Event Reporting in Human Subjects Research Vanessa Hill, MSHS, CCRC, CIP Office of Responsible Research Practices May 2, 2019

Session Objectives Provide an overview of the event reporting policy Review best practices and available resources Provide definitions and discuss case examples Provide an overview of the event report application

Department of Health & Human Services (DHHS) Office for Human Research Protections (OHRP) 45 CFR 46 Food & Drug Administration (FDA) 21 CFR 50 21 CFR 56 21 CFR 312 21 CFR 812 Defines Roles and Responsibilities of Principal Investigator, Sponsor & IRB

PI Reporting Requirements Sponsor FDA DSMB IRB Participant Other When? Each entity may have a different reporting timeline. How? Each entity may have a different way to provide reports. Why? Each entity has a different responsibility in the oversight and conduct of the research.

*1,288 ceded studies to external IRBs *2,006 active exempt studies not included in data Buck-IRB Data 01/11/2019

Routine Reporting to the IRB Initial review Continuing review Amendments Change in research Change in personnel Change in funding Final study report

Prompt Reporting to the IRB: Unanticipated problems involving risks to subjects or others (UPIRSO) Noncompliance Research-related concerns Suspension or termination of research

UPIRSO Unanticipated Problem Involving Risks to Subjects or Others Unexpected events that suggest subjects, research staff, or others are placed at greater risk by the research than previously expected Medical or non-medical in nature Related or possibility related to the research

Noncompliance Failure (intentional or unintentional) to comply with applicable federal regulations, state or local laws, the requirements or determinations of the IRB, or university policy regarding research involving human subjects Can result from action or omission May be non-serious (minor) or serious, and may be continuing

What is the responsibility of the IRB? Unanticipated Problems & Noncompliance What is the responsibility of the Principal Investigator? The PI is responsible for prompt reporting of unanticipated problems involving risks to subjects or others and noncompliance. What is the responsibility of the IRB? The primary purpose of IRB review is to assure the protection of the rights and welfare of the human subjects. What is the responsibility of the sponsor? The Sponsor reports to all investigators and the FDA adverse experiences associated with the investigational product that is serious and unexpected and any finding that may increase risk to human subjects.

Reporting Considerations Expected vs. Unexpected Related vs. Unrelated Change in Risk Ohio State IRB Jurisdiction Internal Event vs. External Event Timing of reporting Prompt Reporting vs. Routine Reporting

Common Examples Requiring Event Reporting Adverse events that are serious, unexpected, and related Breaches of confidentiality involving risks Data safety monitoring board or sponsor safety reports altering risk/benefit Unexpected change in risk level Protocol deviations, violations, or other accidental or unintentional changes to the protocol or procedures involving risks or with the potential to recur Participant complaints Use of incorrect version of consent form/script

Common Examples Requiring Event Reporting Lack of consent or HIPAA authorization Individuals engaged in research prior to IRB approval Enacting amendments without prior IRB approval Use of unapproved documents Audit findings Suspension by the sponsor, investigator, or institutional entity Other problem or finding that could influence the safe conduct of the research

# of Event Reports Submitted CY 2018 # of Event Reports No IRB Review Required Cancer IRB 68 14 Biomedical Sciences IRB 98 15 Behavioral & Social Sciences IRB 31

Buck-IRB Data 01/11/2019

Institutions must have written procedures to ensure prompt reporting IRB Incident Notifications Noncompliance, UPIRSOs, Suspensions, Terminations Institutions must have written procedures to ensure prompt reporting Internal Reporting Institutional Official Dean/ Vice Dean for Research Department chair Co-Investigators Director of ORRP Other (e.g., Director of Sponsored Programs, Technology Commercialization Office, HIPAA Privacy Officer)

Institutions must have written procedures to ensure prompt reporting IRB Incident Notifications Noncompliance, UPIRSOs, Suspensions, Terminations Institutions must have written procedures to ensure prompt reporting External Reporting Sponsor Funding Agency Collaborating Institutions OHRP FDA Participants Other

External Reporting - OHRP & FDA Review Assess the adequacy of the actions taken by the institution and corrective actions implemented to address the UPIRSO, noncompliance, or suspension or termination of IRB approval Ensure that the incident will not happen again, with the investigator or protocol in question, with any other investigator or protocol, or with the IRB. Therefore, when appropriate, corrective actions should be applied institution-wide. Consider whether additional actions are required (i.e. IND Clinical Hold)

