Protocol deviation is an accidental or un-accidental changes or non-compliance to the IRB (Institutional Review Board) approved protocol which may not have significant effect on the subjects.

Protocol violation is a divergence from the protocol that resultant- reduces the quality or completeness of the data, makes the Informed Consent Form inaccurate, or impacts a subject's safety, rights, or welfare.


Protocol violation examples include:

  • Inadequate or delinquent informed consent
  • Incorrect or missing tests
  • Inclusion/exclusion criteria not met
  • Unreported serious adverse events
  • Improper breaking of the blind
  • Use of prohibited medication
  • Mishandled samples
  • Multiple visits missed or outside permissible windows
  • Materially inadequate record keeping
  • Intentional deviation from protocol, Good Clinical Practice, or regulations by study personnel
  • Subject repeated non-compliance with study requirements


What are major or critical protocol deviations?

A major or critical protocol violation is a deviation that has an impact on subject safety, may substantially alter risks to subjects, may have an effect on the integrity of the study data, or may affect the subject's willingness to participate in the study.


Classification of Protocol Deviation

  • Grade 1: No impact on data quality or patient safety.
  • Grade 2: Minor impact on data quality.
  • Grade 3: Minor impact on patient safety.
  • Grade 4: Major impact on data quality or patient safety.
  • Grade 5: Leading to patient/(s) death.


FDA Guidance on Protocol Deviations

FDA drug regulations do not explicitly address protocol deviations. However, the issue is directly addressed in the FDA “Compliance Program Guidance Manual, Program 7348.811, Chapter 48 – Bioresearch Monitoring, Clinical Investigators and Sponsor-Investigators, December 8, 2008.” The manual states:

Protocol deviations. A protocol deviation/violation is generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change. A protocol deviation could be a limited prospective exception to the protocol (e.g. agreement between sponsor and investigator to enroll a single subject who does not meet all inclusion/exclusion criteria). Like protocol amendments, deviations initiated by the clinical investigator must be reviewed and approved by the IRB and the sponsor prior to implementation, unless the change is necessary to eliminate apparent immediate hazards to the human subjects (21 CFR 312.66), or to protect the life or physical well-being of the subject (21 CFR 812.35(a)(2)), and generally communicated to FDA. “Protocol deviation” is also used to refer to any other, unplanned, instance(s) of protocol noncompliance. For example, situations in which the investigator failed to perform tests or examinations as required by the protocol or failures on the part of study subjects to complete scheduled visits as required by the protocol, would be considered protocol deviations.


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