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8.1 Review of Adverse Events and Adverse Device Effects

1.0 Purpose

The purpose of this policy and procedure is to describe 1) the procedureprocess to ensure promptfor reporting ofresearch related Adverse Events (AEs) and Adverse Device Effects (ADEs) to the ORA and the IRB, and 2) the IRB’s process for review.review of AEs and ADEs.

2.0 Policy

It is the policy of the Organization that:

  • 2.1. Internal AEs must be promptly reported to the ORA if the PI determines that the AE is unexpected, AND related to, or possibly related to, the research intervention or procedures.
  • 2.2. Internal UADEs must be reported to the ORA if the PI determines that the ADE is unexpected AND related to (caused by or associated with) the device.
  • 2.3. External AEs must be reported to the ORA if the PI determines that the external AE is unexpected AND related or possibly related to the research intervention or procedure AND serious AND the external AE requires a change to the protocol and/or informed consent form and/or re-consent of subjects.
  • 2.4. The ORA and the IRB will comply with: a) HHS regulations at 45 CFR 46.103(b)(5)(i), b) any additionalwith requirements of Common Rule agencies (as applicable), and c) FDA regulations at 21 CFR 56.108(b)(1), 21 CFR 312.32(a),312 and 21 CFR 812.3(s)812 (as applicable).

    applicable.

3.0 Definitions

  • 3.1. Adverse Event (AE): An AE in the broad context of human subject research is defined as any untoward or unfavorable occurrence in a human subject (e.g., physical, psychological, social, legal, or economic harm) temporally associated with the subject’s participation in the research (whether or not related to participation in the research). This means that theAn AE may be expected or unexpected, and related or unrelated to the subject’s participation in the research.

    This policy does not make a differentiation between medical and non-medical AEs.

    AEs occurring in the context of an FDA regulated clinical investigation are defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related (21 CFR 312.32(a)).

    • 3.1.1. Unexpected AE: An AE in which the specificity, severity, or frequency is not consistent with (a) the IRB application and detailed protocol; (b) Risk information in the ICF; or (c) the current investigator’s brochure;brochure or (d)similar Investigational plan or protocolmaterials.
    • 3.1.2. Related AE: An AE which there is clear causality, or a strong temporal relationship with the research intervention or procedure.
    • 3.1.3. Possibly Related AE: An AE which may have been caused by the research intervention or procedure, but there is insufficient information attribute clear causality. AmAn attribution as “possibly related” requires less certainty than “related”; however, there must still be evidence suggesting such a causal relationship (for example, temporal relationship to the intervention, known pharmacological property of drug, exclusion of other causes).
    • 3.1.4. Serious AE: An AE which results in any of the following outcomes:

      • 3.1.4.1. Death

      • 3.1.4.2. A serious injury, or otherwise seriously impacts on the health, safety or welfare of subjects

      • 3.1.4.3. Inpatient hospitalization or prolongation of existing hospitalization

      • 3.1.4.4. Required intervention to prevent permanent impairment or damage

      • 3.1.4.5. Persistent or significant disability or incapacity

      • 3.1.4.6. Congenital anomaly or birth defect

      • 3.1.4.7. Other serious important medical events

      • 3.1.4.8. Any event that requires treatment to prevent one of the outcomes listed above

        Note: Under FDA IND regulations 21 CFR 312.32(a)) a serious AE is one which results in any of the following outcomes: death,Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect;defect. Events may also be considered serious when they may jeopardize the patient or onesubject whichand requiresmay require medical or surgical intervention to prevent one of the outcomes listed.

        listed
        • in
      this definition (21 CFR 312.32(a)).
  • 3.2. Adverse Device Effect (ADE) is defined as an adverse effect caused by, or associated with, use of a medical device in a clinical investigation.

    • 3.2.1. Unanticipated Adverse Device Effect (UADE): 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 (per 21 CFR 812.3(s)).

