Good clinical practice revision 3: evolution or revolution?

Abstract

The new ICH E6(R3) (1) Good Clinical Practice (GCP) guidelines represent the most significant update to GCP (2) since its inception more than 25 years ago. Published in its final version in January 2025, these guidelines introduce innovative provisions applicable to various types and contexts of clinical trials, ensuring the continued relevance of GCP in an era of rapid technological and methodological advancements. Specifically, the new version encourages a proportionate, risk-based approach to study conduct, promoting fit-for-purpose solutions. Additionally, it strengthens transparency through the public registration of trials and the dissemination of results, while providing further guidance to improve the informed consent process. The R3 update is a substantial shift from the R2 (3) addendum of 2016 (which introduced initial elements of a risk-based approach and electronic data management): the R3 revision fully embraces the new paradigms of clinical research, from quality by design to the use of digital technologies and decentralized trials, with a stronger focus on the patient. From a structural perspective, R3 completely replaces the previous R2 version and redefines its architecture. The document is divided into General Principles (11 GCP principles) and specific annexes. Annex 1 applies to traditional inter-ventional clinical trials (and includes practical appendices on Protocol, Investigator's Brochure, Essential Documents, etc.), while Annex 2 (4), not yet published in its final form, will provide additional considerations for non-traditional trials, such as pragmatic studies, decentralized studies, or those using real-world data. This modularity is designed to keep GCP principles up-to-date as technologies, methods, and study designs evolve, allowing for streamlined and targeted updates through new annexes. Annex 2, in particular, will address innovative elements such as decentralized trials and the integration of Real World Data sources, ensuring that these approaches are also conducted in compliance with GCP principles and fit-for-purpose. The General Principles and Annex 1 will come into effect in July this year, while Annex 2, already under public consultation, will be finalized and made available later. Risk-Based Approach and Quality Management ICH E6(R3) builds on the foundation laid by ICH E8(R1) (General Considerations for Clinical Studies), promoting a culture of quality from the early stages of clinical development. The Quality by Design paradigm is emphasized: quality must be proactively designed into the study, planning from the outset how to prevent deviations that could affect critical data or participant safety. In this context, the new guideline requires the explicit identification of Critical-to-Quality (CtQ) factors for each trial, those aspects of design and conduct whose control is essential to protect participants and ensure the reliability of the data collected. Resources should be concentrated on these critical factors during study planning and management, dedicating proportionate attention to their importance and complexity. The cornerstone principle of R3 is proportionality to risk: processes, control measures, and monitoring activities must be proportionate to the inherent risks for participants and the impact on critical study data. This extends and strengthens the risk-based approach introduced in R2, embracing a holistic view of risk management throughout the study life-cycle, from protocol design to final analysis. In practice, sponsors are encouraged to simplify where possible; operational procedures, data collection, and quality controls should focus on what is critical and avoid burdening the study with unnecessary complexity that does not add value to participant safety or result robustness. A careful evaluation of CtQ factors and associated risks allows for concentration on elements essential to the study's objectives, enhancing efficiency and effectiveness. Operationally, the section on Quality Management has been expanded and clarified. Sponsors must establish a quality management system that includes preventive quality assurance (QA) and quality control (QC) processes, integrated into routine monitoring and study oversight activities. Additionally, the definition of "tolerance limits" for specific key study parameters (the so-called Quality Tolerance Limits