HRPP Manual Section 9-1

Unanticipated Problems Involving Risks to Subjects or Others

Unanticipated problems that may involve risks to subjects or others are incidents, experiences, or outcomes that are:

Unexpected (in terms of nature, severity or frequency) given the research procedures that are described in the protocol-related documents, such as the Institutional Review Board (IRB) approved research protocol and informed consent document and the characteristics of the subject population being studied; and
related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, social, legal, or economic) than was previously known or recognized.

Researchers must promptly report all unanticipated problems that may involve risks to subjects or others to the Michigan State University (MSU) IRB (see Reporting Time Frame below). Any unanticipated problem that may involve risks to subjects or others that also constitutes an adverse event shall be reported, and will be reviewed, following these policies and procedures. Only a small subset of adverse events occurring in human subjects participating in research will meet the definition of an unanticipated problem involving risk to subjects or others. For definitions, see “Adverse Event Definition” section below. Internal and external adverse events should only be reported to the IRB if the adverse event is determined to meet the criteria for an unanticipated problem that may involve risks to subjects or others. The principal investigator (PI) should assess whether it meets the definition of an unanticipated problem involving risks to subjects or others (see “Adverse Event Assessment” below). If an adverse event is submitted to the IRB, it must include a clear explanation of why the adverse event 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.

However, if the U.S. Food and Drug Administration (FDA) Humanitarian Use Device (HUD) regulation (21 CFR 814) applies to the activity, “the medical device reports submitted to FDA in compliance with the requirements of part 803 of this chapter shall also be submitted to the IRB of record.” 21 CFR 814.126(a).

Individuals assigned to review potential unanticipated problems involving risks to subjects or others in a human research study in which they have a conflict of interest cannot review the incident. The policy and procedure described in Human Research Protection Program (HRPP) Manual 10-1 “Conflict of Interest” shall be followed.

Initial Reporting to the IRB

Investigators must report all unanticipated problems that may involve risk to subjects or others to the IRB within the time frame specified in the Reporting Time Frame section below.

Reportable Events

Reportable events may include but are not limited to:

Breach of confidentiality (e.g., lost or stolen research data)
Newly discovered information (e.g., from data analysis or publications) that indicates a greater risk to subjects than expected and that may affect adversely the safety of the subjects or the conduct of the clinical trial
Changes made to research without prior IRB approval in order to eliminate apparent immediate harm
Incorrect dosing or labeling that adversely affects the safety of subjects
Risk to others (e.g., research staff, investigators) related or possibly related to the research (e.g., physical harm)
Adverse events which meet or may meet the definition of an unanticipated problems involving risks to subjects or others (unexpected, involve new or increased risks, and are related or possibly related to the research)
Unexpected serious adverse event
Unanticipated adverse device effect
Unsafe research environments
Threats to subjects or others related or possibly related to their participation in the research
Changes in the research environment that increase the risks to subjects or others due to the research or possibly due to the research (e.g., political or social changes)
Higher occurrence of an adverse event or serious adverse event than expected
An adverse event not mentioned in the consent form or protocol
Incarceration of subjects
Other unexpected incidents

Reporting Time Frame

For urgent unanticipated problems (problems that pose immediate harm to subjects or others), investigators may implement a change in protocol prior to IRB approval to eliminate a hazard to subjects or others. See HRPP Manual 9-5 “Unapproved Change in Protocol” for policies and procedures. Investigators should contact the IRB for guidance when needed.

If the unanticipated problem resulted in a subject death, was potentially life threatening, or risked serious harm to the subject, the investigator should report the problem to the MSU IRB within 24 hours of knowledge of the event or sooner as appropriate.

For all other unanticipated problems, the unanticipated problem reporting form with any pertinent supporting documents (e.g., study sponsor report, communications) should be completed and submitted through the MSU IRB online system by the investigator within 72 hours.

Investigators should not delay reporting for lack of complete information; follow-up information may be submitted.

Immediate Actions

The IRB chair determines if immediate actions are necessary. The IRB chair will review the report (e.g., completed form, supporting documents such as study sponsor report) and any other pertinent documents submitted by the investigator upon receipt and/or make an inquiry into the situation.

Immediate issues to consider will be:

Protect subjects by suspending the protocols according to HRPP Manual 9-3 “Termination or Suspension of IRB Approval”
Notification of current subjects when such information might relate to subjects’ willingness to continue to take part in the research
Notify officials who will take appropriate action (e.g., notify Contract and Grant Administration)

The IRB chair may reach this decision with consultation from other members of the IRB. At any time during the review of a reported unanticipated problem that may involve risk to subjects or others, the IRB chair or IRB may determine that it is necessary to act to protect human subjects by suspending or terminating the protocol according to HRPP Manual 9-3 “Termination or Suspension of IRB Approval.”