Buck-IRB Event Reporting Application Revisions Implemented June 2018 Type of Report Investigator Assessment of the Event Related Intervention(s) Source of the Report Research Status Other Reporting Corrective Actions

Case Studies IRB Event Reporting Consider the following: Should the event be reported to the IRB Promptly? If so, Why and When? Does the event represent an unanticipated problem involving risks to subjects or others? Does the event represent serious and or continuing noncompliance? Are there corrective actions that should be implemented? If so, what are they?

  External Event: The PI received an external safety report of a serious adverse event involving a subject that experienced heart failure. The individual received the oral study drug daily for approximately one year. Both the external study site investigator and sponsor assessed the event of heart failure as possibly related to study drug therapy, which was previously unknown. The same study is being conducted at Ohio State for the same patient population. Ohio State is not the IRB of record for the external site. At this time, the sponsor is not amending the protocol or consent form based on this isolated incident.

Case Example #1 External Event:   UPIRSO?- Yes Serious adverse event Risk not described in ICF & IB (Unexpected) Possibly related to intervention Noncompliance?- No

2. Internal Protocol Deviation:   A participant experienced an adverse event requiring a dose reduction per protocol. The study team entered the dosing orders at the reduced dose. Upon internal review, it was discovered that the participant received the full dose of study medication. According to the PI, the protocol deviation was an unexpected dispensing error by the clinical pharmacist but unrelated to the research. It was noted by the PI that the subject did not experience any additional adverse effects as a result of the dosing error, and thus was not put at increased risk. The PI considered this an isolated event because no other dosing errors were identified for other participants.

2. Case Example #2 Internal Protocol Deviation:   UPIRSO?- Yes Unexpected dosing error Related to the research intervention May have placed the subject at greater risk by the research Noncompliance? Serious? -Yes Failure to follow the currently approved protocol may increase risk to the participants or compromise their rights or welfare, or affect the integrity of the research/data. Continuing? - No No similar incidents previously reported for the study or PI, isolated event

3. Research Records:   The study team conducted an internal review of the research records and found that there were documentation errors. Of the 78 individuals enrolled in the study, a sample of 20 participant records were reviewed. The errors included nine informed consent documents and HIPAA research authorization forms missing dates and times from the participants. There were two informed consents that were missing the signature of the research staff member responsible for obtaining consent, but a note to file was present that explained who obtained consent. There were four informed consents that were discovered to be the incorrect version; the changes appeared to be administrative. It was noted that the research is consider minimal risk. Per the PI, these errors did not increase risk to participants.

3. CASE EXAMPLE #3 Research Records:   UPIRSO?- Not likely Unexpected documentation errors Related to the research Minimal risk study, does not appear to increase risks to participants   Noncompliance? Serious?- No but it is Non-serious/Minor Documentation errors do not appear to increase risk to the participants or compromise their rights or welfare, or affect the integrity of the research/data. Continuing?- Maybe Represents a pattern of ongoing informed consent documentation errors that indicate a lack of understanding of human subjects protection requirements.

Case Examples

Office of Responsible Research Practices Questions?

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Upcoming Education Sessions Office of Responsible Research Practices Upcoming Education Sessions Troubleshooting Informed Consent June 5th at 8 a.m. 115 Biomedical Research Tower Waivers of Informed Consent and HIPAA Research Authorization July 17 at 8 a.m.

Upcoming Education Sessions Office of Responsible Research Practices Upcoming Education Sessions Let’s Work Together: IRB Oversight of Collaborative Research, Part 1 August 21st at 8 a.m. 115 Biomedical Research Tower Let’s Work Together: IRB Oversight of Collaborative Research, Part 2 September 10th at 11 a.m.

Resources FDA - Guidance for Clinical Investigators, Sponsors, and IRBs- Adverse Event Reporting to IRBs-Improving Human Subjects Protection OHRP - Unanticipated Problems Involving Risks & Adverse Events Guidance ORRP - Event Reporting – Unanticipated Problems Involving Risks to Subjects or Others, Adverse Events, and Other Problems ORRP - Event Reporting Investigator Guidance