730. Unanticipated Problems Involving Risks to Participants or Others
Updated July 14, 2021
Per federal regulations, University and affiliate researchers must notify the IRB of unanticipated problems that involve risks to participants or others (henceforth referenced as Unanticipated Problems). Unanticipated Problems may encompass physical, psychological, social, legal, and economic harms; harm to dignity; and unexpected threats to privacy or safety.
To be considered an Unanticipated Problem, an event or situation must:
- be unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the population being studied;
- be 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
- suggest that the research places participants or others at a greater risk of harm than was previously known or recognized (i.e., involves new or increased risk).
Examples of Unanticipated Problems
The following incidents are likely to constitute Unanticipated Problems in the context of a research study:
- A laptop was stolen that contained identifiable participant data and the data were not encrypted.
- A processing error resulted in a participant receiving a dose of study medication much higher than the dose dictated by the IRB-approved research plan but that produced no detectable adverse effect.
- Participants received an investigational product that was obtained from donors who were not appropriately screened and tested for viral contaminants.
- Findings from a research project involving the same drug, indicated an adverse event that was described in the investigator’s brochure, was occurring at greater frequency than expected. A discussion of the divergence from the expected rate must accompany the report.
- A safety monitoring report indicated a change occurred in the nature, frequency, or severity of the expected risks of the research.
- Changes made to the research without prior IRB approval to eliminate apparent immediate harm.
Evaluation of Unexpectedness, Relatedness to Research, and Increased Risk
Evaluation of Expectedness
The following questions may be used to assess expectedness:
- Is the problem among the anticipated risks associated with the research procedures? (Anticipated events are those outcomes or effects that are listed as risks in the clinical protocol, IRB application, or consent documents.)
- If the problem was anticipated at the time of study design, does the problem now suggest that the research places participants at greater risk of harm than was previously known or recognized (i.e., the problem is more severe than expected)?
- If the problem was anticipated at the time of study design, is the problem occurring with greater frequency than expected?
- Did the problem result from the expected natural progression of any underlying disease, disorder, or condition of participants experiencing the problem or the participant’s predisposing risk factor profile for the problem?
Evaluation of Relatedness
Problems in research may be caused by:
- research procedures or interventions;
- an underlying disease or disorder of the participant; or
- something unrelated to the research and underlying diseases or conditions.
The investigator must consider these possibilities when determining if there is a reasonable chance that the problem may have been caused by the procedures involved in the research. Determinations about the relatedness of an event to participation in research generally fall along a continuum between “definitely related to the research” and “definitely unrelated to the research.” The IRB is concerned with events that are definitely or possibly related to the research.
For a single adverse event occurrence viewed as an isolated incident, relatedness to research may be difficult to evaluate. For many types of adverse events, determining the relevance and significance of the event to the research requires an analysis of all occurrences of the same (or similar) event. In multi-center trials, sponsors are in the best position to determine if an adverse event is or could be an Unanticipated Problem. Sponsors are responsible for assessing all events to identify those that are or could be Unanticipated Problems and for informing all investigators engaged in a multi-center trial of likely or possible Unanticipated Problems. Investigators are responsible for reporting events that are or could be Unanticipated Problems to the IRB.
Evaluation of Risk to Participants or Others
The third criterion for an Unanticipated Problem is evaluated by an assessment of whether the event or situation suggests that the research places participants or others at a greater risk of harm (e.g., physical, psychological) than was previously known or recognized.
Serious adverse events as well as adverse events that are not serious can be Unanticipated Problems if they meet the criteria of unexpectedness, relatedness to research, and increased risk. Serious adverse events (i.e., those that are life-threatening or involve death, significant or persistent incapacity; may require hospitalization; or jeopardize the participant’s health) always suggest that the research may be placing participants or others at greater risk of harm than was previously known or recognized. However, adverse events that are not serious may also suggest that the research poses greater risks than anticipated.
Adverse Events as Unanticipated Problems
The term “adverse event” is not defined in the Department of Health and Human Services (DHHS) regulations but is routinely used in clinical trials, and therefore warrants discussion in the context of Unanticipated Problems. Definitions for adverse events and serious adverse events are available on the IRB Policy Manual definitions page. Adverse events may be specific kinds of Unanticipated Problems, if they meet the criteria of unexpectedness, relatedness to research, and increased risk to participants or others.
IRB reporting requirements for adverse events depend on whether they represent Unanticipated Problems. Adverse events that meet all three criteria for an Unanticipated Problem (unexpectedness, relatedness to research, and increased risk) must be reported promptly to the IRB, as specified in this policy. Adverse events that do not meet the criteria for an Unanticipated Problem should be summarized at the time of continuing review, but do not require prompt reporting.