Clearly Not an Unanticipated Problem Involving Risks to Subjects or Others

Reported incidents that clearly do not meet the definition of unanticipated problems involving risks to subjects or others (e.g., postage for survey was more expensive than anticipated) should be documented in the MSU IRB online system by the IRB chair or IRB member assigned by the IRB chair to review the report. Any incident that may meet the definition of an unanticipated problem involving risks must be brought to the convened IRB to determine whether the incident is an unanticipated problem involving risks to subjects or others. Before being brought to the convened IRB for a determination, an investigation may be necessary to gather additional information.

Investigation

Incidents that may constitute unanticipated problems involving risks to subjects or others are investigated by the IRB chair. Materials reviewed by the IRB chair include the verbal report (if applicable), the report submitted by the investigator through the MSU IRB online system (e.g., report of new information, unanticipated problems reporting form, any supporting documents, study sponsor report, or communications) and the study’s submissions in the MSU IRB online system. The complete study is available through the MSU IRB online system or for legacy studies, upon request. The IRB chair will work with the investigator to gather more information, if needed.

The IRB chair may determine that additional review by IRB member(s) is needed before being brought to the convened IRB. If the IRB chair determines that such review is necessary, the IRB member(s) will receive the verbal report (if applicable). The report submitted by the investigator through the MSU IRB online system (e.g., report of new information, unanticipated problems reporting form, any supporting documents, study sponsor report, communications) any pertinent communications between the IRB staff and the investigator, and the study’s submissions in the MSU IRB online system. The complete study is available through the MSU IRB online system or for legacy studies, upon request. If any IRB member feels that they are not qualified to review the research study or has a potential conflict of interest, the IRB staff should be notified. The IRB chair will be consulted to determine an appropriate replacement. If an appropriate replacement is not available, HRPP Manual 5-4 “Additional Expertise” policy and procedures will be followed.

Convened IRB Review

The IRB chair or an IRB member designated by the IRB chair presents the potential unanticipated problem involving risks to subjects or others to the convened IRB for review. Materials provided to IRB members include the verbal report, the report submitted by the investigator through the MSU IRB online system (e.g., report of new information, unanticipated problems reporting form, any supporting documents, study sponsor report, communications), and any pertinent communications between the IRB staff, IRB chair, and/or IRB member, the investigator, and others. The complete study is available through the MSU IRB online system or for legacy studies, upon request.

Further Investigation

The IRB may require further investigation prior to making a determination of whether the event constituted an unanticipated problem involving risks to subjects or others. If further investigation is required, the IRB may:

Request the IRB chair continue their investigation
Impanel an investigative sub-committee of the IRB to review all relevant materials, i.e., the verbal report (if applicable), the report submitted by the investigator through the MSU IRB online system (e.g., report of new information, unanticipated problems reporting form, any supporting documents, study sponsor report, communications), and any pertinent communications between the IRB staff, IRB chair and/or IRB member and the investigator and others. The complete study is available through the MSU IRB online system or for legacy studies, upon request.
Obtain additional expertise (See HRPP Manual 5-4 “Additional Expertise”)

The IRB chair, investigative sub-committee, or an additional expert(s) will report to the convened IRB with recommendations. The convened IRB will then make the determination of whether the unanticipated problem involved risk to subjects or others.

IRB Determinations

The convened IRB determines whether the unanticipated problem involved risks to subjects or others. This decision is based on the definition of an unanticipated problem involving risks to subjects or others. When the IRB is reviewing adverse events to determine whether they constitute an unanticipated problem involving risk to subjects or others, the IRB should also see the Adverse Event Assessment section below.

The IRB will determine whether the investigator satisfactorily resolved the problem, if applicable, and whether corrective/protective actions are necessary.

The IRB is required to consider the range of actions that include:

Suspension of IRB approval of the research
Termination of IRB approval of the research
Notification of current subjects’ when such information might relate to subjects’ willingness to continue to take part on the research

In addition to the required actions, corrective/protective actions which may be taken include, but are not limited to:

Require research study-specific corrective action
Require a plan for corrective action, based on the type and nature of the issues
Require education of the researchers
Modification of the protocol
Modification of inclusion or exclusion criteria (e.g., to mitigate newly identified risks)
Modification of informed consent process and/or documents (e.g., include description of newly recognized risks, information disclosed during consent process)Require observation or monitoring of the consent process (e.g. IRB staff, member, chair, member of the HRPP Compliance Office)
Require that subjects (current or past) be re-contacted and provided with additional or updated information or consent
Require that current subjects be asked to re-consent to participation
Notification of current subjects when such information may relate to the subjects’ willingness to continue to take part in the research
Suspension of enrollment of new subjects
Suspension of research procedures in currently enrolled subjects
Suspension of the research
Termination of the research
Modification of the continuing review schedule (when required)
Additional procedures for monitoring (e.g., subjects, consent process, research) or routine audits
Referral to other organizational entities
Other actions as needed
No action may be needed

Required actions will be communicated to the PI in writing.

