Good Clinical Practice: A Question and Answer Guide2024/2025 Edition - 224

GCP: A Question & Answer Reference Guide
8.18 Q. When should adverse event record keeping begin after informed consent or at first treatment? More
specifically, should adverse events be recorded in a clinical trial database after informed consent is
obtained or beginning at first treatment?
A. Depends on where the study is conducted. Some authorities require reporting of AEs due to study conduct or
due to the protocol instructions, such as withdrawal of medications during placebo lead-in or due to procedures
performed to assess eligibility after informed consent. Commonly, the study period during which the investigator
must collect and report all AEs and SAEs to the sponsor begins after informed consent is obtained and continues
through the protocol-specified post-treatment follow-up period. Since the ICH E2A guidance document defines an
AE as " any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical
product . . . " This definition clearly excludes the period prior to the IMP's administration (in this context a placebo
comparator used in a study is considered an IMP. Untoward medical occurrences in subjects who never receive any
study treatment (active or blinded) are not treatment emergent AEs and would not be included in safety analyses.
Typically, the number of subjects " evaluable for safety " comprises the number of subjects who received at least
one dose of the study treatment. This includes subjects who were, for whatever reason, excluded from efficacy
analyses, but who received at least one dose of study treatment.
There are situations in which the reporting of untoward medical events that occur after informed consent but
prior to the IMP's administration may be mandated by the protocol and/or may be necessary to meet countryspecific
regulatory requirements. For example, it is considered good risk management for sponsors to require the
reporting of serious medical events caused by protocol-imposed screening/diagnostic procedures, and medication
washout or no treatment run-in periods that precede IMP administration. For example, a protocol-mandated
washout period, during which subjects are taken off existing treatments (such as during crossover trials) that
they are receiving before the test article is administered, may experience withdrawal symptoms from removal of
the treatment and must be monitored closely. If the severity and/or frequency of AEs occurring during washout
periods are considered unacceptable, the protocol may have to be modified or the study halted. Some protocols
may also require the structured collection of signs and symptoms associated with the disease under study prior to
IMP administration to establish a baseline against which post-treatment AEs can be compared. In some countries,
regulatory authorities require the expedited reporting of these events to assess the safety of human research.
Additionally, there are other federal agencies with regulations such as Medicare's MMSEA regulation that may
require the collection of safety information starting directly after the patient signs the informed consent form and
subsequent submission.
8.19 Q. Shouldn't every AE be reported as possibly drug related until its causality relationship is known for
sure?
A. For any individual case safety report (ICSR), it is rarely possible to know with a high level of certainty whether
the IMP caused or contributed to the AE/SAE. To date, there are no internationally agreed-upon standards or
criteria for assessing causality in ICSRs. Causality judgments will ultimately be based on the sponsor's analyses
of aggregate data from multiple sources.
Although causality assessments based on aggregate data or case series are usually more meaningful than those
based on ICSRs, the investigator's causality assessment should be completed and may play a role in the early
detection of significant safety events, especially rare ones. In fact, the investigator causality assessment is a leading
factor in the reportability assessment. Taking effect on September 28, 2011, the new IND safety reporting regulation
(21 CFR 312.32) requires investigators to immediately report to the sponsor any SAE, regardless of whether or
not it is considered drug related. In addition, the report must include an assessment of whether or not there is a
reasonable possibility that the drug caused the event. ''Reasonable possibility " means that there is evidence to
suggest a causal relationship between the drug and the adverse event. Investigators should assess the relationship
between an AE/SAE and the IMP based on available information (e.g., facts or evidence) and/or their best judgment
and document their assessments in the CRF. Regulatory authorities do not recommend any specific categorization
of causality, although the categories of probable, possible, and unlikely are sometimes used in protocols.
The CIOMS VI Working Group, which has addressed issues pertaining to the management of clinical trial
safety information, recommends that investigators render a simple binary decision on investigational product
causality (related or not related) for SAEs: " Is there a reasonable possibility that the IMP caused or contributed
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Good Clinical Practice: A Question and Answer Guide2024/2025 Edition

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