Adverse Event Reporting

Overview

To ensure participant safety, Protocol Directors must promptly review and report adverse events (AEs) that occur during the conduct of research to the study sponsor or monitoring entity. A subset of adverse events that meet the criteria for an unanticipated problem involving risks to participants or others (UP) must also be promptly reported to the IRB. Unanticipated problems can include other incidents, experiences, and outcomes that are not AEs, however this guidance focuses on AEs that are unanticipated problems.

This webpage includes:

Protocol Director Responsibilities
Definitions
How to Determine if an Adverse Event is an Unanticipated Problem
IRB Review and Reporting Requirements
Sponsor Responsibilities
Resources

Protocol Director Responsibilities

What Do I need to Report to the IRB?

When a Protocol Director receives an internal or external report of an AE, they should review the report and assess whether the AE is:

unexpected;
related or possibly related to participation in the research; and
serious or otherwise suggests that the research places participants or others at a greater risk of physical or psychological harm than was previously known or recognized.

Only AEs that meet all three criteria must be reported promptly to the IRB as unanticipated problems.

What Should I Include in the IRB Prompt Report?

A prompt report to the IRB submitted via eProtocol should include:

confirmation that the AE has been determined by the Investigator, Sponsor, or monitoring entity to meet the unanticipated problem criteria;
a clear explanation of why the AE has been determined to be an unanticipated problem; and
a description of any proposed protocol changes or other corrective actions to be taken by the investigators in response to the unanticipated problem.

OHRP guidance notes that an unanticipated problem will warrant consideration of substantive changes in the research protocol, informed consent process/documents, or other corrective actions in order to protect the safety, welfare, or rights of participants or others. Corrective actions or substantive changes to consider include:

modification of inclusion or exclusion criteria to mitigate the newly identified risks;
implementation of additional procedures for monitoring participants;
suspension of enrollment of new participants;
suspension of research procedures in currently enrolled participants;
modification of informed consent documents to include a description of newly recognized risks; and
providing information about newly recognized risks to previously enrolled participants.

When Do I Report to the IRB?

Event Type	Timeframe for Stanford PD to Report to IRB
UP that occurs at Stanford when Stanford is Reviewing IRB	Stanford IRB: Within 10 business days from when the PD learns of the event
UP that occurs at Stanford when Stanford is relying on an external IRB	External IRB: Follow external IRB prompt reporting requirements Stanford IRB: Submit UP determination from external IRB within 30 days
UP that occurs at an external site that is relying on the Stanford IRB for review	Stanford IRB: Within 10 business days from when the PD learns of the event
External Safety Report (UP) when Stanford is the Reviewing IRB or external site is relying on the Stanford IRB for review	Stanford IRB: Within 15 business days from when the PD receives the assessment from the sponsor or monitoring entity
External Safety Report (UP) when Stanford is relying on an external IRB	External IRB: Follow external IRB reporting requirements Stanford IRB: Does not require a report submission to the Stanford IRB

For AEs that are not also unanticipated problems, a summary or brief statement can be provided at continuing review indicating there have been no unanticipated problems and whether AEs have occurred at the expected frequency and level of severity as documented in the research protocol, the consent form, or investigator brochure.

Definitions

An adverse event (AE) is any unfavorable medical occurrence, including any sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with participation in the research, whether or not considered related to the participant’s participation in the research.

Any event experienced by participants enrolled at non-Stanford affiliated sites (external sites) and sites using an external IRB, during the research study.

Any event experienced by participants enrolled at Stanford affiliated sites (internal sites) or external sites relying on Stanford IRB, during the research study.

IND Safety Reports must be submitted, typically by the sponsor or monitoring entity, to the FDA for the following events:

Serious and unexpected suspected adverse reactions (SUSARs);
Findings from epidemiological studies, pooled analyses of multiple studies, or clinical studies that suggest a significant risk in humans exposed to the drug;
Findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug; or
Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

The sponsor must report any suspected adverse reaction that is both serious and unexpected to the FDA via an IND safety report. FDA considers events that meet the IND safety reporting criteria, as defined above, to be an unanticipated problem.

