Unanticipated Problems

1. Unanticipated Problems How to sort out the unexpected events that might have to be reported to the IRB John A. Vanchiere, M.D., Ph.D. Associate Professor Department of Pediatrics

2. LSUHSC-S HRPP/IRB Standard Operating Procedures (p 222-234) 8. UNANTICIPATED PROBLEMS AND OTHER REPORTABLE NEW INFORMATION Researchers and Research Staff follow reporting requirements during a research study in accordance with applicable laws, regulations, codes, and guidance; LSUHSC-S policies and procedures; and the IRB’s requirements. (DHHS 45 CFR 46.103(b)(5); FDA 21 CFR 56. 108(b);) (AAHRPP Element III.2.D) The IRB or EC has and follows written policies and procedures for addressing unanticipated problems involving risks to participants or others, and for reporting these actions, when appropriate. (AAHRPP Element II.2.F)

3. Events and information which require prompt reporting to the IRB: 1) Unanticipated Problems involving Risks to Participants or Others 2) Change to Protocol to Eliminate Apparent Immediate Hazard 3) New safety information that indicates a change in Risk 4) Premature Suspension or Termination of Research by Sponsor or Investigator 5) Failure to Follow the Protocol: Protocol Deviation, Violation or Exception 6) Monitoring Reports 7) Non-Compliance 8) Audit, Inspection, or Inquiry by a Federal Agency 9) Participant Incarceration, 10) Participant Complaints, 11) Breach of Confidentiality 12) Unanticipated adverse device effect

4. 1) Unanticipated Problems involving Risks to Participants or Others Unanticipated problem involving risks to participants or others – OHRP considers unanticipated problems, in general, to include any incident, experience, or outcome that meets all of the following criteria: 1. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied; 2. related or possibly related to participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and 3. suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

5. Unexpected Adverse Event – An Unexpected Adverse Event (UAE) is any adverse event and/or reaction, the specificity or severity of which is not consistent with the informed consent, current investigator brochure or product labeling. Further, it is not consistent with the risk information described in the general investigational plan or proposal. Unexpected Death – The death of a research subject in which a high risk of death is not projected as indicated by the written protocol, informed consent form, or sponsor brochure. This definition does not include deaths associated with a terminal condition unless the research intervention clearly hastened the subject’s death. A subject’s death that is determined to be clearly not associated with the research is also not an “unexpected death” for purposes of the reporting requirements of these procedures.

6. 8.3 Investigator Responsibilities Investigators are responsible for promptly reporting unanticipated problems involving risks to participants or others and other Reportable Information to the IRB. For industry sponsored projects, investigators are responsible for maintaining contact with the sponsor, and receiving reports from the sponsor, and if applicable, the monitoring entity (e.g., DSMB, DMC) and reporting suspected Unanticipated Problems and other Reportable Information to the IRB. For Sponsor-Investigator (Investigator Initiated) projects, the principal investigator is solely responsible for promptly reporting Unanticipated Problems and other Reportable Information to the IRB.

7. 8.4.1 All of the following Events and Reportable Information require immediate reporting to the IRB; or within five (5) working days. 1) UNANTICIPATED PROBLEMS INVOLVING RISKS TO PARTICIPANTS OR OTHERS Internal or External Events (deaths, life-threatening experiences, injuries, breaches of confidentiality, or other) occurring during or after the research study, which in the opinion of the Monitoring Entity, Sponsor or the Investigator meet all (a, b & c) of the following criteria must be reported to the IRB within five (5) working days: a) Unexpected in terms of nature, severity, or frequency, given (a) the research procedures described in the protocol-related documents, and informed consent document (b) the characteristics of the subject population being studied; AND b) Related to participation in the research or there is a reasonable possibility 225 that the incident, experience, or outcome may have been caused by the procedures involved in the research; or if a device is involved, probably caused by, or associated with the device; AND c) Harmful suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

8. When investigators are trying to determine if an event is an Unanticipated Problem please use the following guidance to see if all three (3) criteria apply: UNEXPECTED RELATEDNESS HARMFUL

