Good Clinical Practice: A Question & Answer Reference Guide - May 2016 - 292

GCP: A Question & Answer Reference Guide
first subject/first visit, and one third of amendments were avoidable. Each amended protocol had an average of 2.3
amendments resulting in four months of incremental time to implement.
Protocol amendments translate into significant unplanned expense and delays for research sponsors and
unexpected burden for investigative sites. More than half of the protocols required one or more amendments; 56.6%
of protocols (n = 1,979) and 58.8% of completed protocols (n = 772) had at least one amendment. Completed
protocols across all phases had an average of 2.3 amendments, though later-stage Phase 2 and 3 protocols averaged
2.7 and 3.5 amendments respectively. Each amendment required an average of 6.9 changes to the protocol.
Therapeutic areas that had the highest incidence of amendments and changes per amendment include cardiovascular
and gastrointestinal protocols. The incidence of protocol amendments is high. Nearly 60% of protocols examined
required at least one amendment, with the typical protocol having an average of 2.3 amendments. Based on the
cycle time data gathered in this study, the results suggest that pharmaceutical and biotechnology companies are
spending an additional four months to accommodate these 2.3 amendments. Multiply this by the number of global
protocols executed per year for any given pharmaceutical company, and the cumulative unplanned delays incurred
for R&D programs are staggering.
7.5

Q. Has the FDA provided any guidance on the best way to establish, in study protocols, the time windows/
ranges within which study-specific procedures (e.g., blood collection) should be conducted? Or is it best
to provide specific time points (e.g., Study Hour 1) and just to identify any noncompliance with these time
points as protocol deviations?

A. In a recent informal response, the FDA's Good Clinical Practice Program noted that, "there are no regulations
or guidance documents that speak to this specifically. It would be useful to discuss such protocol specifics with the
clinical investigators that will take part in the proposed study. They are the experts in the medical area in question
and should be able to assist you in defining reasonable, medically relevant timeframes for any related procedures.
Unless physiological changes are being monitored at varied times after treatment, and these times are relatively
close together, it would seem that there could even be a reasonable window of time after or before treatment that a
given procedure could be performed and be medically relevant. One way to address this in a protocol is with a plus
or minus time interval as you suggest or, alternatively, to state that it is to occur no earlier than one prescribed time
and no later than another. The extent of the timeframe chosen will depend on both the nature of the procedure and
the intended use of the resulting data in the treatment of the study subjects and/or elucidation of the product safety
and effectiveness endpoints. Since it is difficult to impossible to always perform a procedure at exactly the same
time for every study subject, setting an allowable timeframe also allows for better consistency within the dataset.
While failing to meet a protocol-defined timeframe for conducting a study-required procedure would be considered
a study [deviation], it is more important to the integrity of the study to set timeframes that are possible to achieve
as well as medically relevant."
7.6

Q. According to CDER's "deficiency codes" for categorizing the nature of deficiencies cited in inspections
of clinical investigators, protocol violations can be coded as either "05-Failure to follow the investigational
plan" or "20-Failure to protect the rights, safety, and welfare of subjects," which is a newer deficiency
code that was added in October 2005. In the FDA's view, what types of protocol violations represent a
more ominous sounding "failure to protect the rights, safety, and welfare of subjects"?

A. "There are occasions when a failure to comply with the protocol may be considered a failure to protect the
rights, safety, and welfare of subjects because the non-compliance exposes subjects to unreasonable risks," the
FDA states in an October 2009 final guidance titled, "Investigator Responsibilities-Protecting the Rights, Safety,
and Welfare of Study Subjects." "For example, failure to adhere to inclusion/exclusion criteria that are specifically
intended to exclude subjects for whom the study drug or device poses unreasonable risks (e.g., enrolling a subject
with decreased renal function in a trial in which decreased function is exclusionary because the drug may be
nephrotoxic) may be considered failure to protect the rights, safety, and welfare of the enrolled subject. Similarly,
failure to perform safety assessments intended to detect drug toxicity within protocol-specified time frames (e.g.,
CBC for an oncology therapy that causes neutropenia) may be considered failure to protect the rights, safety, and
welfare of the enrolled subject. Investigators should seek to minimize such risks by adhering closely to the study
protocol."
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Table of Contents for the Digital Edition of Good Clinical Practice: A Question & Answer Reference Guide - May 2016