Good Clinical Practice: A Question and Answer Guide2024/2025 Edition - 160

GCP: A Question & Answer Reference Guide
final guidance titled, " Investigator Responsibilities-Protecting the Rights, Safety, and Welfare of Study Subjects. "
" For example, if the state in which the study site is located permits a nurse practitioner or physician's assistant
to perform physical examinations under the supervision of a physician, but the protocol specifies that physical
examinations must be done by a physician, a physician must perform such exams.
6.9
Q. Would a sponsor be permitted, under GCP requirements/standards, to prospectively approve deviations
from an approved protocol's inclusion/exclusion criteria through so-called " protocol waivers " without
the additional approval of the IRB and the FDA? Or must each and every deviation (for every patient) be
brought to the IRB and/or FDA before the patient who does not meet the enrollment criteria is formally
enrolled? Is there any way that such deviations can be approved on a " systematic " basis on a prospective
basis (for example, in cases in which the sponsor or investigators anticipate many cases in which
inclusion/exclusion deviation cases will present themselves during a trial)?
A. In an informal December 2022 response to this question, the FDA noted that, " '...ensuring that the
investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the
IND...' and '... maintaining an effective IND with respect to the investigations...' [21 CFR 312.50].
" If, as you say, the sponsor 'anticipate[s] many cases in which inclusion/exclusion deviation cases will present
themselves during a trial,' then it is suggested that the sponsor re-think whether the established inclusion/ exclusion
criteria for the study should be changed or the protocol amended. That would be in keeping with 21 CFR 312.23(a)
(6)(ii), which states, 'A protocol for a Phase 2 or 3 investigation should be designed in such a way that if the sponsor
anticipates that some deviation from the study design may become necessary as the investigation progresses,
alternatives or contingencies to provide for such deviation are built into the protocols at the outset. For example,
a protocol for a controlled short-term study might include a plan for an early crossover of non-responders to an
alternative therapy.'
" But, as for 'prospectively' approving such changes without securing FDA or IRB approval, [we] would say no,
and point you to 21 CFR 312.30(b):(b) Changes in a protocol. (1) A sponsor shall submit a protocol amendment
describing any change in a Phase 1 protocol that significantly affects the safety of subjects or any change in a
Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific
quality of the study... (2)(i) A protocol change under paragraph (b)(1) of this section may be made provided two
conditions are met: (a) The sponsor has submitted the change to FDA for its review; and (b) The change has been
approved by the IRB with responsibility for review and approval of the study. The sponsor may comply with these
two conditions in either order.
" Although sponsors may indeed occasionally allow a subject who does not meet all of the inclusion/exclusion
criteria to participate in a study, the sponsor should consider the effect that granting numerous such 'exceptions'
may have on the acceptability of the data and the overall effect on the study. "
In a recent response to a similar question on a sponsor's ability to prospectively approve " protocol waivers "
from a protocol's inclusion/exclusion criteria, the European Medicines Agency (EMA) noted that, " sponsors
and investigators should not use systems of prospectively approving protocol deviations, in order to effectively
widen the scope of a protocol. Protocol design should be appropriate to the populations required and, if the
protocol design is defective, the protocol should be amended . . . GCP inspectors have observed several sponsors
implementing systems where the investigator can contact the sponsor, usually the Medical Monitor, and request
a prospective approval to deviate from the inclusion and/or exclusion criteria. The use of such systematic waiver
systems in clinical trials is not considered to be appropriate and studies using such a system might be regarded as
noncompliant with GCP. "
As noted above, there are often circumstances in which the sponsor anticipates that some aspects of the protocol
might require some flexibility. For example, a protocol with a complex set of screening evaluations might result
in circumstances in which patient scheduling issues may occasionally prevent completion of all assessments
within the protocol screening window. The sponsor may not wish to uniformly extend the screening window
for operational reasons but may also wish to be empowered to allow patients to complete only the remaining
assessments to determine if they are eligible. This flexibility should be described in the protocol, rather than
addressed in a prospective waiver. For example, the protocol may state that patients who cannot complete the
assessments within the screening window may be rescreened, and that certain pre-specified screening procedures
need not be repeated for rescreened patients, with the approval of the sponsor's medical monitor.
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