Unanticipated Problems Involving Risks to Subjects or Others

OHRP considers unanticipated problems, in general, to include any incident, experience, or outcome that meets all of the following criteria:

1.  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 subject population being studied;

2.  Related or possibly related to participation in the research (in this guidance document, 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

3.  Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

An unanticipated problem may be either one of two types:

1. Type 1: Potential harm
2. Type 2 : Actual harm

An unanticipated problem -- because it is associated with potential risks -- is a problem that must be reported even if it is not felt to be serious. Adverse events that are unexpected and related, but not serious, would also be unanticipated problems if they suggest that the research places subjects or others at a greater risk of harm than had previously been known or recognized.

Although the primary mission of an IRB is to protect the rights and welfare of research subjects, federal regulations require investigators to report, and IRBs to evaluate, any unanticipated problem that may pose risks to people who are not the actual research subjects. The ‘others' are most often the researchers themselves or family members of the subjects, although they can be people not associated with the research in any way. If a research subject experienced an unexpected side effect like fainting, and fainted while driving a car, causing an accident in which a stranger was injured, this would be an unanticipated problem even if the subject was unharmed. If a laboratory reagent used in the research, but not actually administered to patients or research subjects, was found to be a potentially dangerous carcinogen, this would be an unanticipated problem posing a risk to others, namely the laboratory workers involved with the research or interacting with the research personnel in the same lab.

Investigators are required to report both internal and external unanticipated problems to the IRB.

A ‘UM' unanticipated problem is one that occurs on a study that is under the direct oversight of a UM investigator or a UM IRB. The participants are UM subjects. The terms ‘Internal' or ‘Local' are sometimes used in referring to a ‘UM' event. ‘UM' includes things that happen to UM subjects anywhere, even if not on University of Michigan property. For example, a problem with a subject enrolled by a UM student conducting a study in Uganda that was approved by a UM IRB is considered a ‘UM' event.

A problem that is not under the primary oversight of UM investigators or a UM IRB is referred to as an ‘External' unanticipated problem. These are events or information about which the UM investigator received a report or read a publication rather than an event the investigator handled. Other terms used include ‘Off-site' or ‘at other sites.'

When an investigator receives a report of an external unanticipated problem it should be submitted to the IRB.

UM investigators participating in multi-site trials and those using sponsored agents routinely receive a large volume of reports of external adverse events. The HHS Office of Human Research Protections (OHRP) has released guidance urging sponsors that individual adverse events should only be reported to investigators at all institutions when a determination has been made by the sponsor that the events meet the criteria for an unanticipated problem.

OHRP recommends that any distributed reports include: (1) a clear explanation of why the adverse event or series of adverse events has been determined to be an unanticipated problem; and (2) a description of any proposed protocol changes or other corrective actions to be taken by the investigators in response to the unanticipated problem.

Nonetheless, investigators may continue to receive reports that have not been assessed by the sponsor. When a UM investigator receives a report of an adverse event that is unexpected and related to an agent or procedure used in the UM study, the UM investigator should review the report and assess whether it meets the criteria above for an unanticipated problem. If it does, then it should be reported to the IRB. Note that many reports labeled ‘unexpected' will not meet the criteria above. It is possible for an external adverse event report from a different study, or use of the agent or procedure in a different population or route of administration to constitute an unanticipated problem for a UM study. The UM investigator should assess whether or not the information in the report indicates a problem that affects the rights and welfare of UM subjects. If in the judgment of the UM investigator it does, then the report should be submitted.

If the report does not contain sufficient information for the UM investigator to make the needed assessment AND the source of the report (e.g. the sponsor) did not state the event is an “unanticipated problem” or an “unanticipated adverse device effect”, then a submission to the IRB is not required. Both FDA and the HHS Office of Human Research Protections have stated their expectation that an individual external adverse event will rarely meet these criteria for an unanticipated problem.

In addition to the general information above, studies involving FDA-regulated devices are required to follow the regulations at 21 CFR 812.

• The investigator must inform the sponsor of any unanticipated adverse device effect (UADE) during an study within 10 days.
• A ‘UADE' is defined as any serious adverse effect on the health or safety of subjects, or any life-threatening problem or death caused by, or associated with, a device, if that problem or death was not previously identified in nature, severity or degree of incidence in the investigational plan.
• A sponsor (the holder of the investigational device exemption (IDE)) must immediately conduct an evaluation of a UADE and report to all investigators within 10 days.
• Investigators must send these reports to IRBs.

Serious unanticipated problems and UADEs must be reported within 7 calendar days of the problem (or within 7 calendar days of the study team becoming aware of the problem). Non-serious unanticipated problems must be reported within 14 calendar days of the problem (or within 14 calendar days of the study team becoming aware of the problem).

If the unanticipated problem involved one or more persons experiencing actual harm , report the unanticipated problem as an adverse event. Refer to the AE Reporting page and follow the instructions provided, using the external or internal form as appropriate.

If a person did not experience actual harm but an unanticipated problem entailed potential harm, and/or risk of harm to subjects or others, refer to the ORIO Reporting page and follow the instructions provided.

If the IRB concurs that an event is an unanticipated problem the IRB will follow the policies and procedures outlined in the University of Michigan Human Research Protection Plan Operations Manual, part 12. (PDF)

• HHS Office of Human Research Protections (OHRP)—regulations require IRBs “have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others , or any serious or continuing non-compliance with this policy or the requirements or determinations of the IRB and (ii) any suspension or termination of IRB approval.” 45 CFR 46.103(b)(5)
• HHS Food and Drug Administration—regulations require “written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of: (1) Any unanticipated problems involving risks to human subjects or others ; (2) any instance of serious or continuing non-compliance with these regulations or the requirements or de terminations of the IRB; or (3) any suspension or termination of IRB approval.” 21 CFR 56.108 (b)
• OHRP– Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events
• FDA — Draft Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting—Improving Human Subject Protection. (PDF)

Posted 9/28/2007, updated 4/16/2015