Adherence to the protocol is a fundamental part of the conduct of a clinical study. Any significant change
to the protocol should be submitted as an amendment to the competent regulatory authority and ethics
committee. Significant changes to the protocol include any change in inclusion and exclusion criteria,
addition or deletion of tests, dosing, duration of treatment etc (see the definition of a substantial
amendment in the ‘detailed guidance for the request for authorisation of a clinical trial on a medicinal
product for human use to the competent authorities, notification of substantial amendments and
declaration of the end of the trial’ published by the European Commission in chapter I, volume 10 of the
rules governing medicinal products in the European Community). Deviations from the inclusion/exclusion
criteria of the protocol might erode the scientific and ethical value of the protocol and its authorisation
and might have an impact on the processes put in place for the care and safety of the study subjects.
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 does permit deviations from the protocol when necessary to eliminate immediate hazards to the
subjects but this should not normally arise in the context of inclusion/exclusion criteria, since the subject
is not yet fully included in the trial at that point in the process GCP inspectors have observed a number of
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 non-compliant with GCP.