9. Serious adverse event is defined by OHRP as an event that: 226 • results in death; • is life-threatening (places the subject at immediate risk of death from the • event as it occurred); • results in inpatient hospitalization or prolongation of existing hospitalization; • results in a persistent or significant disability/incapacity; • results in a congenital anomaly/birth defect; or • 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 in this definition

10. “Not serious” adverse events might also be Unanticipated Problems: adverse events that are not serious would also be unanticipated problems if they suggest that the research places subjects or others at a greater risk of physical, psychological, economic, or social harm than was previously known or recognized. Internal events are those that occur on LSUHSC-S campuses and involve LSUHSC-S investigators. An Internal events that is determined to meet the criteria for an unanticipated problem involves federal reporting requirements by the LSUHSC-S IRB. Reports of external events are those that occur at non-LSUHSC-S sites and do not involve LSUHSC-S investigators. These reports usually involve multi-center or international clinical trials and may require analysis from sponsor, coordinating center or DSMB/DMC to support that the event is considered and unanticipated problem. The LSUHSC-S IRB does not have additional federal reporting requirements on reports of External events.

11. 12) Unanticipated adverse device effect Adverse Device Effect – An Adverse Device Effect (ADE) is any adverse event/effect caused by or associated with the use of a device that is unanticipated and has not been included in the protocol or the Investigator’s Brochure. 12. UNANTICIPATED ADVERSE DEVICE EFFECT Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.)

12. 8.4.2 Submission of Reports Investigators must report possible Unanticipated Problems or Other Reportable New Information to the IRB in writing using the Reportable New Information Form. The written report should contain the following: a. Detailed information about the possible unanticipated problem, or reportable new information including relevant dates. b. Any corrective action, planned or already taken, to ensure that the possible unanticipated problem or event is corrected and will not occur again. c. An assessment of whether any subjects or others were placed at risk as a result of the event or suffered any physical, social, or psychological harm and any plan to address these consequences. d. Any other relevant information. e. Any other information requested by the IRB. A report of a possible unanticipated problem involving risks to participants or others will be immediately forwarded by IRB staff to the IRB Chair or designee if the staff believes that immediate intervention may be required to protect participants or others from serious harm.

13. 8.5.1 Review by IRB Staff and Chairs The IRB staff will screen all submissions of Reportable New Information and forward them to the IRB Chair, qualified designee, or the convened IRB for review. The actions or modifications may include but are not limited to any of the following: o Revision of the protocol including inclusion/exclusion criteria; o Incorporation of new information into the informed consent; o Implementation of additional data monitoring activities; o Informing currently enrolled participants; o Suspension of enrollment of new subjects; o Suspension of research procedures in currently enrolled subjects; o Notification of previously enrolled subjects of the event and any actions they should take; o Termination of the research; o Notification to current participants when such information may relate to participants’ willingness to continue to take part in the research. o Requirement for an appropriate Corrective Action Plan o Requirement for additional training of the investigator and/or study staff o Referral to other organizational entities (e.g., legal counsel, risk management, institutional official)

14. If it was determined that the problem or event is serious, unanticipated, and related to the research and requires that the protocol or consent document warrants modification, the IRB must also determine and document: o Whether previously enrolled subjects must be notified of the modification; and o When such notification must take place how such notification must be documented. If the IRB determines that the problem or event was serious, unanticipated, and related to the research, the Chair or designee will submit a written report to the Institutional Official and copied to the HRPP Medical Director within five business days after the determination. The Institutional Official will review the event and discuss the report with the HRPP Director and IRB Chair. The Institutional Official will ensure notification is sent to OHRP, the FDA if appropriate, the sponsor, and other agency officials as required within 15 working days of the IRB’s determination regarding the Serious Unanticipated Problem involving risk to subjects or others or local Unanticipated Serious Adverse Event.

15. VA Research. Within five (5) business days after a report of a serious unanticipated problem involving risks to subjects or others, or of a local unanticipated SAE, the IRB must determine and document whether or not the reported incident was serious and unanticipated and related to the research. If the IRB determines that the problem or event is serious and unanticipated and related to the research, the IRB must report the problem or event directly (without intermediaries) to the VA Medical Center Director with five (5) business days after the determination. The report must be made in writing, with a simultaneous copy to the ACOS/R&D and RDC Chair.