Solving The Protocol Deviation Puzzle With FDA Draft Guidance
By Leila Cupersmith, founder, CEO, principal clinical trial operations consultant, and patient advocate, Choice ClinOps
The FDA’s draft guidance on protocol deviations (PDs), published in December 2024, is a much-needed road map to bring order to an otherwise chaotic and time-consuming process for clinical trial stakeholders (sponsors, CROs, sites, and IRBs). Currently, PD interpretation is like a game of telephone — what starts as a seemingly clear definition quickly morphs into inconsistent reporting, debates over what constitutes a major versus minor PD, and the ever-present risk of under- or overestimating its impact on patient safety and data integrity. All the while, study budgets disappear faster than planned.
Even the best-written PD sections in study documents — whether in protocols, deviation management plans, or monitoring guidelines — cannot prevent misinterpretation, especially when constant staff turnover introduces fresh sets of eyes (and opinions) throughout a clinical trial. This draft guidance finally offers a common language, bringing much-needed clarity and consistency to PD management across clinical trials. Because, let's face it, we could all use fewer surprises when it comes to protocol deviations.
What The Draft Guidance Got Right
The FDA’s draft guidance, “Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices,” is a critical step toward standardizing how PDs are managed, preventing serious missteps such as overlooked safety labs and incorrect dosing.
For sponsors, the draft guidance reinforces the importance of well-designed protocols with built-in flexibility — such as broader eligibility criteria and streamlined procedures — to reduce avoidable deviations. This opens the possibility of no longer excluding real-world patients due to a barely out-of-range lab value or a stable comorbidity that would not impact the investigational product.
The draft guidance also benefits sites by helping identify and categorize PDs accurately, ensuring uniform reporting to maintain regulatory compliance and fostering better communication between sponsors and sites regarding the nature and significance of PDs. The best part for sites? It reduces the excessive documentation burden that often leaves sites feeling like they are drowning in paperwork instead of running a clinical trial.
By encouraging greater flexibility — such as simplified or automated wearable electronic Patient-Reported Outcome (ePRO) requirements (because not every patient remembers to log their symptoms daily), limiting imaging and lab tests to only essential assessments, modifying hospital criteria to match real-world clinical practice, predefining reasonable adjustments in study drug administration timing (when pharmacokinetics support it), reducing unnecessary procedures, using alternative sample techniques, and expanding decentralized clinical trial (DCT) elements — the draft guidance significantly reduces the burden on study participants, caregivers, and research sites. Investigators benefit from clearer reporting expectations, while IRBs can prioritize critical deviation reviews, improving oversight efficiency.
This draft guidance is a pivotal step toward harmonizing protocol deviation management, fostering regulatory alignment, operational efficiency, and improved trial execution for all stakeholders involved.
What The Draft Guidance Left Out
However, there is room for improvement. The draft guidance falls short in addressing protocol deviations specific to DCTs, such as telemedicine-related failures, remote monitoring inconsistencies, home health visit disruptions, and wearable device data lapses. Existing frameworks from groups like TransCelerate BioPharma and the Decentralized Trials & Research Alliance (DTRA) provide valuable starting points and the incorporation of these practical scenarios into FDA guidance would significantly enhance its relevance.
The draft guidance also lacks insights into AI-driven deviations, such as predictive algorithms that might misclassify patients or risk-based monitoring tools that under-detect emerging deviation patterns. Future guidance should address validation, audit trails, and oversight of AI-driven decision support tools in deviation management, ensuring traceability and regulatory compliance.
Additionally, while the draft guidance mentions documentation, it misses the opportunity to highlight the use of electronic data capture (EDC) and eSource systems for automated deviation tracking, trending, and mitigation alerts — key components of proactive deviation management in today's digital trial ecosystems.
Finally, the draft guidance would benefit from detailing real-world mitigation strategies, such as deviation trending dashboards, integrated risk-based monitoring alerts, and routine deviation-focused training for site and sponsor staff. These additions would strengthen its utility as a practical resource for trial teams.
The Impact Of The PD Draft Guidance
Overall, the PD draft guidance is a strong step toward more patient-centered, resilient trials, with the potential to reduce protocol deviation-related workloads across IRBs, sponsors, and site study teams. A few strategic refinements — particularly addressing DCTs, AI-related deviations, and digital tools — could transform this guidance into a true gamechanger. Clinical research thrives at the intersection of clarity and innovation, and this guidance paves the way.
References:
- EMA – Reflection Paper on Risk-Based Quality Management in Clinical Trials (2013):
Highlights the importance of risk-based approaches to minimize protocol deviations through proactive protocol design and operational strategies. - MHRA – Good Clinical Practice (GCP) Guide (2020):
Provides guidance on managing deviations and emphasizes proportional oversight and documentation according to impact on safety and data integrity. - Health Canada – Guidance Document: Part C, Division 5 of the Food and Drug Regulations “Drugs for Clinical Trials Involving Human Subjects” (GUI-0100) (2019): Emphasizes Sponsor’s responsibility to ensure compliance with Good Clinical Practices (GCPs), including managing protocol deviations effectively.
- TransCelerate BioPharma Inc. – Considerations for Protocol Deviations in Decentralized Trials (2023): Provides industry-aligned guidance for managing deviations specific to decentralized and hybrid trial models.
- DTRA (Decentralized Trials & Research Alliance) – Best Practices for DCT Deviations (2024): A framework addressing common deviations arising from decentralized trial elements, including remote technologies and logistics.
About The Author:
Leila Cupersmith is the founder, CEO, and principal clinical trial operations consultant of Choice ClinOps, LLC. Cupersmith helps small to midsize oncology and rare disease trial sponsors around the globe setup their studies for success, rescue at-risk studies, operationalize and execute streamlined clinical trial operations strategies during mergers and acquisitions, design and implement protocol and site specific patient pathways, develop and manage alliances, site engagement and management strategies, risk and change management, cost avoidance and audits. Leila is also the founder of the LinkedIn group Patient-Centric Oncology Clinical Trials, established in 2018 to bring patient inclusion and personal perspectives to the forefront of oncology clinical trial discussions, keeping the "why" of our work front and center.