Many clinical research sponsors and sites are currently struggling to interpret elements of the ICH E3 and associated guidelines related to protocol deviations, which is causing problems with delays, consistency and reliability of data.
Based on feedback on the issue from sponsors, investigational CROs and sites, TransCelerate has created the Protocol Deviations Initiative – we spoke to Laura Galuchie, TransCelerate Program Lead at Merck, to find out more about it.
What are some of the challenges sponsors and sites are struggling with around ICH E3 and the associated guidelines related to protocol deviations?
Based on survey information, the one common challenge area is definition. Confusion as to how deviations should be defined contributes to a negative impact on investigational sites, reducing time investigators can devote to patients. The following key principles were utilized in the development of a refined definition:
- Build on the ICH E3 Q&A R1 definition of “Protocol Deviation”
- The event occurred (i.e., not theoretical)
- The event is related to data point or process identified in the protocol or documents referenced in the protocol
- Protocol deviations are independent of fault, blame or circumstance
- Incorporate ICH E6 R2 into a proposed definition of “important protocol deviations”
- Important protocol deviations as a subset of protocol deviations and which may significantly impact “key or critical” study data
Thus, refined definition of important protocol deviations is proposed as:
“Important protocol deviations are a subset of protocol deviations that may significantly impact the completeness, accuracy, and/or reliability of key 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 or failing to collect data necessary to interpret primary endpoints, as this may compromise the scientific value of the trial.
In conversation with FDA, they posed no questions or challenges to the proposed definition or clarifying points. The rationale for the key principles, refined definition as well as additional interpretation recommendations can be found in the Definition section of the Protocol Deviation Process Guide (PDPG). The PDPG also contains a Decision Tree to support identification and classification (i.e., importance) of protocol deviations.
How is TransCelerate aiming to help find solutions with the Protocol Deviations Initiative?
Protocol deviation identification and management is a multi-faceted area. In addition to the protocol itself, PD management is heavily influenced by factors such as the safety profile of the investigational product, safety risk with the indication, and company policy, just to name a few. The team drew from existing ICH guidance, as well as published materials from the TransCelerate QMS and CPT work streams to develop a holistic approach to PD identification and management. The result is a toolkit which contains three components:
- Protocol Deviation Process Guide: A proposed framework describing flexible PD management approaches, elements for consideration based upon proposed interpretation of the ICH E3 definition for important protocol deviations and other associated PD Guidance with links to the PD Process Map.
- Protocol Deviation Map: A map of the PD management process containing pathways for both important and non-important deviations.
- Protocol Deviation Assessment Tool - A template to assist in the identification and documentation of protocol specific ‘important’ deviations.
Improving interpretation of guidelines, including definition, and improving management of protocol deviation processes should reduce noise to support rapid identification of important protocol deviations as well as increase process efficiencies at sites and sponsors. These improvements support continued focus on patient safety, rights and welfare, as well as support data integrity and the reliability of study results.
What is the Common Statistical Analysis Plan (SAP) and the Common Clinical Study Report (CSR)?
The SAP and CSR are templates used to develop streamlined documents. The SAP is based on ICH-GCP guidelines and relevant regulations. The CSR adheres to ICH E3 and CORE guidance.
How will these combine to help transform protocol deviation and management?
The CPT, SAP and CSR templates are consistent and streamlined. They eliminate redundancies that can lead to inconsistencies and errors, facilitate automated reuse of content across documents, increase user comprehension, improve efficiency and enable downstream automation of other processes.
Increased site comprehension reduces protocol deviations. Fewer deviations simplify their management and the analysis and reporting of study data. Besides process efficiencies and improved submission timelines, these lead to improved patient safety, study data reliability, human subject protections and data quality.
A case study of TransCelerate's Protocol Deviations Initiative is being presented Catherine Stewart, Executive Director, Clinical Sciences at Pfizer, at Clinical Trials Europe in Barcelona on 20 November. Explore the full agenda here.