Adverse Event and Information Reporting to the IRB: Policy Updates in Monitoring for Unanticipated Problems and Non-Comp

1. Adverse Event and Information Reporting to the IRB: Policy Updates in Monitoring for Unanticipated Problems and Non-Compliance Adam Schechter Research Integrity Coordinator for Education & Quality Assurance/Quality Improvement Office of Research Integrity

2. OVERVIEW A Discussion of Potential Risks in Research Adverse Event Reporting Protocol Deviations FAQ

3. Risks in Research The IRB reviews protocols in recognition of the fact that: Risks are inherent to clinical research, and Every PI needs to have a plan to: Manage and mitigate the known risks Communicate known risks to research subjects accurately

4. Risks in Research When the IRB approves the research it does so in acknowledgment of the known risks and the plan to mitigate them. Then the PI is free to conduct the research as approved by the IRB. During the course of the trial, adverse events may occur, the PI or research staff may deviate from the protocol in error, or new information may come to light that affects the risks inherent in the research. For this reason, regulations require that the IRB monitor protocols for: Unanticipated problems involving risks to subjects Serious or continuing non-compliance with the IRB approved protocol or IRB policies

5. What are Unanticipated Problems? Unanticipated problems involving risks to subjects or others means: Unexpected: Not reflected in the consent document or investigator�s brochure At least probably related to the research procedures, drugs, and/or devices

6. What is Serious or Continued Non-Compliance? Serious Non-Compliance Deviation from the IRB approved protocol or reporting requirements that represents an infringement on the rights and/or welfare of research subjects. Continued Non-Compliance Repeated failure to adhere to IRB approved protocol or regulatory requirements. Self-regulation is key (don�t wait for us to catch it)! Non-compliance is rarely an intentional or malicious thing�it is often an honest mistake! That said, both types of non-compliance can occur (and can be reported after the fact) regardless of whether they were caught by the IRB/ORI. It is essential that research teams are proactive in keeping tabs on their compliance with WCMC (and other) policies and regulations as the studies progress. Non-compliance is rarely an intentional or malicious thing�it is often an honest mistake! That said, both types of non-compliance can occur (and can be reported after the fact) regardless of whether they were caught by the IRB/ORI. It is essential that research teams are proactive in keeping tabs on their compliance with WCMC (and other) policies and regulations as the studies progress.

7. How is the IRB Involved? The IRB needs to evaluate incidents and information that might represent unanticipated problems or serious/continued non-compliance to determine whether the unexpected incident or information renders its initial risk determination incomplete.

8. How is the IRB Involved? Therefore, PI needs to report certain information to the IRB on an ongoing basis with a comment on the effect it has on the protocol itself and the safety of the subjects involved. Depending on the particular circumstances, An amendment to the protocol may be necessary Research subjects and/or federal agencies may need to be notified So, both unanticipated problems and serious non-compliance deal with changes in the risk profile of the research and changes in the research itself.So, both unanticipated problems and serious non-compliance deal with changes in the risk profile of the research and changes in the research itself.

9. Adverse Event Reporting Many adverse events can occur during the course of a research protocol. Which ones do the IRB want to see? Any harm to a research subject that is both unexpected and at least probably related to the research intervention/drug/procedure/device.

10. Adverse Event Reporting The IRB defines unexpected adverse event as: Any harm that occurs to a research subject that is not accurately represented in the IRB -approved consent form, protocol, or investigator�s brochure: A new harm that was not expected A harm already described but that is occurring with greater severity than expected A harm already described, but that is occurring with greater frequency than expected

11. Adverse Event Reporting Why does the IRB only want to immediately review unexpected and at least probably related adverse events? Is it �playing it safe� to submit everything? Any harm to a research subject that is anticipated has already been acknowledged by the IRB in its initial risk determination, including plans to manage and mitigate that risk (which may include the use of a Data Safety Monitoring Board or independent medical monitor). Any adverse event that is, at best, only possibly related to the research intervention, cannot be said to have altered the risk profile of that intervention since its relatedness to that intervention is unclear. An adverse event needs to be �more likely than not� related to the intervention to have altered the intervention�s risk profile.

