Unanticipated Problems, Protocol Deviations and Non-Compliance

1. Unanticipated Problems, Protocol Deviations and Non-Compliance Emory Institutional Review Board Version 8-1-13

2. Objectives Recognize what constitutes a UP/NC/reportable PD. Understand importance of prompt reporting to IRB. Identify reporting requirements per contract/protocol.

3. Course Content Unanticipated Problems Protocol Deviations Noncompliance External Events IRB Reporting Requirements Sponsor Reporting Requirements Examples and Practice Examples

4. What is an Unanticipated Problem? • An unanticipated problem (UP) is an event that involves a riskto the participant or others that probably need changesto the study protocol, consent forms and/or investigator brochure because of increase in study’s risk

5. What is an Unanticipated Problem? • For a event to be classified as UP, it need to fulfill the following requirements: • Is unanticipated • Related to the research • The event suggest that the research places subjects or others at a greater risks of harm than was previously known.

6. From http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm

7. Event is Unanticipated if… • It is not a known risk of the study drug, device, or procedure or patient’s underlying medical condition(s). • It is not in the protocol, consent, or investigator’s brochure. • It is an anticipated event that exceedsthe anticipated frequency, severity, or duration.

8. Event is related to the research if… • It is possible, probably or definitively caused by the study drug, device or procedure OR • It is more likely than not to be related. • Events are not related if: • They are caused by an underlying disease or condition of the subject • Or by other circumstances that are not related to the research.

9. Event increases risk if… • It happens repeatedly • They are rare in the absence of drug/device exposure • They exceed the anticipated frequency, severity and duration • They require a protocol, consent or investigator’s brochure change An event fulfilling all 3 criteria are promptly reportable to IRB

10. From http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm

11. Protocol Deviations • Departure from the IRB-approved protocol (it happens) • To be reportable: has to be substantive and adversely affecting at least one of the following: • Rights, welfare or safety of subjects • Subjects willingness to continue in the study • Scientific integrity of the data

12. Noncompliance • Failure to comply with any of the regulations and policies of the IRB P&Ps and failure to follow the determinations of the IRB • Consult the IRB in what is reportable and how to report it. Minor cases, as determined by the IRB, do not have to be reported. • Consult with Education and QA at the Emory IRB in case of doubt.

13. External Events • Internal vs. External • Internal: represents an event that happened to a subject who was enrolled at an Emory site or at a site in which the Emory IRB was the IRB of record • Only reportable if assessed as UPs • Exception: if external event is under supervision of Emory S-I Check our guidance at Investigator Safety Reporting Obligations to the IRB (ver. 4-25-13)

14. Prompt Reporting • UPs, NC or reportable PDs= 10 calendar days for reporting • Reports should come with an explanation of why they are reportable. This is critical for UP submissions. • Internal research-related deaths= promptly reportable • Other unanticipated information that could increase risk should also be reported. • Late reporting is considered non-compliance as it could impact patient safety!

15. Periodic Reporting • Certain things need to be reported to the IRB in during continuing review, even if they were reported before. • Internal deaths even if not related to study • UPs previously reported (included in a summary) • Internal serious adverse events related to the study (even if they are nor real ups). • Please indicate which events are UPs, and any other tracking data from sponsor.

16. Do not report! • External events that are not UPs (except if external site is under a Emory S-I) • Internal anticipated or unanticipated events that are not related to the research • Internal serious or not serious events that are not related to the research. • Exemption: Internal not related deaths (CR)

18. Sponsor Obligations • Check your contract with the sponsor to understand your reporting requirements (sometimes different from IRB’s) • Record ALL events in your logs, even if they are not reportable to IRB • Stay current with recommendations/data from your DSMB • If you are the sponsor-investigator make sure you are collecting events from all sites and trending the data with the DSMB.

19. What do you think? A medical student, who is not on the IRB-approved list of study personnel, consents a subject for enrollment into a clinical trial. • Noncompliance • Report or consult with the IRB

20. What do you think? A subject comes late to a study visit at the infusion center, and as a result, gets the study medication 2 hours late. • Protocol Deviation • Go through reporting requirements to see if it needs to be reported to the IRB • Report to sponsor per their requirements

21. What do you think? You receive a Medwatch form that reports a death from a car accident in a subject participating in your trial in Texas. The PI in Texas calls it not related to the study. • Go Through UP Questions • See if you and the Emory PI agree it is not related • If not a UP, then it does not need to be reported to the IRB

22. What do you think? You read a notice on the FDA website about a new, unexpected side effect seen in your study drug. • Review UP Questions in guideline • Report to the IRB if it is an UP

23. What do you think? The sponsor sends you a letter reporting a SAE. The SAE is being reported as a UP, but the Emory PI disagrees with the sponsor. What is the process to follow? • Report the event as a UP to the IRB • State that the Emory PI does not agree with this assessment • The FDA puts the responsibility of assessment on the sponsor (IND or IDE holder)

24. What do you think? A subject receiving the study drug was hospitalized after having a stroke. The subject has a history of diabetes, and had a TIA in the past year. The PI does not think this event is related to study participation but is very concerned about the subject. Is this serious event reportable to the IRB? • The event is not related. As such, is not reportable to the IRB • Follow your protocol/contract for your sponsor reporting requirements.

25. What do you think? A subject had serious adverse event while receiving the research chemotherapy regimen. The adverse event is outlined in the ICF, protocol and IB as a possible adverse event, but the subject is experiencing a move severe SAE than anticipated. The PI thinks this is possibly related to study participation. What is the best approach in this situation? • If the infection is not greater in severity, duration or frequency, it may not constitute a UP. • If the event is not considered a UP, does not need to be reported to the IRB. • Keep AE/SAE logs to evaluate for patterns indicating an increase in severity, frequency or duration beyond what is described in the protocol.

26. Questions? Maria G. Davila (404)712-0724 or maria.davila@emory.edu Shara Karlebach (404)712-0727 or shara.karlebach@emory.edu Kevin Wack (404)712-5220 or kwack@emory.edu Sean Kiskel (404)712-0766 or skiskel@emory.edu