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Protocol Deviation Reporting

As per ICH GCP 4.5.2, “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/IEC 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).” 

A protocol deviation is defined by any action or inaction that does not correspond to the approved protocol, including privacy or confidentiality breaches. A protocol deviation may include accidental/unintentional or intentional changes, including changes made to eliminate an immediate hazard to participants or others. Protocol deviations may be major or minor and serious or not serious. Deviations are different from amendments in that they generally apply to a single occurrence or participant and are not intended at the time to modify the entire protocol. 

Major Protocol Deviations

Major deviations adversely affect the rights and welfare of participants, the safety of participants, the integrity of the study data and/or the participant’s willingness to continue project participation. 

Examples of major protocol deviations may include, but are not limited to: 

  • Intentional deviation from the protocol to eliminate immediate hazard to participants or others 
  • Enrollment deviations
    • Enrollment of a participant who did not meet all inclusion/exclusion criteria 
    • Enrollment of a minor as an adult 
    • Enrollment of participants after suspension or expiration of the project 
    • Over-enrollment (exceeding the maximum approved by RITHIM) 
    • Implementation of unapproved recruitment procedures 
  • Consent Deviations 
    • Failure to obtain informed consent, written or verbal, as per RITHIM approval, i.e. there is no documentation of informed consent or informed consent obtained after initiation of project procedures 
    • Failure to obtain child assent, when required by RITHIM 
    • Informed consent obtained by someone other than individuals authorized to obtain consent 
    • Use of an invalid consent form, i.e. unapproved consent form or outdated/expired. 
    • Inappropriate documentation of informed consent, including 
      • Missing the participant signature 
      • Missing the investigator signature 
      • Missing the date of consent 
      • Copy of the consent not given to the person signing the form 
  • Procedural deviations 
    • Performing unapproved research procedures 
    • Increasing the number of procedures without approval 
    • Procedures performed by unapproved personnel or at unapproved locations 
    • Incorrect randomization 
    • Failure to perform a required lab test or other procedure that, in the opinion of the Principal Investigator, may affect participant safety or data integrity 
    • Participant visit conducted outside of required timeframe that, in the opinion of the Principal Investigator, may affect participant safety 
  • Drug/Device Administration 
    • Drug/study medication dispensing or dosing error 
    • Use of expired drug 
    • Use of commercial inventory instead of research inventory 
    • Implant of incorrect device 
    • Implant by unapproved project personnel 
  • Failure to report adverse event and/or follow the project safety monitoring plan 
  • Major breach of confidentiality (e.g., unauthorized release of personal information, failure to de-identify documents leaving the project site) 
  • Findings of multiple minor deviations 

Minor Protocol Deviations

Minor deviations do not impact participants’ rights and welfare, participant safety, the integrity of the study data and/or the participant’s willingness to continue project participation. 

Examples of minor protocol deviations may include, but are not limited to: 

  • Missing the original signed and dated consent form (only a photocopy available) 
  • Sponsor-approved deviations from enrollment criteria 
  • Failure to follow the approved research procedures that, in the opinion of the Principal Investigator, does not affect participant safety or data integrity
    • Research procedure conducted out of sequence 
    • Omitting an approved portion of the protocol 
    • Failure to perform a required lab test 
    • Participant visit conducted outside the required timeframe that does not create risk 
  • Failure by the participant to return study medication 

Protocol Deviations Reporting Requirements

Major protocol deviations should be reported on the Major Protocol Deviation Form in Harmony as they happen – immediately if the deviation has the potential to affect patient safety and no later than 7 days of discovery for all other cases.

Minor deviations should be documented on the Harmony Minor Deviation Log.  At each annual renewal, the Minor Deviation Log should be attached as a pdf to the Harmony Project Renewal Form. At project completion, the completed Harmony Minor Deviation Log should be submitted after the Harmony Project Completion Form.