Keeping Protocol Deviations in Check: Part 1

protocol deviations

Keys to FDA Compliance

Recent FDA Warning Letters have shown serious concern about protocol adherence and the number of deviations documented. I am hearing the same things from colleagues monitoring sites. My fried Chris wrote me last night, “It is unbelievable how much this is still occurring even as we speak.” A clinical research associate confided in me Monday that “They had never heard of GCP!” Clinical sites have been experiencing their own issues regarding protocols which I will discuss in future posts. The only person who seems non-plussed by this is my colleague Judith Lynn. She has been writing protocols and monitoring sites for many years and offers us some sound advice. Needless to say, she begins with some very basic sponsor responsibilities.

Guest Commentary by Judith Lynn-

Manage your study

Recent warning letters from FDA remind us of a fundamental truth about running trials: Sponsors need to manage their studies.

We might do well to consider FDA guidance as a helpful guide, not another obstacle or checkbox. A monitoring plan is a useful exercise for the study manager, to help define critical timepoints, help predict manpower requirements, and data flow. Good monitoring helps ensure reliable data. This in turn helps sponsors make better decisions, either for the next study or for a marketing application. Hiding or ignoring safety or study conduct trends only builds in problems later.

Monitor the study

• Have a communication plan, if your monitor finds something of concern, make sure there is a mechanism to escalate concerns
• Expect monitors to look not only at each subject individually, but also pay attention. Electronic data collection, and review of lab reports over time help with this

Review monitoring visit reports.

protocol deviations FDA

Regular Review of Monitor Reports

Keeping current with review of reports helps the sponsor. If you don’t have time, consider asking for help. If nothing else, for financial reasons (if there is no report, why should you have an expense report)? Issues I have found, both during study conduct or during file audit, include:

~ Reports are delinquent or missing
~ Frequency of visits does not match monitoring plan
~ Different monitor each time (this can affect the ability to track issues over time, and site’s understanding of the protocol)
~ Protocol deviations at sites, pay attention to the number and type of deviations noted

Protocol Deviations

I have recently seen exhaustive notes and lists of protocol deviations at sites. While tabulation of numerous deviations can be tedious, deviations can be an indicator of problems with a site or with the protocol.

~ Inclusion/exclusion criteria are not realistic (if too many subjects enrolled, with sponsor approval, that don’t meet criteria)
~ Site does not understand the study (Retraining?)
~ Study is complex
~ Site may not have appropriate facilities (if procedures often not done, there may be an offsite laboratory or X-ray facility that is difficult for subject to get to)

I have worked in both large and small sponsor companies. Often we have a lot to do and limited time and budget. I encourage you to make the time, and dedicate the resources to manage your study. It will pay off.

Judith Lynn, 17 March 2010

Judith Lynn is a Pharmaceutical Consultant based in Redwood City, CA. Watch for future Guest Commentaries including Protocol Deviations: Part 2 by Sarah Wilson

Protocol Violations: Root Cause Analysis

A Head’s Up for Sponsor-Investigators:

FDA has just issued a Warning Letter for GCP violations to a “sponsor-investigator” someone who both initiates a clinical trial and conducts it. In this case the Warning Letter was sent to the researcher for Sponsor responsibilities as they had passed on the investigator role to another researcher. All of the same responsibilities Judith mentions hold true for academic research and “Investigator-Initiated Research.” Read for yourself:

GxP Perspectives LinkedIn Group

7 Responses to Keeping Protocol Deviations in Check: Part 1

  1. Erica says:

    Hello Judith.
    Monitoring is good but there is a critical step that comes before it. Protocol design.

    I am from the IRB world and we just reviewed another protocol with a design problem. It is NOT a human subjects problem so the IRB shouldn’t/didn’t mention it. But I did as an aside.

    They had required visits on day 111 and day 175! There was no window. How many out-of-window deviations would that monitor pick up. Protocol designers should plan ahead.

    • GxP Perspectives says:

      Thank you, Erica
      Readers should know that Erica is a long time IRB professional and the source of infinite wisdom (she can also be the source of mischief). I hope to have a Guest Commentary by her soon.

  2. Nice way of thinking. I love it. Thanks for posting

  3. Jarrah says:

    I read with interest the Case 1 on your website “”

    In Case 1 it stated “For a psychological study investigating a treatment for bipolar disorder, the protocol requires Dr. X to perform a physical examination that includes a rectal and genitourinary exam.”

    My questions are:
    1 Why would a subject in a psychological study require a rectal and genitourinary examination?
    2 Is it normal to do a GU exam in a study for a psychiatric illness?
    3 Is it a requirement of the FDA or the sponsor to do a GU exam?

  4. L says:

    How detailed is a montoring plan supposed to be? i would think it should be a detailed study specific work instrcutction for the IDE submission, but I have gotten pushback that want to send an overview and if FDA asks we just send them some of our WI and SOp’s.
    I dont agree, any thoughts from seasoned IDE and clinical folks.
    I say why get a question and have teh stand alone document for any monitor to be able to do it in case you have many sites.. what is the norm for medical device clinical trials? thanks

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