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What is a protocol deviation?
The term “protocol deviation” is not defined by either the HHS human subjects regulations (45 CFR 46) or the FDA human subjects regulations (21 CFR 50). For JHM purposes, a protocol deviation is a minor or administrative departure (see definitions below) from the protocol procedures approved by the IRB that was made by the PI without prior IRB approval. Please note: Eligibility exceptions (or eligibility waivers granted by a sponsor) for enrollment of a specific individual who does not meet the inclusion/exclusion criteria in the IRB approved protocol are not deviations. Eligibility exceptions are considered changes in research that require IRB review and approval before a subject who does not meet the approved protocol inclusion/exclusion criteria may be enrolled.
When and how should a PI report protocol deviations to the JHM IRB and the sponsor?
There are several types of deviations from protocol procedures recognized by the JHM IRB, and each type has a different IRB reporting requirement:
A. Protocol deviations that constitute unanticipated problems involving risks require prompt reporting to the JHM IRB
A protocol deviation that constitutes an “unanticipated problem involving risks to subjects or to others” (see Policy No. 103.6(b) for the definition of an unanticipated problem) must be reported promptly to the IRB, as follows:
1. Emergency deviations: When a deviation occurs in an emergency situation, such as when a departure from the protocol is required to protect the life or physical well-being of a participant. The sponsor and the reviewing IRB must be notified as soon as possible, but not later than 5 days after the emergency situation occurred (21 CFR 812.150(a)(4)). The PI must submit a report to the JHM IRB in eIRB under the Further Study Action activity, and use the Problem/Event Report, or for paper studies, use the Unanticipated Problem/Event Report Form (R.F.1)
2. Major, non-emergent deviations without prior approval: A planned deviation that is non-emergent and represents a major change in the protocol as approved by the IRB. The IRB must approve the request before the proposed change is implemented. The PI must submit non-emergent deviations to the IRB for review in eIRB under the Further Study Action activity, and use the Change in Research activity; for paper studies, submit a Change in Research form. If a major, non-emergent deviation occurs without prior IRB approval the event is considered non-compliance. Non-compliance must be reported to the IRB promptly, in eIRB under the Further Study Action activity, and use the Problem/Event Report; for paper studies, use the Unanticipated Problem/Event Report Form (R.F.1) . A PI’s failure to report promptly any major, non-emergent deviation for which the PI did not obtain prior approval is itself an incident of non-compliance. Incidents of non-compliance will be managed in accordance with the Organization Policy on Investigator Non-Compliance Policy No. 103.7 .
B. Protocol deviations that are only minor or administrative
At JHM, minor or administrative protocol deviations are defined as those which do not “affect the scientific soundness of the research plan or the rights, safety, or welfare of human subjects.” If a protocol deviation occurs which meets this definition, the deviation should be reported to the JHM IRB at the time the continuing review application is submitted. In eIRB and for paper studies, use the Protocol Deviation Summary Sheet (R.F. 4) to report these deviations. Examples of minor or administrative deviations could include: follow up visits that occurred outside the protocol required time frame because of the participant’s schedule, or blood samples obtained at times close to but not precisely at the time points specified in the protocol.
C. Protocols that involve an Investigational Device Exemption (IDE)
FDA device regulations at 21 CFR 812.150(a)(4) require prior approval from the sponsor of all planned deviations, including administrative and minor deviations. Planned deviations requested of a sponsor must be submitted for IRB review and approved by the JHM IRB prior to instituting any IDE research planned deviations. The PI must submit in eIRB a Further Study Action, Change in Research activity and for paper studies, a Change in Research form. For device research, the PI must keep on file a copy of the written approval document from the sponsor when a deviation is granted.
What are the protocol deviation reporting requirements for commercially sponsored research?
Sponsored research agreements may require the PI to notify the sponsor of all unplanned deviations or departures from IRB approved protocol procedures. Sponsor reporting requirements for deviations may differ from JHM IRB reporting requirements. It is the PI's responsibility to comply with the reporting requirements outlined in the signed contract. Before a PI signs a research agreement, the PI is strongly advised to read and understand the contract terms.
Does the FDA Good Clinical Practice (GCP) Guidance affect reporting of deviations?
Many sponsors require investigators to follow Good Clinical Practice (GCP) guidelines. The GCP Guidance for Industry states:
“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…of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)).” (4.5.2 at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073122.pdf)
If you have any questions regarding the specific sponsor deviation reporting requirements applicable to a project, please check with the sponsor and obtain clarification before the study enrollment begins.