1. Main Line Hospitals Institutional Review Board Unanticipated Problems Anne Marie Hobson, BSN, JD, ORA Director Theresa Greaves, ORA Manager

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

3. Definitions Unanticipated Problems: Unanticipated problems involving risks to subjects or others are defined as any incident, experience or outcome that meets all of the following criteria: Unexpected (in terms of nature, severity, or frequency) given the research procedures and the subject population being studied; and Related or possibly related to a subject’s participation in the research; and Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

4. 4 Definitions Adverse Event: Any untoward or unfavorable medical occurrence in a human subject, 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

5. Definitions Serious Adverse Event: Any adverse event temporally associated with the subject’s participation in research that meets any of the following criteria: results in death; A life-threatening event (places the subject at immediate risk of death from the event as it occurred); requires inpatient hospitalization or prolongation of an existing hospitalization; results in a persistent or significant disability/incapacity; results in a congenital anomaly or birth defect; or any other adverse event that based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the outcomes in this definition

6. Definitions Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety, or any life-threatening problem or death, caused by or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application, or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

7. Reportable Problems/Events An adverse event (or serious adverse event) may be expected, based on the known risks of the study and information in the informed consent and other study related documents. An adverse event is reportable only if it is also an unanticipated problem. In addition, unanticipated problems, even if not involving physical risks, need to be reported.

8. 8 Adverse Events 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

9. Adverse Events 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

10. Why the Policy Change… OHRP Guidance (January, 2007) FDA Guidance (January 2009) Association for the Accreditation of Human Research Protections Programs (AAHRPP)

11. IRB Process 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; AND 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/drugs or devices involved in the research); AND Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized

12. Ask Three questions… Is the adverse event unexpected? AND Is the adverse event related or possibly related to participation in the research? AND Does the adverse event suggest that the research places subjects or others at a greater risk of harm than was previously known or recognized? When the answer to all three questions is YES, the adverse event is an unanticipated problem and must be reported to the MLH IRB.

13. 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 MLH IRB is trying to capture events and problems in B and C but not in A 13

14. 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.

15. 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.

16. 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.

17. 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

18. 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.

19. Case Study #3 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.

20. Case Study #4 Subjects with coronary artery disease presenting with unstable angina are enrolled in a multicenter clinical trial evaluating the safety and efficacy of an investigational vascular stent Based on prior studies, the investigators anticipate up to 5% of subjects receiving the stent will require emergency CABG surgery Emergency CABG risk is described in the protocol and informed consent document After the first 20 subjects enrolled in the study a DSMB interim analysis reports10 subjects have undergone emergency CABG surgery soon after placement of the investigational stent.

21. Case Study #4 Should this event/problem be reported to the IRB? Yes, (a) the frequency subjects needed to undergo emergency CABG was significantly higher than the expected frequency (b) these events were related to participation in the research; and (c) these events were serious

22. Points to Consider… There is not an “easy answer” to determine if an adverse event is reportable to the MLH IRB. Researchers must look beyond the categories of “related” or “possibly related” and “unexpected” when determining whether to report an event or series of events. Many reports labeled “unexpected” will not meet the definition of an unanticipated problem. MLH investigators participating in multicenter studies receive a large volume of reports of external adverse events and each report must be considered individually.

23. Points to Consider Continued… External Adverse Events Both FDA and the HHS Office of Human Research Protections have stated their expectation that an individual external adverse event will rarely meet the criteria for an unanticipated problem. OHRP has provided guidance urging sponsors that individual adverse events should only be reported to investigators at all institutions when a determination has been made by the sponsor that the events meet the criteria for an unanticipated problem. –OHRP recommends that any distributed reports include: (1) a clear explanation of why the adverse event or series of adverse events has been determined to be an unanticipated problem; and (2) a description of any proposed protocol changes or other corrective actions to be taken by the investigators in response to the unanticipated problem.

24. Points to Consider Continued… External Adverse Events –External adverse event reports from a different study, or use of the agent or procedure in a different population or route of administration may constitute an unanticipated problem for an MLH study. The MLH Investigator should assess whether or not the information in the report indicates a problem that affects the rights and welfare of MLH subjects. If in the judgment of the MLH investigator it does, the report should be submitted. –If the external report does not contain sufficient information for the MLH investigator to make the needed assessment AND the source of the report (e.g. the sponsor) did not state the event is an “unanticipated problem” or an “unanticipated adverse device effect”, then submission to the IRB is not required.

25. Please contact us… Lankenau Institute for Medical Research Suite G-44, NEB Alia Dudley610-645-2678 Theresa Greaves 610-645-3414 Anne Marie Hobson, JD610-645-2692 Albert A. Keshgegian, MD, Ph.D.610-645-3552