8.1 IRB Review of Adverse Events and Adverse Device Effects

1.0 Purpose

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


2.0 Policy

It is the policy of the Organization to comply with: a) HHS regulations at 45 CFR 46.103(b)(5)(i), b) any additional requirements of Common Rule agencies (as applicable), and c) FDA regulations at 21 CFR 56.108(b)(1), 21 CFR 312.32(a), and 21 CFR 812.3(s) (as applicable).


3.0 Definitions

  • 3.1. Adverse Event (AE): An AE in the broad context of human subject research is 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 the 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; (c) the current investigator’s brochure; or (d) Investigational plan or protocol
    • 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. Am 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, 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; or one which requires medical or surgical intervention to prevent one of the outcomes listed.

  • 3.2. 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, or associated with”) and unexpected (“not previously identified”).

    • 3.2.1. Serious UADE: An UADE which results in any of the outcomes listed in section 3.1.4 above, or one in which required intervention to prevent permanent impairment or damage
  • 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 Procedures for Reporting AEs/UADEs

  • 4.1. Internal AEs and UADEs
    • 4.1.1. Internal AEs must be reported to the IRB if the PI determines that all of the following conditions are met:
      • 4.1.1.1. The AE is unexpected.
      • 4.1.1.2. The AE is related to, or possibly related to, the research intervention or procedures.
    • 4.1.2. All internal AEs/UADEs that meet the 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). In addition, if the internal AE/UADE involves a fatal event and it meets the conditions listed above, the IRB must also be notified by either telephone or email within 24 hours.
    • 4.1.3. Internal AEs occurring more than 90 days after the subject has completed study interventions are generally considered “unrelated” and are therefore not reportable; exceptions include congenital anomalies or birth defects, and cancer.
    • 4.1.4. Internal UADEs must be reported for as long as the device is classified as investigational.
    • 4.1.5. Internal AEs/UADEs are reported to the IRB on-line through RSS.
  • 4.2. External AEs
    • 4.2.1. External AEs must be reported to the IRB if the PI determines that all of the following conditions are met:
      • 4.2.1.1. The external AE is unexpected.
      • 4.2.1.2. The external AE is related or possibly related to the research intervention or procedure.
      • 4.2.1.3. The external AE is serious.
      • 4.2.1.4. The external AE requires a change to the protocol and informed consent form and re-consent of subjects.
    • 4.2.2. All external AEs that meet the 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)
      • 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. 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. 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. 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 UADEs

  • 5.1. The report will be reviewed by the IRB Executive Chair/designee to determine if the AE satisfies the criteria in 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, if warranted, immediate halting of the study (per HRPP policy 8.6: Study Hold, Suspension, and Termination).
  • 5.3. Upon completion of the IRB Executive Chair/designee review, all internal AEs which satisfy section 4.1.1, and all internal or external UADEs will be reviewed by the convened IRB.

6.0 IRB Review of Internal AEs and UADEs

  • 6.1. The full IRB will review the reports in accordance with HRPP policy 2.2 (Full IRB Review).
  • 6.2. To approve the AE 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)(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 participants
    • 6.3.5. The current continuing review schedule is appropriate.
  • 6.4. The IRB must determine if the AE/UADE is a UP and that the action plan is appropriate 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