In December 2024, the FDA released a draft guidance titled “Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices.” The guidance provides recommendations for sponsors, clinical investigators, and Institutional Review Boards (IRBs) in defining, identifying, and reporting protocol deviations in clinical investigations.
Understanding the types of protocol deviations is essential for ensuring compliance and maintaining the integrity of clinical trials. The FDA’s guidance not only clarifies definitions but also emphasizes the importance of distinguishing between unintentional and planned deviations to guide appropriate reporting and oversight.
Types of Protocol Deviations
The FDA defines two types of protocol deviations, unintentional and intentional or planned. The most common deviations generally are “unintentional departures from the IRB-approved protocol.” These typically are identified after they occur.
The second type of deviation is a planned protocol deviation. These occur when a sponsor or site wishes to deviate from the protocol for a single participant. A common example of this is when a participant meets an exclusion criterion, but both the sponsor and site agree that it would be in the best interests of the individual to enroll.
The International Conference on Harmonisation (ICH) E3(R1) document defines a protocol deviation as “any change, divergence, or departure from the study design or procedures defined in the protocol” and defines important protocol deviations as “a subset of protocol deviations that might 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.”In this guidance document, the FDA is adopting these ICH E3(R1) definitions.
Key Takeaways for Sponsors:
- Identify and document protocol deviations so that the FDA can assess whether submitted data is accurate and verifiable. Protocol deviations that are particularly scrutinized are often related to safety monitoring/reporting and efficacy endpoints.
- To minimize important deviations, use a quality by design approach focusing on “critical to quality” factors. This is defined in the ICH guidance as “attributes of a study whose integrity is fundamental to the protection of study participants, the reliability and interpretability of the study results, and the decisions made based on the study results.”
- Monitor deviations during the study and ensure investigators are trained to recognize and report all protocol deviations to the sponsor.
Key Takeaways for Investigators:
- Report all protocol deviations to the sponsor, highlighting those considered especially important.
- For planned protocol deviations in drug studies, get sponsor and IRB approval, except where necessary to eliminate an apparent immediate hazard (21 CFR 312.66).
- Similarly for device studies, except in an emergency, get prior sponsor approval for deviations or get prior FDA and IRB approval for changes affecting the scientific soundness, rights, safety, or welfare of participants ((21 CFR 812.140(a)(4)), (21 CFR 212 812.150(a)(4)), and (21 CFR 812.150(a)(4))).
Table 1. Sponsor Reporting Requirements
| Protocol Deviations (PD) | Intentional | Unintentional |
|---|---|---|
| Important1 Affects rights, safety, well-being, and/or data reliability and integrity. | Drug Studies Get IRB approval prior2 to implementation and notify the FDA per the sponsor’s reporting timelines. For urgent situations, allow the investigator to implement the PDs immediately, report to the IRB as soon as possible, and notify the FDA per the sponsor’s reporting timelines. Device Studies Get FDA and IRB approval prior to implementation. For urgent situations, allow the investigator to implement the PDs immediately, inspect records, and report to the IRB as soon as possible or within 5 business days. | Drug Studies3 and Device Studies4 Report to the FDA and share information with investigators and the IRB within the specified reporting timelines. |
| Not Important5 Do not affect rights, safety, well-being, and/or data reliability and integrity. | Drug Studies It is not a requirement to report PDs to the IRB immediately. PDs may be reported on a semi-annual or annual basis via a cumulative events report. Device Studies Allow investigators to implement PDs after reviewing deviations that meet the five days’ notice requirements. | Drug Studies and Device Studies Evaluate during monitoring for reclassification and notify the investigator. Report reclassified events that meet reporting requirements found in the WCG Guide for Researchers. |
| Good Clinical Practice compliance issues which are not PDs. | Drug Studies and Device Studies It is not a requirement to report to the IRB. Refer to reporting requirements found in the WCG Guide for Researchers. | Drug Studies and Device Studies Evaluate during monitoring for quality improvements. It is not a requirement to report to the IRB. |
2 Exceptions occur when there is an urgent need to eliminate an apparent immediate hazard to a participant.
3 Sponsors can refer to 21 CFR 312 Subpart D and must report serious and unexpected suspected adverse reactions for drug products under 21 CFR 312.32; serious adverse events under 21 CFR 320.31(d)(3) for Investigational New Drug (IND) exempt trials include bioavailability/bioequivalence studies.
4 Sponsors can refer to 21 CFR 812 Subpart C and unanticipated adverse device effects under 21 CFR 812.150 (b)(1).
5 Not important: minor, non-critical, and non-significant deviations.
Table 2. Investigator Reporting Responsibilities
| Protocol Deviations (PD) | Intentional | Unintentional |
|---|---|---|
| Important1 Affects rights, safety, well-being, and/or data reliability and integrity. | Drug Studies Get sponsor and IRB approval prior2 to implementation. For urgent situations, implement PDs immediately and promptly report to the sponsor and the IRB. Device Studies Get sponsor, FDA, and IRB approval prior to implementation. For urgent situations, implement PDs immediately, maintain records, and promptly report to the sponsor and IRB within 5 business days. | Drug Studies3 and Device Studies4 Report to the sponsor and IRB within the specified reporting timelines. |
| Not Important5 Do not affect rights, safety, well-being, and/or data reliability and integrity. | Drug Studies Get sponsor approval prior to implementation. Device studies Implement and report to the sponsor within 5 days’ notice. | Drug Studies and Device Studies Report to the sponsor during monitoring. Follow the IRB reporting requirements found in the WCG Guide for Researchers. |
| Good Clinical Practice compliance issues which are not PDs. | Drug Studies and Device Studies Report to the sponsor as per their guidelines. It is not a requirement to report to the IRB. | Drug Studies and Device Studies Report to the sponsor during monitoring. It is not a requirement to report to the IRB. |
2 Exceptions occur when there is an urgent need to eliminate an apparent immediate hazard to a participant.
3 Investigators can refer to 21 CFR 312 Subpart D.
4 Investigators can refer to 21 CFR 812 Subpart E and G.
5 Not important: minor, non-critical, and non-significant deviations.
Conclusion
Protocol deviations, whether unintentional or planned, can significantly impact the quality and credibility of clinical investigations. By aligning with FDA’s draft guidance, sponsors and investigators can better safeguard participant welfare and ensure data reliability. Proactive documentation, training, and communication between stakeholders are key to minimizing deviations and maintaining regulatory compliance.
For further support, WCG’s IRB experts offer resources and personalized guidance to help navigate these complexities.
Check out the resources below, review our Guide for Researchers, or contact us by completing the following form.
Ask the Experts: When Do I Report a Protocol Deviation to the IRB? Do I Need To Report a Summary of Deviations at the Time of Continuing Review?
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Noncompliance: Now What? CAPA Principles and Best Practices in Clinical Research
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What are the requirements for submitting protocol deviations?
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