1. Month, day, year Reporting Adverse Events What, When, How? Cynthia Gross Professor, College of Pharmacy and School of Nursing The MN Center for Health Trajectory Research Presentation 12/3/09

2. Learning Objectives Define key terms and acronyms as used in the context of monitoring and reporting safety in clinical research studies: adverse event UPIRTSO relatedness seriousness and severity (and how these differ). Identify what is to be reported to the UMN IRB and who reports, and in what timeframe. Evaluate case studies and determine whether they meet criteria for expedited reported as UPIRTSOs.

3. Outline of Presentation Regulatory background Define terms Describe systems for coding events Present examples Outline UMN IRB reporting procedures List key resources

4. Regulatory Background: Key Source Document Guidance on Reviewing and Reporting Unanticipated Problems involving Risks to Subjects or Others and Adverse Events from the OHRP - Office for Human Research Protections, DHHS - Dept. of Health and Human Services Guidance document, January 2007 http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm

5. Topics in the Guidance What are unanticipated problems? What are adverse events? How do you determine which adverse events are unanticipated problems? What are other important considerations regarding the reviewing and reporting of unanticipated problems and adverse events? What is the appropriate time frame for reporting unanticipated problems to the IRB and others? Plus topics related to the policies and conduct of IRBs in these processes.

6. The Role of the IRB Each IRB interprets and implements the Guidance with its own policies, procedures and forms. The University of Minnesota’s guidelines are at: http://cflegacy.research.umn.edu/irb/ae/ http://cflegacy.research.umn.edu/irb/ae/ The Mayo Clinic guidelines are at: http://mayoresearch.mayo.edu/mayo/research/irb/upirtso_reporti ng_policy.cfm There will be differences across IRBs – where one IRB defines expedited or prompt reporting as 10 days another may use a 5 day rule.

7. What are adverse events (AEs)? Any unfavorable or unintended sign (including an abnormal exam or lab finding), symptom or disease, temporally associated with the subject’s participation in the research, regardless of whether it is considered related to the subject’s participation in the research. *AEs includes physical and psychological harms. (definition modified from on the 1996 ICH E-6 Guidelines for Good Clinical Practice).

8. What is serious? 1 of 2 A problem/event that results in: In-patient hospitalization, or prolongation of hospitalization; Life-threatening adverse experience; A persistent or significant disability or incapacity; Death; Birth defect or congenital anomaly; or Protocol-defined condition/event. Clearly defined

9. What is serious? 2 of 2 An event/problem is also serious if it is: “deemed by the investigator to have adversely affected the rights, safety or welfare of the subjects or others; including compromising the research data.” from the IRB website Less clearly defined

10. Rights, safety, welfare and data problems Rights1.Confidential records made public 2. Safety1. Contaminant in drug supply 2. Welfare1.Alternative treatment options not shared 2. Data Integrity1. Corrupted data file, no backup, data lost 2. Determination of Problem may not be clear-cut

11. What are unanticipated problems? Unanticipated Problem Involving Risk to Subjects or Others = UPIRTSO 1. Serious AND 2. Unanticipated AND 3. At least possibly related to the research procedures. All 3 conditions must be present.

12. What is unanticipated? Not in the protocol Not in the consent form Not in the investigators brochure Not common in the study populations (e.g., part of the disease process) “An unforeseeable problem or one which occurred at a higher frequency or greater severity than anticipated”

13. What is related? Possibly Probablyto the research Definitely related Determination of relatedness rests with the study investigators and their monitors (site investigator, independent monitor, overall protocol PI, Data Safety Committee, etc.)

14. Classification of relatedness AttributionDescription UnrelatedThe AE is clearly NOT related to the intervention. UnlikelyThe AE is doubtfully related to the intervention. PossibleThe AE may be related to the intervention. ProbableThe AE is likely related to the intervention. DefiniteThe AE is clearly related to the intervention from NCI, CTEP guidelines What is related may not be immediately apparent or may remain uncertain

15. Consequences of unanticipated problems Unanticipated problems will generally warrant consideration of substantive changes in: research protocol informed consent process/document staff training monitoring plan or other corrective actions

16. Example 1 1 of 3 The Event Routine safety monitoring identified more incidences of tooth discoloration than anticipated in an ongoing clinical trial.

17. Example 1 1 of 3 The Evaluation by the Investigator: Seriousness: Yes. Condition was deemed potentially serious since some patients view this as a disfigurement. Unanticipated: Yes. Based on the higher than expected frequency, tooth discoloration was deemed an unanticipated problem. Related: Yes. The research protocol and informed consent documents mentioned tooth discoloration but implied it was a relatively rare problem.

18. Example 1 3 of 3 Decision and action: The Protocol Investigator notified all site investigators, all current participants and IRBs, OHRP, FDA, and other sponsors and relevant parties were notified of this problem. The protocol and wording of the informed consent were revised. As the condition being studied was disabling and severe, this notification had little impact on recruiting or continuation of participants.

19. Serious versus Severe ‘Severity’ is not the same as ‘serious’. Serious is based on event/outcome or actions meeting criteria for posing a threat to rights, safety or welfare. ‘Severe’ is usually a description of intensity (as in mild, moderate or severe headache). Some events rated as ‘severe’, may not be deemed ‘serious’ in the context of a particular study and vice versa. Adapted from NCI, CTEP guidelines

20. Determining which adverse events are unanticipated problems. Most AEs are not unanticipated problems; not all problems are AEs.

