Medical Management Series
Managing protocol violations, a regulatory perspective
Effective management of protocol violations starts with a clear understanding and appropriate implementation of the relevant Standard Operating Procedures (SOPs) and work procedures. As described in an earlier short article in the study setup part of this series, the key documentation for protocol deviations and their reporting and the people responsible for each step in the process should be defined.
The completion of the applicable template forms together with the procedure to be followed while reporting these protocol deviations should be described early during the setup phase and be a subject for project-specific training to the operational team members. A study-specific protocol violation document describing the anticipated instances and categories of protocol violations is highly recommended.
The separate tracking tool should be proactively utilized to identify potential Corrective and Preventive Actions (CAPA). Repeated deviations of a similar nature may be a clear indication that a permanent change (e.g., by means of a protocol amendment) to the study procedures may be required. It should be noted that any violation that has not been reported and subsequently discovered during an audit is considered to be non-compliance by the FDA. Failure to provide CAPA in the recorded protocol violations has resulted in the FDA issuing a warning letter to the CRO tasked with managing the trial.
The FDA has listed verification of protocol violation documentation as an evaluation criteria during the inspection conducted at investigational sites after marketing application. Similarly the EMA has highlighted the importance of reporting violations and inclusion in the Clinical Study Report. However, no guidance is provided by either regulatory bodies on the appropriate threshold for an acceptable or excessive rate of protocol violations. Post hoc evaluation committees analyzing completed FDA Phase III licensing trials have reported protocol violations ranging from 15.6 to 24.9% of all enrolled patients, however neither were classified as excessive or acceptable.
ICH E9 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.” It is therefore imperative that any deviation from the protocol is recorded and assessed for its severity and, where necessary, steps are taken to mitigate any harm to patients or any loss of scientific integrity to the trial data.
Lack of clear regulatory guidance in analyzing and managing these protocol violations leaves IRBs, sponsors, and investigators with no clear direction on how to handle them. Our desire to share our experience and lessons learned from managing multiple clinical trials has led us to write this series of short articles on the medical management of clinical trials and here, specifically, on our recommendations to efficiently prevent and manage the protocol violations and thereby provide a new Risk Management paradigm. By implementing the well-structured approach to manage protocol violations, as described in the earlier study setup article would be an effective way of minimizing the potential risks involved with protocol deviations within clinical research.
ICH E9 statistical principles for clinical trials. NOTE FOR GUIDANCE ON STATISTICAL PRINCIPLES FOR CLINICAL TRIALS (CPMP/ICH/363/96). Available online (Accessed: 22 March 2021)
Mohamed El Malt, MD, PhD and Vijayanand Rajendran, MD. (2016) Medical management in clinical trials: A roadmap to operational excellence (Part 3 -Study Conduct Phase). Journal for Clinical Studies 8(5): 14-20.
Transforming Medical Management of Clinical Trials: Search Engine, European Pharmaceutical Contractor, Page 40-43, March 2015
Mohamed El Malt, MD, PhD and Vijayanand Rajendran, MD. (2016) Medical management in clinical trials: A roadmap to operational excellence (Part 2-Study Setup). Journal for Clinical Studies 8(3): 20-23
Vijayanand Rajendran, MD and Mohamed El Malt, MD, PhD (2014) Prevention and Management of Protocol Violations, Feb 11 Issue. Applied Clinical Trials. Available online (Accessed: 22 March 2021)
Medical Management in Clinical Trials:
A Roadmap to Operational Excellence
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