Regardless of whether they constitute Unanticipated Problems, investigators must report adverse events to the sponsor and safety monitoring board or committee as specified in the clinical protocol or contract.
For reporting purposes, it is also important to distinguish between local and external adverse events: Local events are those that occur at the University or affiliate investigator’s institution. External events are those that occur at a study site other than the University or affiliate investigator’s “home” institution.
Requirements for Reporting Local Adverse Events as Unanticipated Problems
Local events that require prompt reporting include:
- Local adverse events and local serious adverse events that meet the criteria for an Unanticipated Problem;
- Sponsor or monitoring entity notification, report, or assessment of a local adverse event (or series of same) as a possible Unanticipated Problem;
- Routine safety monitoring reports prepared by the Principal Investigator (PI) when the findings identify possible Unanticipated Problems or indicate changes are needed to protect participants.
Requirements for Reporting External Adverse Events as Unanticipated Problems
University and affiliate investigators participating in multi-center trials receive numerous external reports including reports of adverse events that occurred at other sites (i.e., external adverse events), routine safety monitoring reports, and assessments/notifications from the sponsor or safety monitoring board or committee. Reporting requirements vary according to the event, problem, or assessment.
External events that require prompt reporting include:
- Sponsor or safety monitor assessment/notification indicating one or more external adverse event or serious adverse event may be an Unanticipated Problem;
- Sponsor or safety monitor assessment/notification of external adverse events or serious adverse events that indicate immediate changes are needed to protect participants;
- Sponsor or safety monitor assessment/notification of external adverse events or serious adverse events that indicate changes are needed to reduce participant risk or inform participants of new or increased risk.
For non-exempt research, events or situations that meet all three criteria for an Unanticipated Problem (unexpectedness, relatedness to research, and increased risk) must be reported promptly to the IRB, as specified below. Adverse events and adverse device effects that do not meet the criteria for an Unanticipated Problem should be summarized at the time of continuing review.
University/Affiliate investigators conducting investigational uses of humanitarian use devices (HUDs) must comply with the requirements for reporting adverse device effects as Unanticipated Problems.
The IRB requires reporting of Unanticipated Problems to occur within five business days of the problem becoming known, or within 48 hours if the situation or event involves a death or is life-threatening. Requirements for reporting local deaths in VA research are more stringent. See policy for reporting problems in VA research for specifics.
For exempt research, investigators are advised to contact Research Integrity to discuss any Unanticipated Problems that may have occurred in their studies.
Reporting Unanticipated Problems to the IRB
For non-exempt and HUD studies, investigators must report Unanticipated Problems to the IRB by completing and electronically submitting the appropriate Reportable Event Form available in IRBNet. The information in the report should allow the IRB to evaluate each problem or situation. For example:
- Was the incident expected (i.e., identified in the application and consent form) or unexpected?
- Is the problem or situation related or possibly related to participation in the research?
- Does the problem or event suggest participants or others may be at greater risk of harm than was previously known or recognized?
Upon becoming aware of an Unanticipated Problem, investigators must determine if immediate corrective actions are necessary to protect the safety and welfare of research participants. Investigators must also consider what types of corrective measures should be taken to prevent future occurrences. The problem report must include a description and justification for all corrective actions taken without prior IRB approval.
Possible corrective actions investigators may take or propose (if the matter is not urgent) include but are not limited to the following:
- Change study procedures to minimize risks.
- Suspend the research, pending further review by the IRB or results from a monitoring entity or the sponsor.
- Amend the information shared with current and potential participants (as reflected in the consent form).
- Notify currently or previously enrolled participants of the problem, and related new or increased risks.
If the investigator believes that corrective actions are warranted to prevent future occurrences, these may be proposed at the time the report is submitted. If the Research Compliance Officer (RCO), Research Integrity Director, and IRB Chair concur that the proposed actions are sound, the PI may be instructed to submit a Project Amendment for IRB review.
IRB Review of Unanticipated Problem Reports
Within five business days of receiving a report of a possible Unanticipated Problem (or 48 hours if the problem is life-threatening or fatal), the RCO will consult with the Research Integrity Director and IRB Chair (or other qualified IRB member) to assess risk of harm to participants or others to determine if immediate corrective actions are needed to protect the participants or others and will make the necessary recommendations to mitigate such risks. Following this initial assessment, the problem will be evaluated for the three criteria for an Unanticipated Problem:
- The situation or event was unanticipated;
- The situation or event was related or possibly related to participation in the research;
- The situation or event suggests the research places participants or others at greater risk of harm than originally known.
