Adherence to the protocol is a fundamental principle of Good Clinical Practice (GCP). Eligibility criteria are established to ensure subject safety and the scientific integrity of the trial data. An investigator's clinical opinion, while valuable, cannot override the explicit requirements of the protocol. If a potential subject does not meet the specified criteria, they cannot be enrolled. The only correct procedure to enroll such a subject is to formally change the criteria for all future subjects. This requires the sponsor to issue a protocol amendment, which must then be reviewed and approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) before it can be implemented.

B. Repeating the test only confirms the subject's ineligibility according to the current protocol; it does not resolve the issue.

C. A monitor's role is to verify compliance and report deviations, not to approve them. They lack the authority to grant exceptions to the protocol.

D. Documenting an explanation in the chart records a protocol deviation but does not authorize it. Enrolling the subject would still be a violation.

1. International Council for Harmonisation (ICH) E6(R2): Guideline for Good Clinical Practice.

Section 4.5.1: "The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by the IRB/IEC."

Section 4.5.2: "The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of the amendment..."

2. U.S. Code of Federal Regulations, Title 21, Food and Drugs.

Part 312.30(b), Protocol amendments: "A sponsor shall submit a protocol amendment to an IND if he or she wishes to make a change in a protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study... Examples of changes requiring an amendment... are... any change in the inclusion/exclusion criteria."

Part 56.109(a), IRB review of research: "An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by these regulations... An IRB shall require that information given to subjects as part of informed consent is in accordance with § 50.25." (This review function extends to all amendments).

3. Johns Hopkins University, School of Medicine, Office of Human Subjects Research. Guidance on Protocol Deviations and Violations.

Section: Protocol Exceptions: "A protocol exception is a one-time, intentional deviation from the protocol that is planned and approved in advance by the sponsor (if applicable) and the IRB. An investigator may not implement a protocol exception until it is approved by the IRB." This clarifies that even a single-subject exception requires formal IRB approval.