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Unanticipated Problems and Serious Adverse Events

Summary

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.

Definition of Unanticipated Problems

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:

1. The incidence, experience, or outcome is unexpected given the research procedures described in protocol-related documents (e.g., the study protocol, the consent documents, the Investigator's Drug Brochure) and the characteristics of the subject population being studied. An event may be considered unexpected if it exceeds the nature, severity, or frequency described in the study-related documents, Investigator's Drug Brochure, product labeling, or package insert.
2. The incidence, experience, or outcome is related or probably related to participation in the research study. Probably related means the incidence, experience, or outcome is more likely than not to be caused by the research study procedures.
3. The occurrence of the incidence, experience, or outcome suggests that the research places subjects or others at a greater risk of harm (physical, psychological, economic, or social) than was previously known or recognized.

Examples of unanticipated problems under the OHRP guidance include:

• An accidental or unintentional change to the IRB approved protocol that placed one or more participants at increased risk.
• A change to the protocol made without prior IRB review to eliminate an apparent immediate hazard to a research participant.
• Interim findings and/or a safety monitoring report that indicate an unexpected change to the risks or potential benefits of the research in terms of severity or frequency.
• Publication in the literature that indicates an unexpected change to the risks or potential benefits of the research.
• 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.
• A change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol.
• A breach of a participant's confidentiality or privacy that involves potential risk to that participant or others.

Serious Adverse Events vs. Unanticipated Problems

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":

• 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. 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.
• 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.
• Any other adverse event that would cause the sponsor to modify the investigator's brochure, study protocol, or informed consent documents, or would prompt other action by the IRB to assure the protection of human subjects.

IRB Review of Unanticipated Problems and Serious Adverse Events

When reviewing a report of an adverse event or potential unanticipated problem, the IRB assesses the information to determine:

• Whether the reported event is an unanticipated problem involving risks to participants or others according to the definition in this policy
• What action in response to the report is appropriate
• Whether suspension or termination of approval is warranted, and
• Whether further reporting to University officials, the VASNHCS Research Office, federal agencies and department heads is required

The types of action the IRB may take include:

• Requesting the investigator make modifications to the protocol
• Requiring more frequent review of the protocol (e.g., more often that the minimal of annual review)
• Requesting the investigator modify the consent process or consent documents
• Requiring the investigator to provide additional information to current and/or past participants or re-consenting to participation
• Requiring additional training of the investigator and/or study staff
• Reconsideration of IRB approval
• Implementation of monitoring of the research
• Implementation of monitoring of the consent process
• Suspension of the research
• Termination of the research

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.