Adverse Event/Unanticipated Problems Policy and Procedures November 2007

1. Adverse Event/Unanticipated ProblemsPolicy and ProceduresNovember 2007

2. Learning Objectives • Review new Policy and Procedures • Identify what events and problems are reportable to the IRB • Review some brief case studies

3. Adverse Event • Any untoward or undesirable experiences associated with research, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research.

4. Adverse Event • Adverse events may be the result of: • the interventions and interactions used in the research • the collection of identifiable private information in the research • an underlying disease, disorder, or condition of the subject and/or • other circumstances unrelated to the research

5. Adverse Event • Most adverse events are not reportable to the IRB • The majority of adverse events that occur in the context of research are expected: • the known toxicities and side effects of the research procedures • the expected natural progression of the subjects’ underlying diseases, disorders, and conditions, and • subjects’ predisposing risk factor profiles for adverse events

6. UCI Adverse Events and Unanticipated Problems Policy and Procedures Revisions • Provide expanded list of events reportable to the IRB as a guide Investigators • Investigator reporting timelines have increased from 48 hours to either 5 or 10 working days • Reduce reporting requirements at time of Continuing Review – no longer required to submit Adverse Event (AE, SAE) and Safety Report Summary Log • Report only Unrelated Serious Adverse Events (Deaths) that occur on UCI IRB approved study at time of Continuing Review. Use the Internal Unrelated SAE Summary Log

7. UCI Adverse Events and Unanticipated Problems Policy and Procedures Revisions • If Investigators choose to report deviations and other non-reportable events (such as expected or unrelated adverse events) to the IRB, submit the UCI Non Reportable Events Reportto HRP staff for verification. • AE-UP report changes… • No longer required to submit a follow-up report to the IRB unless the event/problem is not resolved as expected or the event/problem results in a chronic condition or death • Check box to indicate other entities notified about the event/problem (e.g., Sponsor, NCI AdEERS, FDA) • Check box to generally describe event/problem from list of descriptions. Investigator may choose more than one description

8. Why the Change? • OHRP Guidance (January 15, 2007) • FDA Guidance (April 9, 2007 draft) • Association for the Accreditation of Human Research Protections Programs

9. IRB’s role will be… To determine whether the event or problem is an Unanticipated Problem Involving Risk To Participants Or Others • Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the IRB-approved documents, such as the protocol and informed consent document, and (b) the characteristics of the subject population being studied • Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the event or problem may have been caused by the procedures involved in the research), and • Suggests that the research places subjects or others at agreater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized

10. If the IRB determines that the event/problem is an Unanticipated Problem… The IRB may take any of the following actions: • Accept the report with no changes • Accept the report with changes to the risk/benefit profile, the protocol, or the informed consent documents (requires submission of e-MOD Request) • Require re-consenting of participants • Increase the frequency of continuing review • Impose additional monitoring requirements • Require additional training of the Investigator and research team • Request an “Administrative Hold” pending further information • Suspend or Terminate the study

11. Case Study #1 • A subject enrolled in a Phase 3, randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of a investigational anti-inflammatory agent for management of osteoarthritis. • The subject develops severe abdominal pain and nausea one month after randomization. • Subsequent medical evaluation reveals gastric ulcers. The IRB-approved protocol and informed consent document indicated that the there was a 10% chance of developing mild to moderate gastritis and a 2% chance of developing gastric ulcers for subjects assigned to the active investigational agent.

12. Case Study #1 • The investigator concludes that the subject’s gastric ulcers resulted from the research intervention and withdraws the subject from the study. • Should this event/problem be reported to the IRB?

13. Case Study #1 • Should this event/problem be reported to the IRB? NO, although the event is related to the research intervention, the risk was foreseeable (described in the IRB-approved documents) and the subject was not placed at greater risk of harm than was previously recognized.

14. Case Study #2 • As a result of a processing error by a pharmacy technician, a subject enrolled in a multicenter clinical trial receives a dose of an experimental agent that is 10-times higher than the dose dictated by the IRB-approved protocol. • While the dosing error increased the risk of toxic manifestations of the experimental agent, the subject experienced no detectable harm or adverse effect after an appropriate period of careful observation. • Should this event/problem be reported to the IRB?

15. Case Study #2 • Should this event/problem be reported to the IRB? Yes, the dosing error constitutes a protocol violation - accidental or unintentional changes to, or non-compliance with the IRB approved protocol without prior sponsor and IRB approval. Violations generally increase risk or decrease benefit, affects the subject's rights, safety, or welfare, and/or the integrity of the data

16. Case Study #3 • A subject with seizures enrolls in a randomized, Phase 3 clinical trial comparing a new investigational anti-seizure agent to a standard, FDA-approved anti-seizure medication. The subject is randomized to the group receiving the investigational agent. • One month after enrollment, the subject is hospitalized with severe fatigue and on further evaluation is noted to have severe anemia. • The known risk profile of the investigational drug does not include anemia, and the IRB-approved protocol and informed consent document for the study do not identify anemia as a risk of the research. • Should this event/problem be reported to the IRB?

17. Case Study #3 • The known risk profile of the investigational drug does not include anemia, and the IRB-approved protocol and informed consent document for the study do not identify anemia as a risk of the research. • Should this event/problem be reported to the IRB? Yes,anemia is (a) unexpected in nature; (b) possibly related to participation in the research; and (c) places subjects at greater risk of harm.

18. Case Study #4 • An investigator conducting behavioral research collects individually identifiable sensitive information about illicit drug use and other illegal behaviors by surveying college students. The data are stored on a laptop computer without encryption, and the laptop computer is stolen from the investigator’s car on the way home from work. • Should this event/problem be reported to the IRB?

19. Case Study #4 • Should this event/problem be reported to the IRB? • Yes, this is a breach in confidentiality that caused harm or places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm).

20. Unanticipated Problems… Under 45 CFR Part 46 and 21 CFR Part 56 the IRB is required to have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of any unanticipated problems involving risks to subjects or others UCI IRB is trying to capture events and problems in B and C but not in A

21. Any questions?

22. Thanks for listening!