approval for Federally-supported research.

7. 45 CFR 46 Reporting Requirements for Investigators In summary, AE reporting to the IRB: Unanticipated problems involving risks to subjects or others in any covered research. In summary, AE reporting to the IRB: Unanticipated problems involving risks to subjects or others in any covered research.

8. FDA – 21 CFR 312.66 AE Reporting Requirements for Investigators -promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others. -promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others.

9. FDA – 21 CFR 312.64 (b) AE Reporting Requirements for Investigators -promptly report to the sponsor any adverse event that may reasonably be regarded as caused by, or probably caused by, the drug. -promptly report to the sponsor any adverse event that may reasonably be regarded as caused by, or probably caused by, the drug.

10. FDA – 21 CFR 812 AE Reporting Requirements for Devices -provides different reporting requirements for investigational devices, -provides different reporting requirements for investigational devices, called adverse device effects called adverse device effects

11. Developing an Institutional Policy for AE reporting -must be all-inclusive; -consistent with all federal regulations

12. Columbia’s Old Policy for AE reporting (May 5, 2003) -Serious and/or unexpected adverse events must be reported to the IRB.

13. Columbia’s New Policy for AE reporting (April 13, 2004) -Decreases the number of AEs that need to be reported promptly to the IRB. -All other AEs will be reported in summary to the IRB at the time of continuing review

14. Columbia’s New Policy for AE reporting (April 13, 2004) Internal AEs: -Report AEs that are: -serious AND unanticipated to the IRB within 48 hours. to the IRB within 48 hours.

15. Columbia’s New Policy for AE reporting (April 13, 2004) External AEs: -Report AEs that are: -serious AND unanticipated -And possibly related to study procedures -And possibly related to study procedures to the IRB within 5 business days. to the IRB within 5 business days.

16. Columbia’s New Policy for AE reporting (April 13, 2004) Unanticipated Problems (at any site): -Report to the IRB within 5 business days. -Report to the IRB within 5 business days.

17. Unanticipated Problems Any unexpected event that affects the rights, safety, or welfare of subjects or others that results from the study. The event could be physical, such as an adverse experience. The event could also involve social harm or risk, or psychological or legal harm or risk. Examples include, but are not limited to, breach of confidentiality, protocol violations and deviations, and complaints about the research procedures or treatments by key personnel on the research team.

18. Adverse Events Not seriousSerious Anticipated Report in summary at time of continuing review. Report in summary at the time of continuing review UnanticipatedReport in summary at the time of continuing review. Report promptly in accordance with terms of this policy. (external or internal)* Unanticipated Problems NatureAction Involves risk to subjects or othersReport promptly in accordance with terms of this policy Does not involve risk to subjects or others No report required

19. IRB Review of Adverse Events IRBs usually are not equipped to adequately review AEs because they lack full information: -for double-blind studies; -from multi-center studies (e.g. all AEs or the denominator); all AEs or the denominator); -and may lack necessary statistical expertise

20. IRB Review of Adverse Events IRBs, nevertheless, are responsible for receiving and reviewing AEs. IRBs review AEs to: -assess whether risk(s) can be minimized for subjects experiencing an ongoing Serious AE (SAE); -assess whether the SAE alters the initial risk/benefit analysis for the study

21. IRB Review of Adverse Events IRBs review AEs to (cont’d): -assess whether risk(s) can be minimized to all subjects in the future; -assess whether disclosure of new information must be made to new and existing subjects.

22. Review of Adverse Events Investigator’s role in review of AEs: -ensure that all results are reported promptly to the investigator -system to ensure prompt review, by a physician, of all lab results and clinical data to identify AEs;

23. Anticipated and Unanticipated Adverse Events Investigator is responsible for determining when an AE exceeds its expected frequency or severity. Investigator must know and keep track of a list of expected AEs and their incidence, to the extent possible, for each study. Investigator must have a system for determining when an AEs exceed their expected frequency and/or severity and report such AEs promptly to the IRB.