Reporting Requirements for Studies Involving Other Investigational Agents, Including Investigational Drugs

Version Date: March 3, 2017

UW-Madison Health Sciences IRB and Health Sciences Minimal Risk IRB Adverse Events Reporting Guidelines for Clinical Trials Testing Drugs or Biologics for Research Teams


Federal regulations, including those of the Department of Health and Human Services (DHHS) and the FDA, require institutions engaged in human subjects research to have written procedures for ensuring prompt reporting to the IRB of “unanticipated problems involving risks to subjects or others.” [45 CFR 46.103; 21 CFR 56.108]. “Unanticipated problems involving risks to subjects or others” is a broad term, which includes not only unfavorable outcomes that were not expected, but also the development of potentially increased risks of harm occurring in the future.

In an effort to reduce over-reporting of adverse events (AEs) and serious adverse events (SAEs) on FDA-regulated trials to the IRB, the UW-Madison Health Sciences (HS) IRBs Office has developed guidelines regarding which events meet the definition of an unanticipated problem and thus, require reporting to the IRB.

This set of guidelines addresses only the reporting to the University of Wisconsin-Madison HS IRBs of AEs/SAEs that occur on FDA-regulated trials involving drugs or biologics. These guidelines do not substitute for the researcher’s obligation to report AEs/SAEs to the sponsor of the research or to other bodies, such as the FDA, Madison VA, data monitoring committees, or the Clinical Research Unit.

Note: Reporting requirements for AEs/SAEs studies involving Investigational Devices are unique and are not addressed in this document. See: Reporting Guidelines for Device Studies for further details.

The objective of this document is to provide the University of Wisconsin-Madison research community with guidelines regarding:

Definition of Adverse and Serious Adverse Events

“Adverse event” (AE) is a broad and generally defined term referring to an untoward or unfavorable medical occurrence in a human subject or others that happens during or after participation in a research study.

FDA guidance further defines “Serious AEs” (SAEs) as events temporally associated with the subject’s participation in research that meets any of the following criteria:

  • result in death

  • are life-threatening (places the subject at immediate risk of death from the event as it occurred)

  • result in persistent or significantly disability/incapacity

  • require an inpatient hospitalization or prolongation of hospitalization

  • result in a congenital anomaly or birth defect

  • constitute, based upon appropriate medical judgment, an event that may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed above.

The VA definition of SAEs generally parallels the FDA definition, but adds that an event also can be an SAE if it requires a behavioral, social, or other intervention to prevent a serious outcome as described above.

AEs Requiring Reporting to the IRBs

In general, ONLY AEs and SAEs that meet the definition of an unanticipated problem require reporting to the IRB. To determine whether an AE or SAE is an unanticipated problem, the following questions should be asked:

  • Is the AE/SAE unexpected (either in nature, severity or frequency)?
  • Is the AE/SAE caused by or probably (i.e., more likely than not) related to participation in the research?
  • Does the AE/SAE suggest that the research places subjects or others at a greater risk of harm than was previously known or recognized?

If the answer to all three questions is yes, then the AE is an unanticipated problem and must be reported to the IRB.

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Examples of AEs That Are Reportable to the IRBs

In January 2009, the FDA adopted guidance regarding which AE/SAEs are likely to represent unanticipated problems involving risks to subjects or others and require report to the IRB:

  • A single occurrence of a serious, unexpected event that is uncommon and strongly associated with drug exposure (such as angiodema, agranulocytosis, hepatic injury, Stevens-Johnson Syndrome).

  • A single occurrence, or more often a small number of occurrences, of a serious, unexpected event not commonly associated with drug exposure, but uncommon in the study population (e.g., tendon rupture, progressive multifocal leukoencephalopathy).

  • Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be an unanticipated problem. There should be a determination that the series of AEs represents a signal that the AEs were not just isolated occurrences and involve risk to human subjects (e.g. a comparison of rates across treatment groups reveals higher rate in the drug treatment arm versus a control).

  • An AE that is described or addressed in the investigator’s brochure, protocol, or informed consent documents that occurs at a specificity or severity that is inconsistent with prior observations OR for which the rate of occurrence in the study represents a clinically significant increase in the expected rate of occurrence.

  • Any AE or safety finding (e.g., based on animal or epidemiologic data) that would cause the sponsor to modify the investigator’s brochure, study protocol, or informed consent documents, or would prompt other action by the IRB to ensure the protection of human subjects.

When to Report an AE to the IRBs

The timing and format for submitting an AE/SAE report to the IRBs depends on the severity of the event and whether the event occurred on a study under the purview of the Madison VA.

  1. Immediate Report to the IRB

    An AE/SAE meeting the above definition of an unanticipated problem must be reported to the IRB immediately if both of the following conditions are met:

    • The event occurred at a site under the purview of the UW Health Sciences (HS) IRB or Minimal Risk (MR) IRB

    • The event is immediately life threatening or severely debilitating to other current subjects

    An investigator participating in a multicenter study may rely on the sponsor’s assessment of an event that occurred at another site (not under the purview of the HS or MR IRB) and any implications that event may have for the study as a whole. If the event that occurred at a site not under the purview of the HS or MR IRB requires changes to the study, the study team should submit either a change of protocol or New Information Report within 14 business days of becoming aware of the event. Please see additional guidance here.

    The IRBs expect that these reports will be rare. SAEs that meet these conditions must be reported to the IRB Chair or IRB Director via telephone (preferred) or email as soon as possible, but no later than 1 business day after the local research team becomes aware of the event. The research team will then discuss with the IRB Chair or IRB Director what action needs to be taken related to the occurrence (e.g., suspension of study enrollment, change in treatment regimen) to prevent further harm from occurring. This initial report to the IRB Chair or IRB Director must be followed with the submission of a reportable event in ARROW within 2 business days after the local research team becomes aware of the event.

  2. Report to the IRB within Five (5) Business Days: VA Studies Only

    All AE/SAEs that occur in subjects under UW-Madison IRB purview who are enrolled in research studies that have been reviewed and approved by the Madison VA’s Research & Development Committee (i.e., fall under Madison VA purview) that are considered to be serious and unanticipated as defined above must be reported by the research team to the IRB and Associate Chief of Staff for within 5 business days of the local research team becoming aware of the event.

  3. Report to the IRB within Fourteen (14) Business Days

    Any other AE/SAEs that meet the definition of an unanticipated problem as described above must be reported to the HS or MR IRB within 14 business days.

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Format of AE/SAE Reports

In general, AEs/SAEs that require reporting to the IRB will be submitted via Reportable Event form in ARROW as an unanticipated problem or new information report (see guidance: How to complete reportable events in ARROW).

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See Also:

Keywords:Adverse event, unanticipated problem, AE, SAE, serious adverse event, gene transfer, VA   Doc ID:18294
Owner:Monica E.Group:Health Sciences IRBs
Created:2011-04-25 18:00 CSTUpdated:2017-03-07 09:54 CST
Sites:Health Sciences IRBs
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