Is any task dreaded more by the clinical research team than capturing, categorizing, classifying, tracking, responding to, and closing out protocol deviations? Let me count the ways: After hours of effort, we end up with multiple versions of trackers, all slightly different, documenting hundreds of identical corrective and preventative actions to "Retrain the site," with little evidence that said retraining actually occurred.  Then we need to do it all over again for the CSR, with vaguely different results that need to be reconciled. Sound familiar? In this series, we'll cover everything you wanted to know but were afraid to ask about protocol deviations, including

• Regulatory requirements
• Objectives
• Collection
• Categorization and classification
• Trend analysis
• Remediation
• Statistical analysis

Let's dive in!  First, the regulations. Protocol deviations are mentioned in the following regulations and guidances:

• ICH GCP E6 states that investigators should promptly report to the IRB/IEC "deviations from, or changes of, the protocol to eliminate immediate hazards to trial subjects," a requirement echoed in 21 CFR 56, which states that IRBs will follow written procedures to ensure that sponsors and clinical sites report "any unanticipated problems involving risks to human subjects or others," which implies reporting of deviations.
• E6 also states that investigators should not implement any "deviation from...the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion of the IRB/IEC...except where necessary to eliminate an immediate hazard..." If such unplanned deviations do occur, "the investigator...should document and explain any deviations from the approved protocol."
• E6 specifies that monitoring reports should describe "deviations and deficiencies." A newly-added section in R2 specifies that one purpose of centralized statistical monitoring is to identify protocol deviations.
• 21 CFR 312.56 states that "A sponsor who discovers that an investigator is not complying with the...investigational plan...shall promptly either secure compliance or discontinue shipments of the investigational drug..."  This requirement implies that sponsors must monitor protocol deviations (non-compliance with the investigational plan).
• ICH GCP E3 states, "All important deviations related to study inclusion or exclusion criteria, conduct of the trial, patient managements [sic] or patient assessment should be described" in the Clinical Study Report. It goes on to say, "In the body of the text, protocol deviations should be appropriately summarized by center and grouped into different categories, such as:  Those who entered the study even though they did not satisfy the entry criteria; those who developed withdrawal criteria during the study but were not withdrawn; those who received the wrong treatment or incorrect dose; those who received an excluded concomitant treatment."  "Such as" is doing some heavy lifting; put a pin in that, because we'll come back to it later.
• FDA's Guidance for Industry: E3 Structure and Content of Clinical Study Reports explains, "Important protocol deviations are a subset of protocol deviations that might significantly affect the completeness, accuracy, and/or reliability of the study data or that might significantly affect a subject's rights, safety, or well-being."

As usual, our regulations are silent on the nuts and bolts that would really be helpful. How, exactly, do we collect, classify, categorize, trend, track, and respond to deviations? Or even - to what end?   Stay tuned!