Adverse Events in Human Subjects Research Policy

Purpose

Principal Investigators (PI) conducting research with human subjects are required to report to the Institutional Review Board (IRB) all research-related incidents involving risks to subjects or others. Incidents requiring prompt reporting to the IRB may involve physical, psychological, social, legal, or economic harms, and can occur in any type of research. Research incidents include Unanticipated Problems and Adverse Events. Some incidents may meet the definition of both. This policy is intended to clarify how the board receives, reviews, and makes determinations regarding research incidents.

Policy Narrative

An unanticipated problem is defined as any incident, experience, or outcome that meets all three of the criteria listed below. The incident:

1. Was unexpected (in terms of nature, severity, or frequency) given the research procedures that are described in the protocol-related documents and the characteristics of the subject population being studied;
2. Was related or possibly related to participation in the research (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 greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

An adverse event is defined as any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign, symptom, or disease, temporally associated with the subject’s participation in the research, whether considered related to the subject’s participation in the research or not. The event can be physical and/or psychological.

The primary investigator of research approved for the use of human subjects is responsible for reporting any adverse events or unanticipated problems as soon as possible, but no later than 7 days after first becoming aware of the problem. A report can be submitted through the online submission process by adding a Research Incident submission to the relevant protocol record. The principal investigator must independently begin initiation of any measures necessary to ensure participant safety while preparing and submitting the required report. The report must contain sufficient information for the IRB to make an assessment of risk. The IRB may request additional information from the PI, which should be provided within one business week, or sooner if specified by the IRB.

Serious Adverse Events

A serious adverse event is one that (based on FDA regulations at 21 CFR 312.32(a)):

• 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 participant’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

Those adverse events that are unexpected, related or possibly related to participation in research, and serious are considered to be the most important ones to review because they suggest that the research places subjects or others at greater risk of physical or psychological harm than was previously known or recognized and often warrant substantive changes in the research protocol to protect the safety, welfare, or rights of participants. Adverse events that are not considered serious may still warrant changes to the research protocol.

The Review Process

A qualified IRB administrator will initially assess the report submitted by the PI with regard to the seriousness of the incident and risks to subjects and will confirm that the incident represents an unanticipated problem and/or a serious adverse event involving risks to the subjects or others. The IRB administrator may, as necessary, consult with the IRB chair in making this determination. If the administrator determines that the report does not meet the three criteria in the definition of an unanticipated problem and/or the criteria for an adverse event that would require a protocol modification, then further review will not proceed. The PI will be notified of this decision.

If the event does meet the qualifications of an unanticipated problem or an adverse event involving risks to subjects or others, the event report will be reviewed by one or more IRB members, typically the Chair or Vice-Chair or member designated by the Chair. Upon receiving a report of an unanticipated problem or adverse event, the IRB reviewer(s) may take one or more of the following actions:

• Acknowledge the report, with no changes to the informed consent and/or protocol necessary
• Request additional information
• Request changes to the informed consent and/or protocol in response to the report
• Approve changes to the informed consent and/or protocol submitted by the PI in response to the report as long as these modifications are minor changes.
• Refer the report to the next convened IRB meeting
• Temporarily suspend the research study and/or require the termination of the related research study procedures. The IRB has the authority to suspend or terminate its approval of a study. When practical, such action will be taken by vote of the members at a convened IRB meeting. In the case of an emergency, in order to protect the safety of the study participant(s), the IRB Chair or a Vice-Chair may suspend enrollment and/or any portion of a study without waiting for a convened meeting of the IRB; however, the Chair or a Vice-Chair may not terminate the study. In such cases, the IRB Chair (or Vice-Chair, as appropriate) will notify the IRB members of the suspension at the next regularly scheduled meeting of the IRB.

A suspension/termination may be appropriate for any of the following reasons:

• Unexpected death or serious harm to a study participant
• Unanticipated problems involving serious harm or risk of serious harm to a study participant, such as known or suspected contamination of a study drug or extreme psychological stress
• Failure of the Principal Investigator to provide information requested by the IRB
• Known or potential non-compliance with human subject regulations or the requirements or determinations of the IRB (by the Principal Investigator and/or a research team member)
• Other circumstances that, in the judgment of the IRB, the IRB Chair, or a Vice-Chair necessitate suspension/termination to protect study participants from harm

In all cases, in a timely manner, the IRB Chair or Vice-Chair will inform the Principal Investigator in writing of the suspension/termination. The letter to the Principal Investigator must state the reason for the suspension/termination. In cases of immediate, significant risk to human subjects, the IRB Chair or designee may communicate the suspension/termination orally while written materials are prepared.

In the case of a suspension, the letter is to specify whether the suspension applies only to the enrollment of new subjects, or also requires the cessation of all study procedures on subjects who have already been enrolled.

In the case of a termination, no new subjects may be enrolled and all study activities involving enrolled subjects must cease. Exceptions may be made by the Chair or Vice-Chair in circumstances where subjects are receiving intervention that cannot be discontinued for safety reasons. These potential instances will be reviewed on a case-by-case basis. The IRB Chair or Vice-Chair will immediately notify the Institutional Official and the Office of Research Compliance, Integrity and Safety of the suspension or termination.

The unanticipated problem will be reported to the Office of Human Research Protections if the answers to all four of the following questions are yes:

1. Is the problem unexpected?
2. Is the problem related or possibly related to participation in the research?
3. Does the problem suggest that the research places participants or others at a greater risk of harm than was previously known or recognized?
4. Does the project have federal funding?

Principal investigators with other regulatory (e.g., FDA) or contractual reporting requirements related to unanticipated problems involving risks to participants or others are responsible for providing any reports required under those regulations/agreements.

Approved by the convened Institutional Review Board and the VP for Research in August 2023.