FDA Draft Guidance on Protocol Deviations in Clinical Investigations – Key Takeaways

Romillie Cruz MD, Vice President Medical & Scientific Services, Simbec-Orion

The FDA has released a draft guidance last December 2024 on protocol deviations in clinical investigations of drugs, biological products, and medical devices. This document provides essential recommendations for sponsors, investigators, and IRBs to help ensure compliance, data integrity, and patient safety.

Key Highlights:

  • Classification of Protocol Deviations:
    • Important protocol deviations—those that may significantly impact data accuracy, participant safety, or regulatory compliance, such as failure to conduct critical safety procedures like essential lab assessments.
    • Other protocol deviations—those that do not substantially affect the study’s reliability or participant well-being.
  • GCP Compliance Considerations:
    • The guidance clarifies that not all Good Clinical Practice (GCP) compliance issues should be reported as protocol deviations. Issues such as a missing delegation log signature, which do not stem from protocol requirements, should instead be documented and addressed through quality management processes, such as site monitoring reports or corrective and preventive action (CAPA) plans. Proper classification helps avoid inflated reporting and ensures meaningful documentation.
  • Protocol Flexibility:
    • Incorporating appropriate flexibility in protocol design—such as reasonable visit windows and eligibility criteria—can help minimize the need for deviations and support consistent trial conduct. Sponsors should ensure flexibility is built into protocols to reduce the occurrence of deviations requiring IRB approval.
  • Reporting Expectations:
    • IRB approval is required for all protocol deviations, including intentional deviations for a single participant, which must have prior sponsor and IRB approval. These deviations should be rare, as protocols should incorporate appropriate flexibility.
    • Urgent changes to minimize hazards can be implemented without prior IRB approval or IND amendment but must still be reported as protocol deviations, and IRB approval must be sought as soon as possible afterward.
    • Sponsors should document and report important deviations in clinical study reports (CSRs) and ensure comprehensive listings in appendices or data submissions.

What This Means for Simbec-Orion:
At Simbec-Orion, we are already applying most, if not all, of these principles in our current studies. We will continue to stay closely aligned with this guidance, recognizing the critical role of protocol deviation reporting in enhancing patient safety monitoring and ensuring data integrity compliance. By maintaining rigorous oversight and proactive reporting practices, we reinforce our commitment to supporting our sponsors with the highest standards in clinical trial execution.

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