Federal regulations require the reporting of unanticipated problems involving risks to participants or others to the IRB, institutional officials and federal agencies and department heads. UW-Madison has developed this guidance to assist investigators and research staff to meeting their obligations under the federal regulations.
An “unanticipated problem involving risks to participants or others” is an event that:
§ negatively affects the risk and benefit ratio of the research
§ is one that was not described in the protocol, Investigator’s Brochure or informed consent document or exceeds the specificity, severity, or frequency described in the protocol, the Investigator’s Brochure or informed consent document
§ is more likely than not related to the research study.
The following types of events should be reported to the IRB as potential unanticipated problems:
§ An accidental or unintentional change to the IRB approved protocol that placed one or more participants at increased risk, or has the potential to occur again.
§ A change to the protocol made without prior IRB review to eliminate an apparent immediate hazard to a research participant.
§ Data safety monitoring board report or interim findings that alters the risks, including severity or frequency, to participants.
§ Receipt of new safety information (such as from an Action Letter or journal article) that alters the risks, including severity or frequency, to participants.
§ Publication in the literature that indicates an unexpected change to the risks, including severity or frequency, to participants.
§ A complaint of a participant that indicates unexpected risks or that cannot be resolved by the research team.
§ Incarceration of a participant in the course of a study.
§ Inadvertent breach of a participant’s confidentiality or privacy (e.g., theft or loss of identifiable subject data) that involves risk to that participant or others.
§ Premature completion of a study.
§ Adverse events in FDA-regulated studies that are also unanticipated problems under the UW-Madison Unanticipated Problem Policy, Section IV.
§ Any other unanticipated event reasonably related to the research that poses risks to participant or others or alters the risks, including severity or frequency, to participants (e.g., medication overdose).
In FDA-regulated studies, the following events are reportable as unanticipated problems (in addition to those listed above).
§ The following adverse drug experiences (or events) should be reported promptly to the IRB as “unanticipated problems”:
– Any adverse experience that, even without detailed analysis, represents a serious unexpected adverse event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome).
– A series of adverse events that, on analysis, is both unanticipated and a problem for the study. It is expected that there would be a determination that the series of adverse events represents a signal that the adverse events were not just isolated occurrences and were significant to the rights and welfare of subjects. A summary and analysis supporting the conclusion should accompany the report.
– An adverse event that is described or addressed in the investigator’s brochure, protocol, or informed consent documents, or expected to occur in study subjects at an anticipated rate (e.g., expected progression of disease, occurrence of events consistent with background rate in subject population) but that occurs at a greater frequency or at greater severity than expected. A discussion of the divergence from expected rates should accompany the report.
§ A change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol.
§ Any unanticipated adverse device effect occurring during the investigation. [21 CFR 812]
In FDA clinical trials, all reports to the IRB of unanticipated problems should explain clearly why the event described represents a “problem” for the study and why it is “unanticipated.”
Investigators or research staff members who encounter any of the events listed above in the course of conducting research should submit a report to the IRB that approved the research in which the event occurred. Reports can be made to the reviewing IRB office, director or chair. Contact information for each IRB office is on the Human Research Protection Program’s website (http://info.gradsch.wisc.edu/research/hrpp/irblinks.html)
Reports of unanticipated problems may also come form other sources such as participants, sponsors, patient advocate offices or family members. All reports, regardless of their source, are handled by the IRBs in the same way.
The IRB offices will assist those making reports to assure all necessary information is supplied.
If an event requires immediate intervention to prevent serious harm to participants or others, the report should be made to the IRB chair or director within 48 hours of an investigator receiving notice of the event. Other events should be reported within ten (14) business days from the date of the event or from the date the investigator is notified of the event. In FDA trials involving an investigational device, any unanticipated adverse device effect occurring during the investigation must be reported to the IRB within ten (10) working days after the investigator receives notice of the event.
Reports of possible unanticipated problems are first screened by the IRB director who refers those reports requiring immediate action to the IRB chair. All other reports are referred to the full IRB for review at their next meeting.
When a report is sent to the IRB, the IRB evaluates the report and determines whether the event constitutes an unanticipated problem. The IRB will also make a decision as to what the appropriate remedies should be, including whether research should be suspended or terminated, and whether the event needs to be reported to federal departments or agencies, such as Office of Human Research Protection (OHRP), the VA or the Food and Drug Administration (FDA), research sponsors and UW-Madison officials.
Generally, if the event is determined to be an unanticipated problem, the IRB will give the investigator an opportunity to present written information or to appear in person at the IRB meeting before it makes its final decision.
The
investigator may appeal the IRB decision to the Human Research Protection
Advisory Committee within 10 business days from receipt
of notice of the decision. The appeal must be made in writing and must explain
the basis for the appeal. The investigator’s appeal will be considered at an
Advisory Committee, and the Advisory Committee will notify the investigator,
the IRB and the UW-Madison Institutional Official of the final outcome.
The IRB chair may immediately suspend research if a reported event, listed above, suggests immediate intervention is necessary to protect research participants. The IRB may also suspend research pending a final decision by the IRB as to whether the event constitutes an unanticipated problem involving risk to participants or others. If federally funded research is suspended by the IRB or the IRB chair, the IRB or chair will immediately report the suspension to the UW-Madison Institutional Official.
If the IRB decides that an event constitutes an unanticipated problem involving risks to participants or others, when required by UW-Madison policy and federal law, the event will be reported to the OHRP, FDA and any other federal department or agency that funds or supports the research in which the unanticipated problem occurred.
See, also, UW-Madison’s Unanticipated Problem Policy, Suspension and Termination of Research Policy and Reporting to Federal Authorities Policy posted on the HRPP Policies page: http://www.grad.wisc.edu/research/hrpp/HRPPpolicy.html.