What is a protocol deviation?
The term “protocol deviation” is not defined by either DHHS human subjects regulations (45 CFR 46) or FDA human subjects regulations (21 CFR 50). For JHM purposes, a protocol deviation is a departure from the approved protocol’s procedures made with or without prior IRB approval. Such departures may be major or minor/administrative in nature (see below).
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 IRBs, and each type has a different IRB reporting requirement:
A. Emergency Deviations require prompt reporting to the IRB promptly after they occur
1. Emergency deviations are those occurring in an emergency situation, such as when a departure from the protocol is required immediately to protect the life or physical well-being of a participant. In such cases there is no time to prospectively seek the approval of the IRB. The sponsor and the IRB of record 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 IRB of record in eIRB via a Further Study Action for Protocol Event Report. Deviations of this nature are always considered to be unanticipated problems involving risks to subjects or others (see Policy No. 103.6(b)).
* (Note that the reporting standard in 21 CFR 812.150(a)(4), which applies to studies involving Investigational Device Exemptions, shall apply broadly to all emergency deviations at JHM).
B. Major, non-emergent deviations require approval by the IRB before they occur
Major, non-emergent deviations are planned deviations that are non-emergent and represent a major change in the approved protocol. These deviations are changes that the IRB must approve before the proposed change is implemented (via submission of a Further Study Action for Change in Research in eIRB). Examples include exceptions to eligibility criteria, exceptions to the form and manner of obtaining informed consent, and exceptions to the schedule of administration of an investigational product.
If a planned major, non-emergent deviation occurs without prior IRB approval, the event is non-compliance which must be reported promptly to the IRB via Further study Action for Protocol Event Report in eIRB. 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.
C. Minor or administrative protocol deviations require reporting to the IRB at continuing review
Minor or administrative deviations are 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 using the Protocol Deviation Summary Sheet (R.F. 4). Examples of minor or administrative deviations include: follow up visits occurring outside the protocol required time frame because of the participant’s schedule, or blood samples being obtained at times close to but not precisely at the time points specified in the protocol.
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/favorable 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 investigators have any questions regarding a sponsor’s specific deviation reporting requirements, they should check with the sponsor and obtain clarification before the study enrollment begins.