Good Clinical Practice: A Question and Answer Guide2024/2025 Edition - 150

GCP: A Question & Answer Reference Guide
Cause Analysis and CAPA are referenced in warning letters when findings have not been adequately addressed by
the study site or sponsor. In addition, ICH GCP E6, R2 references CAPA applications are part of risk management.
The rationale for adding it to a monitoring plan stems from the fact that clinical monitors are often the first to
identify data integrity issues, site performance risks or issues of nonconformity. Observations from monitors
are very important as they are the closest to the task or event and can provide invaluable information. Building
a response plan into the Monitoring plan provides a step-by-step escalation process that allows the monitor to
identify the perceived problem, evaluate and prioritize nonconformities, summarize interventions and if actions fail
to resolve the issue, how to escalate the problem.
5.64 Q. When considering reducing selective safety data in later stage trials, should the sponsor consult with
the relevant FDA review division or divisions to determine whether such collection would be considered
appropriate, and if so, gain insight into the Agency's thoughts on its plan for implementation?
A. The sponsor should discuss its specified plan with the relevant FDA review division or divisions at the
appropriate time (e.g., at the end-of-phase 2 meeting for selective safety data collection for a phase 3 trial) to
determine whether the plan is acceptable and to reach an agreement with the division or divisions on the details of
the plan. The agreement should be incorporated into the procedures for safety data collection in the protocol, the
monitoring plan, and other appropriate trial documents. These steps should help ensure consistent implementation
across trial sites, help support risk-based monitoring efforts, and help alleviate potential inspectional problems
related to safety data collection.
5.65 Q. What Types of Clinical Investigations May Be Considered for Selective Safety Data Collection?
A. In general, selective safety data collection will vary depending on a range of factors, including the disease being
studied, the patient population, subgroup or subgroups of interest, nonclinical findings, prior experience with the
drug and drug class, and study design. Selective safety data collection may be appropriate in the following types of
clinical investigations. However, these are not the only circumstances where selective safety data collection may
be appropriate, and this is not intended to be a complete list.
* Clinical investigations of new indications of approved drugs: Selective safety data collection may be
appropriate in clinical investigations for new indications if the existing safety database is relevant to such
investigations, including, for example, the similarity of the population studied in the new investigation to
patients previously studied and the doses used.
* Post approval clinical studies and trials conducted to fulfill post marketing requirements and post
marketing commitments: When the study population in these types of studies or trials is generally the same
as or is similar to the population from which the premarket safety database was derived, safety data collection
can often be limited to the primary safety endpoint and other endpoints of interest.
* Late-stage premarket and post approval outcome clinical trials: Outcome clinical trials usually involve
relatively large populations (often 5,000-15,000 patients) similar to populations previously studied and are
usually of longer duration than earlier studies. Typically, a fairly substantial safety database is in existence
before initiation of an outcome clinical trial, and this database already provides sufficiently precise estimates
of common, non-serious adverse events (e.g., those that occur in 5 percent or more of exposures). Even when
there is not extensive prior safety data, full data could be collected in a subset of patients (e.g., 1,000) with
more selective data collection in other patients.
* Premarket clinical investigations for some original applications: Unless sufficient safety data already
exist to adequately characterize the safety profile of a drug, comprehensive safety data collection is expected
throughout premarket clinical development intended to support approval of a new drug application (NDA)
or a biologics license application (BLA) for a novel agent in order to elucidate occurrence, dose-response,
and subset (demographic, concomitant illnesses, concomitant therapy) variations for the full range of adverse
events of the drug. However, even in a development program for a novel agent, if sufficiently comprehensive
safety data become available before completion of clinical development, selective safety data collection
in some late-stage investigations may be appropriate. For example, selective safety data collection may be
appropriate in phase 3 trials where the existing safety database adequately characterizes a drug's safety for
more common, non-serious adverse events; therefore, data on those events may not need to be collected.
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