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Protocol Deviations

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Preventing Protocol Deviations:

Good protocol writing anticipates where problems might occur; flexibility is added to avoid protocol deviations. In particular, there should be a reason for each inclusion and exclusion criteria and these criteria should be adhered to rigidly. Study visit windows and blood draw windows should be wide enough to prevent inadvertent protocol deviations when subjects can't keep visit appointments. The research regulations (e.g. 21 CFR 56) require that, changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject.

Protocol deviations or violations (referred to from here on simply as Protocol Deviations) are any alteration or deviation from the IRB-approved research plan as defined in the study protocol. Some institutions distinguish between the terms deviation and violation; at CHOP they are considered to be equivalent.

Unplanned Protocol Deviations 

Protocol deviations are not usually anticipated and those that result in harm or have the potential for harm are considered Unanticipated Problems involving risk to subjects or others. Below is a framework to help investigators distinguish between those protocol deviations that require prompt reporting and those that don't.

Deviations that don’t require prompt reporting can occur frequently during the course of a research study. For example, subjects may fail to show up for a scheduled clinic visit or it may be difficult to get all of the required blood samples at the specified times for a PK study. Although these are protocol deviations, they usually cause no harm and have no potential to cause harm to the research subject or others. Such deviations can be submitted to the IRB at the time of continuing review when continuing reviews are required (e.g. “5 subjects had visits one day outside the study window because these visits would have been on a Sunday.”). They can be tracked and documented internally by the investigators, but not submitted to the IRB, when continuing reviews are not required. 

Deviations that do require prompt reporting, on the other hand, are typically events that cause or could cause harm to subjects or others or that affect the fidelity of the research. They require prompt reporting as Reportable Events (as they may constitute Unanticipated Problems). 

Examples of Deviations that do require prompt reporting:

  • produce actual harm to a participant or others (an AE);
  • have the potential to produce harm to a subject;
  • result in the enrollment of an ineligible subject;
  • cause a subject to be withdrawn from the study;
  • prevent the subject from being evaluable for the study’s primary endpoint;
  • result in enrollment of more than the IRB-approved number of subjects (not applicable to studies determined to meet the exempt criteria).

Examples of Deviations that don’t require prompt reporting:

  • don’t produce or have the potential to cause actual harm;
  • don’t impact the integrity of the trial;
  • often can’t be avoided due to subject’s schedules (e.g. soccer match) or natural events (e.g., hurricanes).

Please note that the IRB generally requires a corrective action plan to prevent future occurrences of reported protocol deviations. The corrective action plan needs to include specific steps taken by the Principal Investigator (who is responsible for the conduct and oversight of the study) to ensure compliance with the IRB-approved research plan going forward. 

Planned Protocol Deviations (for non-emergent situations)

In non-emergent situations, the investigator should obtain IRB-approval for the planned prospective protocol deviation

Frequently Asked Questions

  1. What should be included in the Protocol Deviation Report?

    For unplanned protocol deviations, the report should be made in eIRB in the Reportable Events workspace as a “Protocol Deviation/Violation that has already occurred”. The submission should include a summary of what happened, an analysis of why it happened and a corrective action plan describing the steps that have been/will be taken to prevent a recurrence. The corrective action plan needs to include specific steps taken by the Principal Investigator (who is responsible for the conduct and oversight of the study) to ensure compliance with the IRB-approved research plan going forward.

  2. Can an investigator ever deviate from the protocol-defined research plan?

    An investigator may deviate from the protocol whenever necessary to eliminate apparent immediate hazards to the subject, i.e. protect the subject's health, rights or welfare. For example, a study medication should be stopped if a subject develops a medically significant adverse reaction during administration. In such an emergent situation, the physician should provide whatever medical treatment is necessary to the subject.

  3. How do I request a prospective protocol deviation?

    In non-emergent situations, the investigator should obtain IRB-approval for the planned deviation. Approval from the study sponsor or medical monitor may also be necessary but by itself is not sufficient. The request should be made in eIRB in the Reportable Events workspace as a “Prospective Protocol Deviation (has not occurred, Single Subject Amendment)”. It should, at a minimum, include the date of the planned deviation, a description of how the investigator proposes to deviate from the approved protocol and why, a risk assessment (as appropriate), and relevant sponsor approval (as applicable).
    For research involving more than minimal risk: If the investigator is the study sponsor (e.g. holds the IND) then a letter from a physician independent of the research should be obtained that confirms that the change will not adversely impact risk to the participant.
    If the investigator anticipates that there will be future requests for the same deviation, then the protocol should be amended.