Contains Nonbinding Recommendations
The major exceptions to the general rule that an isolated event is not informative are serious AEs that are uncommon
and strongly associated with drug exposure, such as angioedema, agranulocytosis, anaphylaxis, hepatic injury, or
Stevens Johnson syndrome. In most cases, a single, unexpected occurrence of this type of event would be
considered an unanticipated problem involving risk to human subjects and, thus, must be reported to the IRB.
Similarly, one or a small number of serious events that are not commonly associated with drug exposure, but are
otherwise uncommon in the study population (e.g., tendon rupture, progressive multifocal leukoencephalopathy)
should be considered an unanticipated problem involving risk to human subjects.
Because they have been previously observed with a drug, the AEs listed in the investigator’s
brochure would, by definition,
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not be considered unexpected and thus would not be
unanticipated problems. Possible exceptions would include situations in which the specificity or
severity of the event is not consistent with the description in the investigator’s brochure, or it can
be determined that the observed rate of occurrence for a serious, expected AE in the clinical trial
represents a clinically important increase in the expected rate of occurrence.
Therefore, FDA recommends that there be careful consideration of whether an AE is an
unanticipated problem that must be reported to IRBs. In summary, FDA believes that only the
following AEs should be considered as unanticipated problems that must be reported to the IRB.
A single occurrence of a serious, unexpected event that is uncommon and strongly
associated with drug exposure (such as angiodema, agranulocytosis, hepatic injury, or
Stevens-Johnson syndrome).
A single occurrence, or more often a small number of occurrences, of a serious, unexpected
event that is not commonly associated with drug exposure, but uncommon in the study
population (e.g., tendon rupture, progressive multifocal leukoencephalopathy).
Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be an
unanticipated problem. There should be a determination that the series of AEs represents a
signal that the AEs were not just isolated occurrences and involve risk to human subjects
(e.g., a comparison of rates across treatment groups reveals higher rate in the drug treatment
arm versus a control). We recommend that a summary and analyses supporting the
determination accompany the report.
An AE that is described or addressed in the investigator’s brochure, protocol, or informed
consent documents, but occurs at a specificity or severity that is inconsistent with prior
observations. For example, if transaminase elevation is listed in the investigator’s brochure
and hepatic necrosis is observed in study subjects, hepatic necrosis would be considered an
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An unexpected adverse drug experience is defined as “[a]ny adverse drug experience, the specificity or severity of
which is not consistent with the current investigator brochure; or, if an investigator brochure is not required or
available, the specificity or severity of which is not consistent with the risk information described in the general
investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic
necrosis would be unexpected (by virtue of greater severity) if the investigator brochure only referred to elevated
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by
virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents. Unexpected, as used
in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the
investigator brochure), rather than from the perspective of such experience not being anticipated from the
pharmacological properties of the pharmaceutical product.” (21 CFR 312.32(a))
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