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Identification, reporting, and evaluation of protocol violations during a clinical trial are integral in adding value to the study data. Preventable errors in study conduct may lead to avoidable patient harm and may result in false negative trial results. Hence designing a plan to prevent/minimize and effectively manage the protocol violations would save time and resources whilst adding quality to the collected data. Investigators are required to conduct their research according to the plans reviewed and approved by Institutional Review Boards (IRBs) and Health Authorities (HAs). 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 protocol violations. Though 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.
Mitigation during early set-up phase
Steps to prevent protocol violations can well be initiated during the protocol development phase by carefully avoiding inconsistent information in different parts of the protocol, and by clearly defining the requirements and recommendations in line with the current medical practice. Collection of feedback from various stakeholders, particularly from all involved clinical operation affiliates, regarding the plausibility of medical procedures and timings described in the protocol would make an essential step during the protocol development. Development of an exclusive and explanatory protocol violations document early during the study set up would enable proper training of the trainers, and dissemination of information to all the site monitors. Vigilance during early parts of the trial by collecting and analyzing feedback on the identified violations from the site monitors and recommended steps to prevent them should be in place. A strong quality management program including regular review of regulatory binder, consent documents, and source documents would minimize the occurrence of study violations.
Management plans during the study conduct
Effective management of protocol violation would start with clear understanding and appropriate implementation of the relevant SOPs and/or work procedures. The key components of protocol violation documentation and reporting, and the stakeholders responsible for each step, should be defined. The completion of the applicable template forms together with the procedure to be followed while reporting should be described early during the set-up phase and be a subject for project-specific training to the operational staff. An exclusive protocol violation document describing the anticipated instances and categories of protocol violations is highly recommended. This document would be designed as exhaustive as possible so that majority of the potential protocol violations occurring either during patient enrollment or during the study conduct are categorized and actioned in a timely fashion. The tracking tool should be proactively utilized to identify potential Corrective and Preventive Actions (CAPA). Repeated violations of a similar nature may be a clear indication that a permanent change (by means of protocol amendment for example) to the study procedures is necessary. There is a recent instance in late 2013 wherein a warning letter was issued to a CRO by the FDA for failure to provide CAPA in the recorded protocol violations.1,2 Note that any violation not reported and later discovered by an audit is considered as non-compliance by the FDA.
Protocol violations, a regulatory perspective
The FDA has listed verification of protocol violations documentation as an evaluation criteria during the inspection conducted at investigational sites after marketing application.3 Similarly the EMA has highlighted the importance of reporting violations and inclusion in the study report.4 However no guidance is provided by both the regulatory bodies on the appropriate threshold for acceptable and excessive protocol violations rate. Post hoc evaluation committees analyzing completed FDA Phase III licensing trials have reported protocol violations ranging from 15.6% 5 to 24.9% 6 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.” Thereby, it is 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 subjects or any loss of integrity to the trial data and information.
Lack of clear regulatory guidance in analyzing and managing these protocol violations leaves the IRBs, sponsors, and investigators with no clear direction on how to handle them. Our experience and lessons learned from multiple global clinical trials had culminated in putting forward these recommendations to efficiently prevent and manage the protocol violations, thereby providing a new Risk Management paradigm. A well-structured approach to manage the violations, as described here, when implemented would be an effective contingent plan to minimize the potential risk for patient safety and increase the credibility of the study data.
About the Authors
Mohamed El Malt, MD, PhD, is Chief Medical Consultant, Medical Consultancy Division, at Europital
Vijayanand Rajendran, MD, is Clinical Research Physician, Medical Consultancy Division, at Europital. He can be reached at firstname.lastname@example.org