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  1. #1

    Violations and deviations - definition

    Hi all, I am looking for information on violations and deviations in non-commercial organisations. The regulations are quite clear about the criteria for a serious breach and what is required to be reported to the MHRA, but does anyone have a more specific definition of violation or deviation in their procedures?

    Is there a difference between a violation and a deviation? Is it necessary to quantify exactly what constitutes a violation or deviation in an SOP or protocol? E.g. if x number of tests are missed, does this constitute a deviation or violation? Is it necessary to quantify when a deviation / violation becomes a breach?


  2. #2
    Forum Member
    Join Date
    Nov 2011
    This issue has generated much debate over the years. Some would argue that a protocol violation is anything that would preclude the data from the efficacy analysis (if evaluation of efficacy is the main objective) whereas a deviation is a minor discrepancy e.g. missing a visit window that does not put the trial subject at risk nor compromises evaluation of the intervention.
    A good way forward would be to agree and write definitions (SOP on protocols?) to be used in your organisation then apply them consistently and see what feedback you get. Such definitions should be incorporated into protocols so that they will be reviewed by funders, sponsors, ethics committee and the MHRA before a trial starts.
    Speak to a statistician and get their advice and take a look at ICH E9 which states
    It is desirable to identify any important protocol violation with respect to the time when it occurred, its cause and influence on the trial result. The frequency and type of protocol violations, missing values, and other problems should be documented in the clinical study report and their potential influence on the trial results should be described.”

  3. #3
    Forum Member
    Join Date
    Nov 2011
    ICH E3 - EMA Q&A Document Revised (rev1) July 2012 might help

    Q; What is the distinction between a protocol deviation,
    important protocol deviation, and a protocol violation?

    Can these terms be clarified?
    Additionally, does the guideline allow sponsors’ flexibility
    in defining what constitutes an important protocol
    deviation for a trial?

    A: protocol deviation is any change, divergence, or departure from the
    study design or procedures defined in the protocol.

    Important protocol deviations are a subset of protocol deviations that may
    significantly impact the completeness, accuracy, and/or reliability of the
    study data or that may significantly affect a subject's rights, safety, or
    well-being. For example, important protocol deviations may include
    enrolling subjects in violation of key eligibility criteria designed to ensure a
    specific subject population or failing to collect data necessary to interpret
    primary endpoints
    , as this may compromise the scientific value of the trial.
    Protocol violation and important protocol deviation are sometimes used
    to refer to a significant departure from protocol
    requirements. The word “violation” may also have other meanings in a
    regulatory context. However, in Annex IVa, Subject Disposition of the ICH
    E3 guideline, the term protocol violation was intended to mean only a
    change, divergence, or departure from the study requirements, whether by
    the subject or investigator, that resulted in a subject’s withdrawal from
    study participation. (Whether such subjects should be included in the study
    analysis is a separate question.)
    To avoid confusion over terminology, sponsors are encouraged to replace
    the phrase “protocol violation” in Annex IVa with “protocol deviation”,
    shown in the example flowchart below. Sponsors may also choose to use
    another descriptor, provided that that the information presented is
    generally consistent with the definition of protocol violation provided above.
    The E3 guideline provides examples of the types of deviations that are
    generally considered important protocol deviations and that should be
    described in section 10.2 and included in the listing in Appendix 16.2.2.
    The definition of important protocol deviations for a particular trial is
    determined in part by study design, the critical procedures, study data,
    subject protections described in the protocol, and the planned analyses of
    study data. In keeping with the flexibility of the guideline, sponsors may
    amend or add to the examples of important deviations provided in E3 in
    consideration of a trial’s requirements. Substantial additions or changes
    should be clearly described for the reviewer.

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