Reporting

Unanticipated problems that involve risk to subjects and others will be reported (e.g., to institutional officials, government agencies) pursuant to policies and procedures in HRPP Manual 4-8 “Reporting Policy.”

Noncompliance

Unanticipated problems that also constitute noncompliance with federal regulations and university policies and procedures are subject to policies and procedures in HRPP Manual 9-2 “Noncompliance.”

Communications with Investigators

The IRB provides notice to investigators of its determinations and corrective/protective actions, if any, through the MSU IRB online system.

An investigator who believes that the IRB has erred in its finding of an unanticipated problem involving risks to subjects or others may submit a written request asking the IRB to reconsider within 30 days of when the unanticipated problem involving risk to subjects or others determination letter was made available through the MSU IRB online system. The request should clearly indicate the facts or the interpretation in dispute, providing supporting evidence where applicable. This process follows the appeal process described in the Disapproval section of HRPP Manual 8-3 “Committee Review Procedure.” See HRPP Manual 8-3 “Committee Review Procedure” and 5-5 “Meetings.”

Adverse Event Definitions

The definitions found below are modified from “Guideline for Industry Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, ICH-E2A.”

Adverse event: Any untoward or unfavorable medical occurrence in a clinical investigation with a human subject administered a pharmaceutical product or medical device and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (e.g., abnormal laboratory finding, physical exam), system or disease temporally associated with the use of a medicinal product or device, whether or not considered related to the medicinal product or device.

External adverse event: An adverse event experienced by subjects enrolled by investigators at other institutions engaged in the clinical trial. External adverse events occur in the context of multi-center clinical trials.

Internal adverse event: An adverse event experienced by subjects enrolled by the investigator(s) or study team subject to oversight by an MSU IRB. For single-center clinical trials, all adverse events would be considered internal adverse events.

Local subject: A subject that has been enrolled by the MSU researchers for the MSU approved research study.

Non-local subject: A subject that has not been enrolled by the MSU researchers for the MSU approved research study (i.e., for multi-site, clinical studies).

Serious adverse event: Any untoward medical occurrence that at any time:

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 persistent or significant disability/incapacity
Results in a congenital anomaly/birth defect
Based on appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition

Unanticipated adverse device effect: “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.” 21 CFR 812.3(s)

Unexpected adverse event or unexpected serious adverse event: An adverse event or serious adverse event, the nature or severity of which is not consistent with the applicable product information (e.g., investigator’s brochure, protocol or informed consent).

Adverse Event Assessment

Whether the unexpected adverse event is an adverse event occurring in one or more subjects participating in a research protocol, the nature, severity, or frequency of which is not consistent with either:
1. The known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in:
  1. Protocol-related documents, such as the IRB-approved research protocol, any applicable investigator brochure, and the current IRB-approved informed consent document, and
  2. Other relevant sources of information, such as product labeling and package inserts; or
2. The expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the adverse event and the subject’s predisposition risk factor profile for the adverse event.
Whether the adverse event is related or possibly related (there is a reasonable possibility that the adverse event may have been caused by the procedures) to participation in research:
1. Considered related to the research if at least partially caused by:
  1. The procedures in the research.
2. Considered unrelated to the research if the adverse event solely caused by:
  1. Underlying disease, disorder, or condition of the subject.
  2. Other circumstances unrelated to either the research or any underlying disease, disorder, or condition of the subject.
Whether an adverse event suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized.
1. Whether the adverse event is considered a serious adverse event (see Definitions).

This policy and procedure supersedes those previously drafted.

Approved By: Vice President of Research and Graduate Studies, 4-21-2005. Revision 1 approved by VP Research & Graduate Studies on 2-1-2006. Revision 2 approved by VP Research & Graduate Studies on 3-9-2008. Revision 3 approved by VP Research & Graduate Studies on 5-6-2008. Revision 4 approved by VP Research & Graduate Studies on 1-6-2010. Revision 5 approved by VP Research & Graduate Studies on 7-21-2011. Revision 6 approved by Assistant VP Regulatory Affairs on 12/2/2015. Revision 7 approved by Assistant VP Regulatory Affairs on 12-7-2021.

Human Research Protection Program Office of Research Regulatory Support