2k Clinical Consulting, Inc.

All About Protocol Deviations

The protocol for a clinical trial describes the entire study in detail, including the operational details of how it should be carried out. The purpose of the study protocol is to protect the health and safety of study participants while also proving efficacy of the product; however, when tasks are done outside the protocol, deviations are required.

What is a Protocol Deviation?

A protocol deviation happens when the activities of a researcher deviate from the Institutional Review Board-approved protocol without having severe implications, such as missing a visit window because the participant is travelling. It’s not as bad as a protocol violation which is a deviation from protocol that materially:

  • Decreases the quality or integrity of the information,
  • Causes the Informed Consent Form to be erroneous, or
  • Has an impact on the safety, rights, or wellbeing of a participant.

How Protocol Deviations Fit in a QMS

Some examples of protocol deviations occurring are:

  • Enrolling ineligible subjects
  • Lack of re-consenting subjects after amended protocols
  • The consent is missing signatures from subjects.

When deviations occur, the handling and resolution is intertwined in the QMS to ensure inspection readiness.  The organization could have a brainstorming session to discuss the deviation’s potential causes and effects in addition to what steps will be taken to prevent or mitigate the risk. These mitigations can then be monitored and reviewed on a regular basis, with specified thresholds for when a problem with trial registration becomes a substantial problem.

Important vs Non-Important Deviations

Once a procedure deviation has been found, it can be classified as either important or not important. Important protocol deviations can be defined using risk-based methodologies from ICH E6 R2.

Important protocol deviations are defined as subsets of protocol deviations that have the potential to have a major influence on the completeness, correctness, or reliability of essential study data, as well as a subject’s rights, safety, or well-being. Important protocol deviations, for example, could include enrolling individuals who do not meet critical eligibility criteria or neglecting to collect data needed to interpret primary endpoints, both of which could jeopardize the trial’s academic validity.

The International Conference on Harmonization (ICH) does not have a clear definition of a non-important protocol variation. As a result, if a procedure deviation does not match the requirements for being vital, it is considered non-important. Important and minor protocol deviations are both gathered, processed, and reported, albeit the processes may differ.


The cornerstone of a well-executed clinical trial is a well-thought-out and thorough protocol. Attend all sponsor-related meetings linked with the clinical study as the lead investigator. If you have any questions about the protocol or any study-related documentation, you should ask them right away to avoid any problems later. Finally, review the study, visit schedule and make plans ahead of time to prevent deviations.  

Struggling with minimizing protocol deviations for your site or department?  We’d love to hear from you to discuss strategies!