The Food and Drug Administration (FDA) has released a draft guidance to standardize the reporting and classification of protocol deviations in clinical trials. This guidance aims to assist clinical trial sponsors, investigators, and Institutional Review Boards (IRBs) in defining, identifying, and reporting protocol deviations, enhancing the integrity and reliability of clinical study data. The recommendations address inconsistencies in current practices and incorporate a risk-based 'quality by design' approach to clinical research.
The draft guidance defines a 'protocol deviation' as any change, divergence, or departure from the study design or procedures defined in the protocol. It further specifies that an 'important protocol deviation' is a subset of these deviations that could significantly affect the completeness, accuracy, and/or reliability of the study data, or that might significantly affect a subject’s rights, safety, or well-being.
Key Recommendations for Sponsors and Investigators
The guidance outlines several key responsibilities for sponsors and investigators:
- Training: Sponsors should train investigators to identify 'important' protocol deviations.
- Reporting: Investigators should report all protocol deviations to the sponsor, highlighting the important ones. Sponsors should inform investigators of the expected timeframe and manner for reporting deviations.
- Documentation and Evaluation: Sponsors should document and evaluate deviations not initially classified as 'important' to determine if reclassification is necessary. Root-cause analyses should be conducted for recurrent deviations.
- Site Management: Sponsors should consider closing trial sites that cannot maintain Good Clinical Practice (GCP) standards or address recurring 'important' protocol deviations.
IRB's Role in Evaluating Protocol Deviations
The draft guidance advises that investigators report 'important' protocol deviations to the IRB when they are identified, in accordance with IRB procedures. IRBs are encouraged to review these deviations promptly to determine any impact on participant safety or study conduct. While deviations not classified as 'important' do not require immediate reporting, the guidance suggests they should be reported to IRBs at some point.
Examples of Important Protocol Deviations
The FDA provides a non-exhaustive list of protocol deviations generally considered important:
- Failing to conduct study procedures designed to assess safety or adequately monitor participants.
- Administering treatments prohibited by the protocol that could increase risks to participants.
- Failing to obtain informed consent or comply with human subject protection requirements.
- Failing to protect a subject’s identifiable, private, protected health information.
- Administering the wrong treatment or incorrect dose to trial participants.
- Enrolling a subject in violation of key eligibility criteria.
- Failing to collect data to evaluate important study endpoints.
- Prematurely unblinding a trial participant’s treatment allocation.
Impact and Next Steps
This draft guidance consolidates recommendations from various ICH guidance documents and aims to create a more consistent and interpretable system for managing protocol deviations. Public comments on the draft are being accepted until February 28, 2025. The FDA will consider these comments before finalizing the guidance.
