Federal regulations, including those of the Department of Health and Human Services (DHHS), the Food and Drug Administration (FDA), and Veterans Administration (VA), require institutions engaged in human subjects research to have written procedures for ensuring prompt reporting to the IRB of "unanticipated problems involving risks to subjects or others." Unanticipated problems involving risks to subjects or others (henceforth unanticipated problems) can occur during a research study regardless of the level of risk (e.g., minimal or risk more than minimal risk) or type of research (biomedical, social or behavioral). This document describes the federal guidance for IRBs related to what events constitute unanticipated problems, how unanticipated problems differ from adverse events, and what determinations and actions IRBs can take when unanticipated problems occur.
Unanticipated problems is a broad term that includes not only unfavorable outcomes that have occurred that were not expected, but also the development of potentially increased risks of harm occurring in the future. According to guidance developed by the Office for Human Research Protections (OHRP), an unanticipated problem is an incidence, experience, or outcome that meets all 3 of the following criteria:
Examples of unanticipated problems under the OHRP guidance include:
In the context of FDA-regulated trials involving drugs, biologics or devices, unanticipated problems are more commonly called adverse events by the research community. These are events that happen to subjects during or after participation in drug and device trials and relate to the possible safety of the drug or device. As the Venn diagram below from OHRP illustrates, most adverse events are not unanticipated problems but those that constitute unanticipated problems are required by the regulations to be reported to the IRB.
Because many study sponsors and research teams view adverse events and unanticipated problems involving risks to subjects or others as synonymous, many IRBs are flooded with adverse event reports that do not, in fact, provide new information about the risks, benefits, and alternatives for subjects.
From the FDA's perspective, with few exceptions, an individual adverse event report cannot be readily concluded to represent an unanticipated problem, even if the event is not addressed in the investigator's brochure, protocol, or informed consent documents. As the FDA notes, individual adverse event reports generally require an evaluation of their relevance and significance to the study, including an evaluation of other adverse events, before they can be considered to be an unanticipated problem. According to its guidance, the FDA believes that only the following adverse experiences (or events) should be reported to the IRB as "unanticipated problems":
When reviewing a report of an adverse event or potential unanticipated problem, the IRB assesses the information to determine:
The types of action the IRB may take include:
When reviewing adverse events, the IRB takes into consideration whether a Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) exists for the study. At the University of Nevada, Reno, studies that have DSMBs or DMCs are not required to provide individual adverse event reports to the IRBs. When a study does not have a DSMB or DMC, the IRB will generally review adverse events that are (a) unexpected (b) serious; and (c) possibly related to the study treatment or intervention. Adverse events that are serious, unexpected, and probably related to the study treatment or intervention are of primary concern to IRBs. "Serious" means the occurrence of the event suggests that the research study places the subjects or others at greater risk of harm than was previously known or recognized. Generally, events that meet the definition of "serious" either result in or require intervention to prevent events such as, but not limited to, death, life-threatening reactions, significant disability (either physical or psychological), inpatient hospitalization, congenital anomaly/birth defect, or other significant medical incident that, based upon appropriate medical judgment, may jeopardize the subject and require medical or surgical intervention to prevent one of the previously listed outcomes. "Unexpected" means the event is not anticipated given the subject population being studied and the specificity, severity or frequency of the adverse event is not consistent with the protocol consent documents, current investigator brochure, product labeling, or package insert. "Related" means the adverse event is more likely than not to be caused by the research procedures.
If the event is determined to be serious, unexpected, and possibly related, the IRB also determines the potential effect of the event on the risks, benefits, and alternatives for subjects as well as whether any additional action is needed, as described above. This determination will be influenced by the severity of the subjects' condition and treatment options, phase of the research and whether the test article has been FDA-approved for conditions other than those under study, and the frequency or severity of the event. For example, the assessment of the potential significance of an adverse event may differ depending on whether it occurred on a phase I study that is the first to test a drug in humans versus a phase 3 study that involves testing an FDA-approved drug for a new indication.