Medical Management Series
Prevention of protocol deviations
Investigators are required to conduct their research according to the ICH-GCP guidelines and the protocol as reviewed and approved by Institutional Review Boards and Health Authorities. Instances where this does not occur, either inadvertently due to circumstances beyond the investigator’s control, or due to errors of omission or commission by research project staff, are considered to be protocol deviations.
Protocol deviations are defined in the ICH-GCP E6 guidelines as non-compliance with an approved protocol during clinical trial conduct. Although protocol violations and protocol deviations have different definitions, GCP guidelines do not make a distinction between these two, but violations are considered to be those which are serious, such as whenever a deviation results in the withdrawal of the concerned subject from the study.
Effective management of protocol deviations relies on a clear understanding and appropriate implementation of, the relevant guidelines, standard operating procedures (SOPs), and work procedures. Steps to prevent protocol deviations can be initiated during the Clinical Study Protocol development phase by carefully reviewing and avoiding inconsistencies in the information provided in different sections of the protocol. Deviations can also be avoided by clearly defining the requirements and recommendations in line with current medical practice. Collection of feedback from the various stakeholders, particularly from investigational sites and operation affiliates involved, regarding the plausibility of medical procedures and timings described in the protocol marks an essential step during the development of the protocol.
The people responsible for each step and the key components of the recommended protocol deviation documentation and reporting should be defined prior to enrolling the first patient. The Major Protocol Deviations Guidance document should be developed based on the final version of the protocol. This comprehensive document facilitates the prevention and management of all protocol deviations and ensures the appropriate and timely identification, reporting and recording of any major protocol deviations. This guidance document is designed to illustrate all anticipated medical or procedural significant deviations that could occur during the study and those that would also impact the safety of study subjects or the scientific integrity of the study data.
The Major Protocol Deviations Guidance document also outlines the applicable strategy for the Corrective and Preventive Actions (CAPA) associated with protocol deviations. Additionally, the types of deviations are to be prospectively classified and categorized and the reporting procedure described. Specific instances of potential deviations are listed accordingly as eligibility or study conduct deviation. Together with the guidance document, the concurrent development of a study-specific Protocol Deviation Report Template and a designated Major Protocol Deviation Tracker at this stage will establish the tools for appropriate protocol deviation management and the identification of potential CAPA during the study conduct phase.
Developing a well-prepared Major Protocol Deviations Guidance document early in the study setup phase enables the appropriate training of all site monitors. Vigilance during the early parts of the trial by collecting and analyzing feedback on the identified deviations from the site monitors, and recommended steps to prevent them, should be in place. A strong operational management approach including regular review of the regulatory binder, consent documents, and source documents minimizes the occurrence of these study deviations.
Ideally, an electronic system that allows identification, reporting and evaluation of protocol deviations can be established in the trial to allow essential recording and tracking of all protocol deviations. This has the benefit of introducing operational efficiency and thereby augmenting the quality of this important aspect of the clinical study’s conduct.
Guideline for good clinical practice E6(R2). (PDF) (Accessed: 08 FEB 2021)
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
Mohamed El Malt, Vijayanand Rajendran (2015) Transforming medical management of clinical trials: Search Engine. European Pharmaceutical Contractor, March p40-43 (PDF).
Mohamed El Malt, MD, PhD and Vijayanand Rajendran, MD (2014) Prevention and Management of Protocol Violations, Feb 11 Issue. Applied Clinical Trials. (Accessed: 25 JAN 2021)
Medical Management in Clinical Trials:
A Roadmap to Operational Excellence
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