      Note: The FDA device regulations at 21 CFR 812.3(s) define an adverse device effect which is different than the definition of an adverse event in FDA IND regulations at 21 CFR 312.32(a). Significantly, an AE may be expected or unexpected, related or unrelated, or serious or not serious. An UADE is related (“caused by,by or associated with”)with) and unexpected (“not previously identified”)identified).

      • 3.2.1.2. Serious UADE: An UADE which results in any of the outcomes listedas indescribed sectionabove 3.1.4for above,serious AEs, or one in which required intervention to prevent permanent impairment or damagedamage.

    • 3.3. Internal AE or UADE: An AE/UADE experienced by a subject in a study conducted at the Organization or at an external site under the jurisdiction of the UNMC IRB.

    • 3.4. External AE or UADE: An AE/UADE experienced by a subject in a study conducted at an external site (a site not under the jurisdiction of the UNMC IRB).

    4.0 ProceduresInvestigator for Reporting AEs/UADEsResponsibilities

    • 4.1. Internal AEs and UADEs

      • 4.1.1. Internal AEs must be promptly reported to the IRBORA if the PI determines that all of the following conditions are met:
        • 4.1.1.1. The AE is unexpected.
          • unexpected,
        • 4.1.1.2. The AE isAND related to, or possibly related to, the research intervention or procedures.
        • Internal
      • 4.1.2.AEs All internal AEs/UADEs that meetmeeting the above conditions listed above must be reported promptly to the IRB (in no case later than two business days following PI notification that the event occurred).occurred, Inor addition,within 24 hours if the internal AE/UADEAE involvesis afatal. fatal
        • 4.1.1.1. eventExcept for congenital anomalies or birth defects, and itcancer, meets the conditions listed above, the IRB must also be notified by either telephone or email within 24 hours.
        • 4.1.3. Internalinternal AEs occurring more than 90 days after the subject has completed study interventions are generally considered “unrelated”unrelated and are therefore not reportable;reportable.
          • exceptions include congenital anomalies or birth defects, and cancer.
      • 4.1.4.2 Internal UADEs must be reported to the ORA if the PI determines that the ADE is unexpected AND related to (caused by or associated with) the device. Internal ADEs meeting the above conditions must be reported no later than two business days following PI notification that the event occurred, or within 24 hours if the internal ADE is fatal.
        • 4.1.2.1. Internal ADEs meeting the above conditions must be reported for as long as the device is classified as investigational.
      • 4.1.5.3. Internal AEs/UADEsAEs arethat occur on studies for which the Organization is relying on another IRB must be reported to the ORA if the PI determines that the AE is unexpected, AND related to, or possibly related to, the research intervention or procedures.
        • 4.1.3.1. Internal AEs that occur on studies for which the Organization is relying on another IRB on-linemust throughalso RSS.be reported to that IRB in accordance with the reliance agreement.

    • 4.2. External AEs

      • 4.2.1. External AEs must be reported to the IRBORA if the PI determines that all of the following conditions are met:
        • 4.2.1.1. The external AE is unexpected.
          • unexpected
        • 4.2.1.2. The external AE isAND related or possibly related to the research intervention or procedure.
          • procedure
        • 4.2.1.3.AND Theserious externalAND AE is serious.
        • 4.2.1.4. Thethe external AE requires a change to the protocol and informed consent form and re-consent of subjects.
      • 4.2.2. All externalExternal AEs that meetmeeting the above conditions listed above must be reported promptly to the ORA (in no case later than five business days following PI notification that the event occurred)occurred.
        • 4.2.2.1. The IRB will be notified of External AEs that meet the above criteria
        • 4.2.2.2. It is expected that the submission of a report of an External AE which satisfies the criteria of section 4.2.1 will be followed by a Change Request, and the IRB will review the Change Request in accordance with HRPP policy 2.4 (IRB Review of Changes in Previously Approved Research).
      • 4.2.3. The PI is responsible for keeping up-to-date on all information which impacts risk(s) or subject safety and submitting to the IRB changes in the protocol and the ICF as necessary.
      • 4.2.4.3. The IRB will not accept, acknowledge or review external safety reports if there are no changes required in the protocol, IRB application and/or ICF.
      • 4.2.5. The external site’s IRB is responsible for dealing with events which qualify as UPs and reporting those events to OHRP, FDA, and sponsors as required.