21. Sources of Adverse Event Data Study Subject Lab tests Exam- inations Imaging reports Other The Obituaries Letters Interviews AE checklist Patient comments

22. Systems for recording adverse events: MedDRA The Medical Dictionary for Regulatory Activities (MedDRA) is a medical terminology system for classifying adverse events for drugs and devices, reporting and drug labeling. MedDRA was developed by the International Conference on Harmonization (started by the US, EU and Japan) and is owned by the International Federation of Pharmaceutical Manufacturers. Current version is MedDRA 12.1. MedDRA is available by subscription and has coding and training classes. MedDRA does not determine severity or establish relatedness. http://www.meddramsso.com/

23. NCI Common Terminology Criteria for Adverse Events (CTCAE) A standard system for eliciting, grading and reporting adverse events in cancer clinical trials. Each AE has a grading (severity scale). CTCAE terms map to MedDRA. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev4.pdf

24. Cancer Adverse Event Reporting System (caAERS) An open-source software tool that is used to collect, process, and report AEs Tool supports regulatory compliance and allows local collection, management, and querying of routine and expedited AEs (UPIRTSOs) https://cabig.nci.nih.gov/tools/caAERS#tools

25. Investigator Responsibility Investigators have the primary responsibility for AE identification, documentation, evaluation/grading and assignment of attribution. Investigators have to report to their IRB, sponsors and others. MedDRA and CaAERS assist by providing common terminology and classification systems, but the determination of severity, attribution (relatedness) require the direct involvement and judgment of the investigators – ultimately the study principal investigator.

26. What to report to the UMN IRB 1 of 3 Reported within 10 days: UPIRTSOs: 1. Any serious event (including on-site and off-site adverse events, injuries, side effects, deaths or other problems) which in the opinion of the local investigator was unanticipated, involved risk to subjects or others, and was possibly related to the research procedures. Plus….

27. What to report, continued 2 of 3 2. Serious accidental or unintentional protocol change that involves risk or potential to recur. 3. Protocol deviation to eliminate immediate hazard to a research subject. 4. Publications, safety reports or interim results that indicate an unexpected change to the risk/benefit ratio Plus…

28. What to report, continued 3 of 3 5. Breach in confidentiality that may involve risk to the subject or others. 6. Complaint of a subject that indicates an unanticipated risk or that cannot be resolved by the research staff. 7. Any other serious and possibly related event which in the opinion of the investigator constitutes an unanticipated risk.

29. UMN form to report UPIRTSOs

30. What about non- UPIRTSOs? Non-UPIRTSO events/problems are reported with the annual continuation report.

31. Example 2 from Guidance Document 1 of 3 The Event: A behavioral study in college students involves completion of a detailed survey asking questions about early childhood experiences. During the completion of the survey, one subject has a transient psychological reaction manifested by intense sadness and depressed mood that resolved without intervention after a few hours.

32. Case Example 2 from Guidance Document 2 of 3 The Evaluation by the Investigator: Serious: Yes. The events suggested that the research places subjects at a greater risk of psychological harm than was previously known or recognized. Unanticipated: Yes. The investigator had not expected that such reactions would be triggered by the survey questions. The protocol and informed consent document for the research did not describe any risk of such negative psychological reactions. Related: Yes. Upon further evaluation, the investigator determines that the subject’s negative psychological reaction resulted from certain survey questions that triggered repressed memories of physical abuse as a child.

33. Case Example 2 from Guidance Document 3 of 3 Actions: What would you do? Note for additional examples see Guidance document and Mayo IRB website.

34. Summary of Investigator Responsibilities Continually monitor and track adverse events and potential problems; Maintain current knowledge of issues (e.g., new publications, FDA rulings) relevant to the risk/benefit of the study interventions; Report any UPIRTSOs within the 10 days of learning of the event using the UMN IRB form. Include proposed changes to protocol, consent or other procedures, and relevant documentation (identified only by study ID #) of the event and its consequences. Comply with all other reporting requirements ( the DSMB, study sponsors, the NIH, FDA, etc.). The IRB will evaluate UPIRTSOs and notify the OHRP/DHHS, university officials and others; and take actions as per its policies.

35. Reminder from the Guidance The Guidance expects that only a small subset of adverse events occurring in human subjects participating in research will be unanticipated problems that must be reported under 45 CFR part 46.* * HHS regulations for protection of human subjects.

36. Who can answer my questions? Patrice Webster, CIP Assistant Director, Human Research Protection Program (UMN IRB) webst019@umn.edu 612.626.5654 (HRPP main line) 612.626.5941 (direct line and voice mail) 612.626.6061 (fax) www.research.umn.edu/subjects/ www.research.umn.edu/subjects/ Clinical and Translational Science Institute (CTSI) phone number:(612)625-2874 e-mail: ctsi@umn.eductsi@umn.edu and suggest that the inquiry to be directed to a Research Project Manager(RPM) or to a Clinical Research Associate (CRA).

37. Main Resources used in this talk: Main Resources used in this talk: Reporting Unanticipated Problems, Institutional Review Board (IRB), University of Minnesota http://cflegacy.research.umn.edu/irb/ae/ UPIRTSO Reporting Policy, Office for Human Research Protection, Mayo Clinic http://mayoresearch.mayo.edu/mayo/research/irb/upirtso_reporting_poli cy.cfm Guidance Document: Office for Human Research Protections (OHRP) Department of Health and Human Services (DHHS) http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm Guidance Document: Office for Human Research Protections (OHRP) Department of Health and Human Services (DHHS) http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm