Adverse Events, Unanticipated Problems, Protocol Deviations & other Safety Information

1. Adverse Events, Unanticipated Problems, Protocol Deviations & other Safety Information Which Form 4 to Use?

2. Reason for Reporting Unanticipated Problems “to assure the protection of the rights and welfare of the human subjects”

3. UTHSC IRB Submission Forms • 4a: Reportable local adverse events • 4b: Reportable external adverse events • 4c: Protocol problem or protocol deviation/violation • 4d: Non-reportable local or external adverse events or problems • 4e: Methodist Hospital & Le Bonheur Children’s Hospital adverse event • Data Safety Monitoring Board (DSMB)/Annual Reports

4. Adverse Event(adverse effect, adverse experience, unanticipated problem or unanticipated adverse device effect) • 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. Internal vs. External Adverse Events (AEs) • Internal Adverse Events • For a multi-center trial, those AEs experienced by subjects enrolled by the local investigator at the institution • For a single center trial, all AEs would be considered internal • External Adverse Events • Those AEs experienced by subjects enrolled by investigators at other institutions engaged in the clinical trial

6. Serious Adverse Event (AE) • Death • Life-threatening (places the subject at immediate risk of death from the event as it occurred • Inpatient hospitalization or prolongation of existing hospitalization • Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions • Congenital anomaly/birth defect • Any other AE that, based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed

7. Unexpected Adverse Event (AE) An AE or suspected adverse reaction is considered “unexpected” if it is: • Not listed in the investigator’s brochure (IB), package inserts, or product labeling, or not listed at the specificity or severity that has been observed • Not consistent with the risk information described in the general investigational plan (protocol) or elsewhere in the current application (consent form)

8. Relationship of AE to Research What is the likelihood that the AE, incident, experience or outcome may have been caused by the procedures involved in the research: • Possibly; • Probably; or • Clearly caused by research intervention

9. IRB Procedures for submitting Unanticipated Problems/AE Use the appropriate Form 4 via iMedRIS: • 4a: Reportable local adverse events • 4b: Reportable external adverse events • 4d: Non-reportable local or external adverse events or problems • 4e: Methodist Hospital & Le Bonheur Children’s Hospital adverse event

10. Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) The FDA defines a DSMB as: “a group of individuals with pertinent experience that reviews on a regular basis accumulating data from an ongoing trial. The DSMB advised the sponsor regarding the continuing safety of current participants and those yet to be recruited, as well as the continuing validity and scientific merit of the trial.”

11. Purpose of a DSMB or DMC • Identify unacceptably slow rates of accrual • Identify high rates of ineligibility determined after randomization • Identify protocol violations that suggest clarification of changes to protocol are needed • Identify unexpectedly high dropout rates that threaten the trial’s ability to produce credible results • Ensure the credibility of the study • Ensure the validity of study results • Protect the safety of trial participants

12. Is a DSMB necessary for my study? • Is there a large study population, or are there multiple study sites? • Is the trial intended to provide definitive information about effectiveness and/or safety of a medical intervention? • Do prior data suggest that the intervention being studied has the potential to induce unacceptable toxicity? • Does the trial evaluate mortality or another major endpoint, such that inferiority of one treatment arm has safety and effectiveness implications? • Would it be ethically important for the trial to stop early if the primary question addressed has been definitively answered, even if secondary questions or complete safety information were not yet fully addressed?

13. IRB Procedure Use the iMedRIS Submission Form “Data Safety Monitoring Board/Annual Reports” for the following: • FDA Safety Alerts • FDA Public Health Advisories • DSMB/DMC Reports • Sponsor Interim or Annual Reports *Must be submitted with 10 working days of receipt by the investigator

14. Protocol Deviations/Violations A failure to follow procedures specified in the approved research protocol in the absence of a protocol waiver.

15. Major vs. Minor Protocol Deviations Minor Protocol Deviation: • has no substantive effect on the risks or benefits for the individual research subject, and • has no substantive effect on the value of the data collected, and • does not result from willing or knowing misconduct on the part of an investigator or study staff. Major Protocol Deviation: • has harmed or has posed a significant risk of substantive harm to the individual research subject, or • has compromised the scientific integrity of the data collected for the study, or • appears to result from the willing or knowing misconduct on the part of an investigator or study staff, or • appears to involve some other serious or continuing noncompliance with federal, state or local research regulations.

16. Protocol Waiver (Eligibility Exception or Eligibility Waiver) A prospective decision by a sponsor or investigator to permit accrual of a subject who does satisfy the approved inclusion/exclusion criteria for enrollment.

17. IRB Procedure Submit a Form 4c: Protocol problem or protocol deviation/violation via iMedRIS • All major protocol deviations must be reported with 5 working days • Minor protocol deviations are not required to be submitted for IRB review • Protocol waivers from a study sponsor must include supporting documentation from the sponsor

18. iMedRIShttps://ris01.uthsc.edu

19. UTHSC IRB Websitehttp://www.uthsc.edu/research/research_compliance/IRB/policies.php