Did that just happen? And What do I do now?

2. Did that just happen?And What do I do now? Identifying and Reporting Adverse Events and Protocol Deviations Elizabeth Mathis, CCRP 18 February 2014

3. Adverse Events Serious Adverse Events Protocol Deviations Overview and Objectives http://www.hhs.gov/ohrp/policy/advevntguid.html

4. Unanticipated Problem Definition • Incident, Experience, or Outcome • Unexpected • Possibly related to participation in Research • Places subjects or others at greater risk of harm • Nature • Physical • Psychological • Frequency • Severity • Social • Economic http://www.hhs.gov/ohrp/policy/advevntguid.html

5. Unanticipated Problem or Not? Behavioral Study Checklist: ⃝ Incident, experience, or outcome? ⃝ Unexpected? ⃝ Related to participation? ⃝ Greater risk of harm? • Collects identifiable info • Illicit drug use and illegal behaviors of college students • Data stored on unencrypted laptop • Laptop stolen from car

6. Unanticipated Problem or Not? Device Intervention Study Checklist: ⃝ Incident, experience, or outcome? ⃝ Unexpected? ⃝ Related to participation? ⃝ Greater risk of harm? • Vascular stent placement vs surgery for severe carotid artery stenosis • Patient assigned to stent placement study group • After procedure, the patient suffers a severe stroke resulting in left-sided paralysis • Protocol and ICF indicated a 5-10% chance of stroke for both study groups. The DSMB concludes the occurrence of stroke was expected as well as frequency.

7. Unanticipated Problem or Not? Drug Intervention Study Checklist: ⃝ Incident, experience, or outcome? ⃝ Unexpected? ⃝ Related to participation? ⃝ Greater risk of harm? • For essential hypertension testing new anti-hypertensive drug.  • Three of the first ten subjects have severe GERD symptoms that began within one week of starting the investigational drug and resolve after drug discontinued. • At beginning of trial, no documented evidence of GERD in protocol and ICF do not describe GERD as risk. • Investigator determines that GERD symptoms were caused by the study drug and warrant modification of the ICF to include GERD as a risk of the research. 

8. Adverse EventsDefinition http://www.hhs.gov/ohrp/policy/advevntguid.html

9. Unanticipated Problemvs.Adverse Events Adverse Events B= Adverse Events that are Unanticipated Problems • A= • Adverse Events that are not Unanticipated Problems • C= Unanticipated problems that are not Adverse Events http://www.hhs.gov/ohrp/policy/advevntguid.html Unanticipated problems

10. AE or Not? Subject # 1 On quadruple therapy study for Hepatitis C ICF states: Decreases in laboratory tests measuring white blood cells, platelets, red blood cells.

11. AE or Not? Subject # 1

12. AE or Not? Subject # 2 On triple therapy study for Hepatitis C Package insert states:

13. AE or Not? Subject # 2 Progress note for Follow up week 24 visit:

14. AE or Not? Subject # 3 Device study to detect mucosal oxygenation during AAA repair From ICF:

15. AE or Not? Subject # 4 On triple therapy study for Hepatitis C http://sv-galena.com/Trip6/201012Bahamas/Part01.html

16. Serious Adverse EventsDefinition http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm

17. SAE or Not? Subject # 5 On quadruple therapy study for Hepatitis C

18. SAE or Not? Subject #6 (1) Subject #389204 had Week 8 laboratory tests collected on February 18, 2008, and the corresponding laboratory report that was faxed to your site on February 20, 2008, showed that the subject’s creatinine (CR) level measured 3.2 mg/dL.* * Normal range is 0.5 -1.2 mg/dL. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm244336.htm

19. Serious Adverse Events Important Distinction

20. Protocol Deviations

21. Protocol Deviations Definition

22. ProtocolDeviations Definition http://research/f/f#Forms-IRBAdmin

23. Deviation or Not? Subject # 7 On treatment for PBC-related liver enzyme elevation Exclusion Criteria #4: Prohibited 6 months prior to Day 0 and throughout the trial (i.e., to last dose to last dose and/or EOT): azathioprine, colchicine, cyclosporine, methotrexate, mycophenolatemofetil, pentoxifylline; fenofibrate or other fibrates; budesonide and other systemic corticosteroids;

24. Deviation or Not? Subject # 8 On triple therapy for Hep-C

25. Deviation or Not? Subject # [Redacted] • Records of each subject's case history are not all accurate and complete. Specifically, individual subject case history files including source documentation and CRFs contain missing or discrepant information, including, but not limited to the following: • for subject [redacted] missing documentation of required physical examinations, incomplete or missing documentation regarding the placement of [redacted] and Complications Report or Intercurrent Event Report not completed; • missing information regarding surgical complications, the number of devices implanted, and device accountability for subject [redacted] and, • source worksheets and CRFs do not record any information or measurements regarding required evaluations for subjects [redacted] http://www.fda.gov/ICECI/EnforcementActions/WarningLetter

26. Adverse Events, Serious Adverse Events, and Protocol Deviations Overview and Objectives

27. AE Review

28. AE Review

29. SAE Review

30. Deviation Review http://www.nia.nih.gov/sites/default/files/protocoldeviationscoreformfillable.pdf

31. Overview and Objectives Adverse Event, Serious Adverse Event, and Protocol Deviations

32. Adverse Events Reporting to IRB http://research/f/f#Forms-IRBAdmin

33. Internal Serious Adverse Events Reporting to Sponsor CTSC Research Guidebook, pg 79

34. Internal Serious Adverse Events Reporting to IRB http://research/f/f#Forms-IRBAdmin

35. Internal Serious Adverse Events Reporting to IRB http://research/f/f#Forms-IRBAdmin

36. External Serious Adverse Events

37. External Serious Adverse Events Reporting to IRB

38. External Serious Adverse Events Reporting to IRB

39. Protocol Deviations Reporting to Sponsor

40. Protocol Deviations Reporting to IRB http://research/f/f#Forms-IRBAdmin

41. Protocol Deviations Reporting to IRB http://research/f/f#Forms-IRBAdmin

42. Recap Adverse Events Serious Adverse Events Protocol Deviations

43. Resources • IRB Forms http://research/f/f#Forms-IRBAdmin • OHRP guidance: http://www.hhs.gov/ohrp/policy/advevntguid.html • FDA Warning Letter http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm244336.htm • SACHRP recommendations on Protocol Deviations: http://www.hhs.gov/ohrp/sachrp/mtgings/2012%20Feb%20Mtg/protocoldeviations.pdf • IRB SOPs: http://research.ucdavis.edu/gt/irb-sop