12. Adverse Event Reporting When does the IRB want to immediately review unexpected and at least probably related adverse events? PIs must report unexpected and at least probably related adverse events within 7 calendar days Exception: If the unexpected and at least probably related adverse event is the death of a research subject, then the adverse event must be reported within 24 hours

13. Adverse Event Reporting As per federal regulations, the IRB will, at the time of annual review (i.e. Continuing Review), look at a summary of all adverse events in a cumulative table to assist in its annual assessment as well. The form can be found at the following web address: http://weill.cornell.edu/research/rea_com/irb_adv.html

14. Protocol Deviations After the IRB approves a PI�s protocol, the PI is free to conduct the research as approved by the IRB. During the course of the study, the research team may, intentionally or unintentionally, deviate from the IRB protocol. Such incidents might adversely affect the rights or welfare of research subjects, so the Code of Federal Regulations requires that: � (The IRB must) follow written procedures�for ensuring that changes in approved research during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects.� (21CFR56.108(a)(4)) NOTES ON PROCESSING AMENDMENTS: Amendments to existing protocols are generally either expedited or full board. The determining factor in deciding which involves the risk level of the amendment. If the risk level is minimal, the amendment will usually qualify for expedited review. If the risk level is greater than minimal, it will usually have to be reviewed by the IRB at large. Other determining factors include the use of vulnerable populations in the amendment, such as the elderly, the very young, pregnant women, prisoners, etc.�if an amendment incorporates a vulnerable population, it will likely go to the full board for review. NOTES ON PROCESSING AMENDMENTS: Amendments to existing protocols are generally either expedited or full board. The determining factor in deciding which involves the risk level of the amendment. If the risk level is minimal, the amendment will usually qualify for expedited review. If the risk level is greater than minimal, it will usually have to be reviewed by the IRB at large. Other determining factors include the use of vulnerable populations in the amendment, such as the elderly, the very young, pregnant women, prisoners, etc.�if an amendment incorporates a vulnerable population, it will likely go to the full board for review.

15. Protocol Deviations This means that if a PI intends to deviate from the protocol in anything other than an emergency situation (e.g., change in dose, admission of a subject that doesn�t meet enrollment criteria, rescheduling a research subject meeting*), prior approval by the IRB is required: The PI will need to fill out an exception request for one-time use ?

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17. Protocol Deviations The Code of Federal Regulations also requires that �(The IRB must) follow written procedures for ensuring prompt reporting to the IRB of�any instance of serious or continuing non-compliance with these regulations or the requirements or determinations of the IRB�� (21CFR56.108(a)(3))

18. Protocol Deviations This means that any time there is a protocol deviation, the IRB needs to be notified of this deviation to determine whether or not the deviation constitutes serious or continuing non-compliance. The IRB will also need to know what corrective actions were taken (or will be taken) to prevent future recurrences of the same deviation.

19. What Should Be Reported? The following must be reported with 7 calendar days, except where �within 24 hours� reporting is specified: 1. Information that indicates a change to the risks or potential benefits of the human research. For example: An interim analysis, safety monitoring report, publication in the literature, or revised investigator brochure that indicates an increase in the frequency or magnitude of a given harm, uncovers a new risk, or provides more information about the benefits of the human research. Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a human research protocol.

20. What Should Be Reported? Information indicating a change in risks/benefits (cont) Protocol deviation that harmed participants or others or that indicates participants or others might be at increased risk of harm. If the WCMC-NYPH study site is the lead or coordinating site, then deviations from all sites must be reported within 7 calendar days of PI notification. Reporting Timeline Exception: If the protocol deviation was made in order to eliminate an apparent immediate hazard to a participant, the PI must submit the information within 24 hours. Complaint of a participant that indicates participants or others might be at increased risk of harm or at risk of a new harm.

21. What Should Be Reported? 2. Any harm (i.e., adverse event) experienced by a participant or other individual, whether occurring to a subject enrolled at WCMC-NYPH or elsewhere, including Investigational New Drug (IND) reports and MedWatch reports, which is both unexpected and at least probably related to the human research procedure(s), intervention(s), and/or device(s). A harm is �unexpected� when its specificity and severity are not accurately reflected in the consent document or investigator�s brochure. A harm is �at least probably related� if the research procedure(s), intervention(s), and/or device(s) more likely than not caused the harm. Reporting Timeline Exception: If the unexpected and at least probably related harm is death of a research subject, the PI must report the information within 24 hours.

22. What Should Be Reported? 3. Finding of Non-Compliance or Allegation of Non-Compliance. 4. Protocol Deviations: Failure to follow the protocol due to the action or inaction of the investigator or research staff. If the WCMC-NYPH site is a lead/coordinating site, then reports received from other sites must be sent to the WCMC-NYPH IRB within 7 calendar days of PI notification. Reporting Timeline Exception: If the protocol deviation was taken in order to eliminate an apparent immediate hazard to a participant, the PI must report the information within 24 hours.