An event is considered possibly related if there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research.

A reasonable possibility means that there is evidence to suggest a causal relationship between the drug and the adverse event. This can include:

A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome);
One or more occurrences of an event that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug (e.g. tendon rupture); or
An aggregate analysis of specific events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a current or historical controls group. Such events are known consequences of the underlying disease or condition or events that commonly occur in the study population independent of drug therapy.

A serious adverse event (SAE) (or serious suspected adverse reaction) is an adverse event that:

results in death;
is life-threatening (places the participant 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
may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed above

A suspected adverse reaction is any adverse event for which there is a reasonable possibility that the drug caused the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.

A serious unexpected suspected adverse reaction (SUSAR) is any serious suspected adverse reaction that is not listed in the investigator brochure, consent form, or protocol (i.e., unexpected).

An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the following criteria:

unexpected in terms of nature, severity, or frequency;
related or possibly related to participation in the research; and
suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

An unexpected adverse event is any adverse event where the nature, severity, or frequency of the event is not consistent with either:

the known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) the protocol–related documents, including the IRB-approved research protocol, investigator brochure, and the current IRB-approved consent form, and (b) other relevant sources of information, such as product labeling and package inserts; or
the expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the adverse event.

How to Determine if an Adverse Event is an Unanticipated Problem

To determine whether an adverse event is an unanticipated problem, the following questions should be asked. Select each of the questions below to review important details and considerations.

The PD should consider:

the known toxicities and side effects of the research procedures;
the expected natural progression of participants’ underlying diseases, disorders, and conditions; and
the participants’ predisposing risk factor profiles for the AE.

An AE is unexpected when the nature, severity, or frequency of the AE is not consistent with:

the known or foreseeable risks associated with the research procedures described in the protocol-related documents, such as the IRB-approved protocol and consent form, investigator brochure, or other relevant sources of information, such as product labeling and package inserts; or
the expected natural progression of any underlying disease, disorder, or condition of the participant experiencing the AE and the participant’s predisposing risk factor profile for the AE.

The PD should consider:

any underlying disease, disorder, or condition of the participant;
other circumstances unrelated to either the research or any underlying disease, disorder, or condition of the participant;
the temporal relationship of the event to drug administration;
biologic plausibility;
the mechanism of action of the drug or similar drugs in the same class

An AE is at least possibly related to participation in the research if there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research.

The PD should consider if the adverse event:

results in death;
is life-threatening (places the participant 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
may jeopardize the participant’s health and may require medical or surgical intervention to prevent one of the other outcomes listed above

SAEs always meet the “harmful” criterion. The AE could also place subjects or others at increased risk of harm, even if no harm occurred from the event.

IRB Review and Reporting Requirements

The IRB will make a determination confirming an event is an Unanticipated problem at a convened IRB meeting. Unanticipated Problem determinations may need to be reported to the FDA, OHRP, study sponsors, and other federal agencies in fulfillment of Stanford University’s regulatory reporting requirements. External safety reports that meet the unanticipated problem criteria are acknowledged.

Sponsor Responsibilities

The FDA believes that the sponsor is generally in the best position to determine whether an SAE should be classified as a serious suspected adverse reaction because the sponsor may have access to SAE reports from multiple study sites and multiple studies and would be able to aggregate and analyze these reports. The sponsor should carefully consider the investigator’s assessment of causality; however, it is ultimately the sponsor’s responsibility to determine whether an SAE meets the definition of a SUSAR and requires IND Safety Reporting.

Resources

OHRP Guidance - Reviewing and Reporting UPs Involving Risks to Subjects or Others and Adverse Events
FDA Regulations - Investigational New Drug – Safety Reports [21 CFR 312.32(a)]
FDA Guidance - Investigator Responsibilities: Safety Reporting Requirements for Investigational Drugs and Devices
FDA Guidance - Sponsor Responsibilities: Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies

Page updated February, 2026