    • 4.3. External UADEs

      • 4.4.3.1. External UADEs which occur at other institutions must be reported to the UNMC IRB (in no case no later than five business days following PI notification from the sponsor that the event occurred) in accordance the requirements of 21 CFR 812.150(b)(1).
      • 4.5. The PI should submit the report received from the sponsor along with any required Change Request.
      • 4.6.3.2. Once the status of a study is changed to “completed”, the IRB will no longer accept external UADE reports except under circumstances where the report involves important new risk information.

    5.0 ORA Procedures for Pre-Review of Internal AEs and UADEsResponsibilities

    • 5.1. TheAEs reportreported to the ORA will be reviewed by the an IRB Analyst, in consultation with the Executive Chair/chair or designee to determine if the AE satisfies the criteria infor reporting per section 4.1.1 (unexpected, and related to, or possibly related to, the research) or the event is a UADE (related and unexpected).
    • 5.2. The IRB Executive Chair/designee will take all actions necessary to protect human subjects including,in ifaccordance warranted, immediate halting of the study (perwith HRPP policy 8.6: (Study Hold, Suspension, and Termination).
    • 5.3. Upon completion of the IRB Executive Chair/designee review, allAll internal AEs which satisfy the criteria for reporting per section 4.1.1, and all internal or external UADEs will be reviewedreferred byto the convened IRB.

    6.0 IRB Review of Internal AEs and UADEsResponsibilities

    • 6.1. The fullconvened IRB will review thereports reportsof AEs and UADEs in accordance with HRPP policy 2.2 (Full IRB Review).
    • 6.2. To approve the AE or UADE report, the IRB must ensure the following criteria are met:
      • 6.2.1. The risk/benefit relationship of the research remains acceptable.
      • 6.2.2. No additional changes in protocol are necessary to further minimize risk.
      • 6.2.3. No additional monitoring of data is necessary to ensure the safety of subjects.
      • 6.2.4. The consent document(s) as written/revised are acceptable.
      • 6.2.5. Currently enrolled subjects will be provided new information related to the AE per requirements at 45 CFR 46.116(b)c)(5) and/or 21 CFR 50.25(b)(5).
    • 6.3. The IRB must determine whether
      • 6.3.1. Re-consent must be obtained from currently enrolled subjects, and, if so, how soon such re-consent must occur.
      • 6.3.2. Currently enrolled subjects may continue on study.
      • 6.3.3. Further subject accrual is permitted.
      • 6.3.4. Additional information must be provided to past participantssubjects.
      • 6.3.5. The current continuing review schedule is appropriate.
    • 6.4. The IRB must determine if the AE/UADE is aan UPUnanticipated and that the action plan is appropriateProblem in accordance with HRPP policy 8.3 (IRB Review of Unanticipated Problems Involving Risk to the Subject or Others).

    7.0 Reporting AEs/UADEs that are UPs to Institutional Officials, OHRP, FDA, and Department or Agency Heads

    • 7.1.

      All required reports will be submitted in accordance with HRPP policy 8.7 (Reporting Incidents to Institutional Officials and Federal Agencies).

    DOCUMENT HISTORY:

     Written: 1/18/2016 (Approved: 1/18/2016) - original author not recorded

     Revised: 11/27/2017 - revision not documented

     Revised: 5/4/2023 - Clarified investigator responsibilities for reporting AEs that occur on studies for which the Organization is relying on another IRB; deleted expectation that reportable external AEs be followed by change request (since such AE reports often are made in the context of a change request) (section 4.2.1); stylistic changes.{Approved Rusty McCulloh (Institutional Official), Bruce Gordon (Assistant Vice Chancellor for Regulatory Affairs, Executive Chair)}

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