23. What Should Be Reported? 5. Breach of confidentiality. Reporting Timeline Exception: The PI must report the information within 24 hours. 6. Change to the protocol taken without prior IRB review to eliminate an apparent immediate hazard to a participant. Reporting Timeline Exception: The PI must report the information within 24 hours.

24. What Should Be Reported? 7. Incarceration of a participant in a protocol not approved to enroll prisoners. 8. Complaint of a participant that cannot be resolved by the research team. 9. Unanticipated adverse device effect: Any harm caused by an investigational device that was not previously identified in nature, severity, or degree in the investigational plan or application (including a supplementary plan or application). Reporting Timeline Exception: If the unexpected and at least probably related adverse device effect results in the death of a research subject, the PI must report the information within 24 hours.

25. 24 Hour Reporting Quick Guide Three Reporting Exceptions to Report Within 24 Hours Any protocol deviation that was made in order to eliminate an apparent immediate hazard to a participant. Any death of a participant that is unexpected and at least probably related. Breach of confidentiality

26. Where Should I Report My Unexpected, Study-Related Adverse Events, Incidents, and Information? Institutional Review Board (IRB): If the study is a human research study, then reporting to the IRB is required via submit2irb@med.cornell.edu. Institutional Biosafety Committee (IBC): If the study is a human gene transfer study, or any other human research study approved by the IBC, then reporting to the IBC is required via submit2ibc@med.cornell.edu. Weill Cornell Medical College Data Safety Monitoring Board (WCMC DSMB): If the study uses the WCMC DSMB, then reporting to the WCMC DSMB is required via submit2dsmb@med.cornell.edu. Clinical and Translational Science Center (CTSC): If the study uses the CTSC, then reporting to the CTSC is required via ctscrsa@med.cornell.edu.

27. How Should My Report be Submitted? All reports must contain a cover letter with PI name and signature, the IRB protocol number, title, and detailed information about the incident or information and its impact on the WCMC-NYPH research and/or research subject(s). Exception: In the case of adverse events or protocol deviations, use of the Adverse Event Reporting Form with current consent documents or Protocol Deviation Reporting Form with current consent documents is required. No cover letter is necessary. Both forms can be found at: http://weill.cornell.edu/research/for_pol/ins_rev_boa.html

30. How Should My Report be Submitted (cont)? Submissions must be sent as a single bookmarked PDF document. The IRB submission can be CC�d to all applicable committees in lieu of creating a separate submission for each committee. For large documents, submit via http://transfer.med.cornell.edu: IRB: submit2irb@med.cornell.edu IBC: submit2ibc@med.cornell.edu WCMC DSMB: submit2dsmb@med.cornell.edu CTSC: ctscrsa@med.cornell.edu

31. Example #1: Is it Immediately Reportable? A subject with chronic gastroesophageal reflux disease enrolls in a randomized, placebo-controlled, double-blind, phase 3 clinical trial evaluating a new investigational agent that blocks acid release in the stomach. Two weeks after being randomized and started on the study intervention the subject develops acute kidney failure as evidenced by an increase in serum creatinine from 1.0 mg/dl pre-randomization to 5.0 mg/dl. The known risk profile of the investigational agent does not include renal toxicity, and the IRB-approved protocol and informed consent do not identify kidney damage as a risk of the research. Evaluation of the subject reveals no other obvious cause for acute renal failure. The investigator concludes that the episode of acute renal failure probably was due to the investigational agent. Is this immediately reportable? Why or why not?

32. Example #2: Is it Immediately Reportable? A subject participating in a phase 3, randomized, double-blind, controlled clinical trial comparing the relative safety and efficacy of a new chemotherapy agent combined with the current standard chemotherapy regimen, versus placebo combined with the current standard chemotherapy regimen, for the management of multiple myeloma develops neutropenia and sepsis. The subject subsequently develops multi-organ failure and dies. Prolonged bone marrow suppression resulting in neutropenia and risk of life-threatening infections is a known complication of the chemotherapy regimens being tested in this clinical trial and these risks are described in the IRB-approved protocol and informed consent. The PI concludes that the subject�s infection and death are directly related to the research interventions. Review of all data so far reveals that the incidence of severe neutropenia, infection, and death are within the expected frequency. Is this immediately reportable? Why or why not?

33. CONTACT INFORMATION Lauren Odynocki Adverse Event CoordinatorPhone: (646) 962-8192Email: lao2003@med.cornell.edu On the web at http://www.med.cornell.edu/research/rea_com/irb_adv.html