Possible Unanticipated Problems will be reviewed at the next convened IRB meeting to confirm or reject a determination of Unanticipated Problem and make recommendations for the PI or others. If there are potential risks to participants which require action prior to a convened meeting, an emergency meeting may be convened (with the members attending either in person or via teleconference) or in exceptional safety circumstances, the Chair has the authority to suspend some or all the research activities. When this authority is exercised by the Chair, it will be reported at the next convened University IRB meeting. All sponsor assessments involving likely or possible Unanticipated Problems are reviewed by the IRB Chair or IRB subcommittee to determine if immediate action is necessary to reduce participant risks and will be reviewed at the next convened IRB meeting to confirm or reject a determination of Unanticipated Problem and make recommendations for the PI or others.
The materials for IRB review are available via access to the project in IRBNet (granted to Primary Reviewer and IRB members planning to attend the meeting), and include:
- Problem report or complaint form;
- Report of findings prepared by the RCO or designee, or IRB sub-committee; and
- Approved research plan and study documents (approved documents that are relevant to the review may be flagged as such).
To facilitate the review, the RCO sends the assigned reviewer the criteria for an Unanticipated Problem as defined by the DHHS Office for Human Research Protections (OHRP), and relevant excerpts from the IRB policy manual.
Possible IRB Recommendations Following Determination of Unanticipated Problem
The IRB takes whatever actions are deemed necessary to address the unanticipated problem(s). IRB votes as to whether the event represents an unanticipated problem involving risks to participants or others, serious noncompliance and/or continuing noncompliance. This vote will be recorded in the meeting minutes. If the University IRB votes to suspend or terminate the research study, the reasons for the suspension or termination will be documented.
Following determination of an Unanticipated Problem, the IRB may:
- request additional records or information about the event and its outcome;
- require training or education for research personnel;
- require monitoring of research activities by appropriate persons;
- require monitoring of the informed consent process by appropriate persons;
- request the IRB Chair (or Co-Chair) to meet with the involved investigator and/or research staff, and the appropriate department chair and/or dean to discuss the event/problem;
- require the PI to inform past and/or current research participants of the new or increased risk;
- require the PI to re-consent enrolled participants;
- require amendments to the research plan;
- require the PI to report to the IRB more frequently for this or all of her/his/their studies;
- reduce the approval period (i.e., require more frequent continuing reviews);
- require periodic audits by the RCO or other quality assurance or improvement auditors;
- restrict the PI’s research practice (e.g., limiting her/his/their research privileges to minimal risk or supervised projects);
- suspend IRB approval for one or more of the PI’s studies; or
- terminate IRB approval for one or more of the PI’s studies.
For multi-center studies, if the IRB or the local investigator proposes changes to the protocol or informed consent document/process, in addition to those proposed by the study sponsor or the coordinating center, the IRB should request in writing that the local investigator discuss the proposed modifications with the study sponsor or coordinating center and submit a response or necessary modifications for review by the IRB.
If the IRB determines that an Unanticipated Problem may violate other University policies, the appropriate authority will be notified of the IRB’s findings for possible further review and resolution by those bodies.
PI Notification of IRB Determination and Confirmation of Completion of IRB Required Actions
The PI will be notified in writing of the IRB’s determination and required actions.
Within 30 days of the IRB notification, the investigator must submit written confirmation that all actions have been implemented as required by the IRB.
The RCO will acknowledge receipt of the PI’s confirmation of implementation.
At a minimum, the following information should be included in the RCO report of IRB findings: 1. The nature of the event. 2. The findings of the University or IRB 3. Actions taken by the University or IRB 4. Reasons for the University’s or IRB’s actions. 5. Plans for continued investigation or action.
RCO Distribution of Unanticipated Problem Report
In addition to the IRB correspondence sent to the investigator, reports of any unanticipated problems involving risks to participants or others, any serious or continuing noncompliance, any suspension or termination of IRB approval will be sent to all applicable parties, which may include:
- The Office for Human Research Protections –for research funded by any agency that is a signatory to the “Common Rule” at 45 CFR 46;
- The Food and Drug Administration – for research that is subject to the FDA regulations at 21 CFR 50 and 56;
- The federal or non-federal external funding agency;
- The VA R&D Committee and the regional VA Office of Research Oversight;
- The Office of Sponsored Projects;
- Other University offices;
- The department chair;
- University legal counsel;
- University institutional officials.
Suspension or Termination of IRB Approval
If a study is suspended or terminated, new participants may not be enrolled and no study procedures may take place unless the IRB or IRB Chair determines that continuation of study procedures is in the best interest of currently enrolled participants (see policy for suspension and termination of IRB approval).