Good Clinical Practice: A Question and Answer Guide2024/2025 Edition - 216

GCP: A Question & Answer Reference Guide
results for example elevated liver analyses such as elevated levels of aspartate transaminase (AST), and alanine
aminotransferase (ALT). It is only when information across all study subjects is reviewed that an incident can truly
be ruled to be unrelated. However, only AEs of a given type or severity would need to be reported to the sponsor
with any urgency. Additionally expected AEs, for example post-surgery bleeding or pain, need to be captured on a
CRF, as the severity and/or duration of such could signal a problem caused by the investigational product. This is
also true of abnormal laboratory results.
The protocol should specify the type and severity of AEs that require immediate reporting to the sponsor,
including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs). Additionally, the
investigator is required to report serious adverse events (SAEs) to the sponsor and must include an assessment
of whether the investigator considers that there is a reasonable possibility that the drug caused the event (21 CFR
312.64). The sponsor is required to report Serious and Unexpected Suspected Adverse Reactions (SUSARs) to
FDA and all participating investigators (21 CFR 312.32(c)(1) within a defined time frame, usually 7 days or 15
days depending on the nature and regulatory classification of the suspected reaction.
8.8
Q. Clinical findings that are expected from the placement/removal procedures and normal wound healing
typically are not reported as adverse events. Recently, we have been asked to delete these AEs from the
source AE log and electronic case report form (eCRF) AE pages. Is this acceptable?
A. As discussed above, sponsors are often confused on what needs to be recorded versus what needs to be reported
within a given timeframe. The site is expected to document all deviations from normal and adverse events in their
source documents such as medical records. The protocol and CRF instructions will define what information should
be recorded on the CRF. Where or how the sponsor wants to capture these types of events should be described in
the protocol. As long as the events are collected and evaluated, the exact location of documentation is a matter of
sponsor preference. Thus, the deletion of these clinical findings from the source AE log would be acceptable as
long as the information and details are captured elsewhere in the subject's medical record.
8.9
Q. Can IND study protocols list certain expected serious events and exclude them from the requirement
that investigators report them immediately to the sponsor?
A. In IND studies of severely ill patients, with certain critical diseases, who are likely to experience numerous
expected disease-related manifestations or non-treatment related complications that meet the definition of a SAE
(e.g., oncology studies), some protocols list specific expected events that investigators are required to record in
the CRF, but that are exempt from immediate reporting to the sponsor as SAEs. This has been a common practice,
particularly in oncology trials, subject to regulatory authority approval of the protocol.
The revised IND regulation for investigator reports (21 CFR 312.64) now requires investigators to immediately
report all SAEs to the sponsor, regardless of whether they are considered drug-related or not, including those listed
in the protocol or investigator brochure as anticipated. Study endpoints that are SAEs (i.e., the study is evaluating
whether the IMP reduces the rate of the SAE) do not require immediate reporting to the sponsor, unless there is
evidence suggesting a causal relationship between the drug and the event. For example, a death ordinarily would
not require immediate reporting to the sponsor as a SAE if it were to occur in a trial designed to compare all-cause
mortality in subjects receiving either drug treatment or a placebo. On the other hand, in the same trial with an allcause
mortality endpoint, if the death occurred as a result of an anaphylactic reaction that coincided with initial
exposure to the drug, or as a result of fatal hepatic necrosis, the death must be immediately reported to the sponsor
as an SAE. The identification of the requirements to report the study endpoints that are SAEs immediately to the
sponsor should be spelled out in the protocol.
Although investigators are required to report all SAEs to the sponsor immediately, including those listed in the
protocol or investigator brochure, the sponsor can identify in the protocol those SAEs that it does not plan to report
individually in an expedited manner (i.e., as IND safety reports to the FDA and participating investigators) because
they are anticipated to occur in the study population at some frequency independent of drug exposure.
It is not possible or desirable to list in the protocol every adverse event that may be common in the study
population. Factors that should be considered when deciding which adverse events to identify include, for example,
characteristics of the study population, natural progression of the disease, background event rates, co-morbid
conditions, and past experience with similar populations. The sponsor should limit the list to those events that
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Good Clinical Practice: A Question and Answer Guide2024/2025 Edition

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