The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) released a draft guideline update- the ICH E6 (R3)- that focuses on the application of Good Clinical Practice (GCP) to new trial designs, technological advancements, and enhancing a risk-based approach in clinical trials.
The ICH E6 (R3) serves as an update to the current guideline, E6 (R2). The purpose of this update is to provide a framework for adapting GCP to the rapidly evolving landscape of the clinical research sector, where new processes and technologies are emerging on a frequent basis.
The release of this draft aims to ensure that clinical trials continue to maintain high ethical and scientific standards while effectively incorporating innovative trial designs and leveraging technological advancements. By strengthening the risk-based approach, this guideline seeks to enhance the quality and efficiency of clinical trials in light of the evolving landscape of the industry.
Significance of ICH E6-GCP guidelines
ICH E6-GCP is a set of guidelines that establish standards for conducting ethical and scientifically sound clinical trials involving human subjects. Its purpose is to ensure the quality, integrity, and reliability of trial data, as well as the protection of human subjects.
One specific aspect addressed by ICH E6-GCP is the consent process. The ICH has outlined a list of 20 required elements that should be included in consent forms used in studies involving investigational pharmaceutical agents. Pharmaceutical sponsors are expected to draft consent forms that adhere to these requirements when applicable [1].
While the primary focus of ICH E6-GCP is on clinical trials conducted for regulatory submission purposes, the guideline acknowledges that its general principles can also be applied to other types of clinical investigations.
The initial version of ICH E6-GCP, E6 (R1), was released in 1996. In 2016, an integrated addendum to the guidance, E6 (R2), was issued [2]. This addendum aimed to address advancements in technology and changes in clinical trial practices since the release of E6 (R1), with the goal of promoting greater efficiency in clinical trials.
What’s new in ICH E6 (3)?
The ICH E6 (R3) introduces a section that focuses on quality management in clinical trials, emphasizing the importance of a quality management system (QMS). The guideline outlines key components of the QMS, including risk management and continuous improvement. It clarifies the roles and responsibilities of stakeholders and promotes clear communication and coordination [3].
The new guideline adopts a principles-based approach, providing greater flexibility and encouraging the use of innovative methods and technologies. It prioritizes participant-centricity, ensuring participant needs and preferences are considered. The concept of data reliability is introduced, guiding stakeholders in ensuring trustworthy trial data.
The emphasis is on quality by design (QbD) principles and leveraging technology to enhance trial efficiency. Technology and digital oversight play a crucial role in data management, responsibilities, and monitoring. The COVID-19 pandemic has accelerated the adoption of decentralized trial models, supported by technology.
The ICH E6 (R3) highlights the importance of risk assessment activities and critical quality factors in trial design. Customization and fit-for-purpose approaches are necessary to optimize trial processes, considering individual participant characteristics and specific trial designs. The goal is to benefit patients and minimize risks through efficient and tailored trial operations.
Being compliant with the ICH E6 (R3) guideline requires a proactive approach to quality, integrating it into the trial design rather than just monitoring it. Organizations should strategically identify critical quality factors related to patient safety and trial validity. QbD approaches should be applied to both the clinical trial itself and supporting processes.
Risk-based approaches to trial management and monitoring are recommended to expedite the process while maintaining patient safety and result validity. Data integrity is crucial, and the new guideline encourages a holistic approach to assess the reliability of trial results on a larger scale.
A clear definition of roles, tasks, and responsibilities is essential for all stakeholders involved in the trial. Mastering the ICH E6 (R3) principles requires a strategic mindset and thorough preparation when addressing trial design and conduct.
E6 and E8: guidelines that go hand-in-hand
The E6 (R3) and E8 (R1) guidelines aim to address key challenges in the clinical trial industry, such as standardization, ethical conduct, quality management, effective data management, roles and responsibilities, and risk management. They both strive to improve the design, conduct, and overall quality of clinical trials [4].
In comparing the E6 (R3) and E8 (R1) guidelines, E6 (R3) focuses on QbD, RBQM, and CTQ, while E8 (R1) emphasizes design considerations for clinical studies. E6 (R3) provides detailed guidance on managing risks at the system and trial level, whereas E8 (R1) discusses safety monitoring without delving into risk management. E6 (R3) highlights the role of Data Monitoring Committees in ensuring safety, while E8 (R1) emphasizes the importance of an independent data monitoring committee. Additionally, E6 (R3) offers some guidance on reporting results, while E8 (R1) provides more detailed instructions on reporting clinical study results.
Overall, the release of the E6 (R3) guidelines signifies a significant development in clinical trial guidance, promoting a more dynamic and risk-based approach. The E8 (R1) guidelines complement the E6 (R3) guidelines by offering specific information on study design and reporting, showcasing how these two guidelines can work together to shape the future of clinical trials.
References and Further Reading
[1] Dombeck C, Swezey T, Forrest A, Tenaerts P, Corneli A. Stakeholders’ views on the most and least helpful aspects of the ICH E6 GCP guideline and their aspirations for the revision of ICH E6 (R2). Contemporary Clinical Trials Communications. 2022 Oct 1;29:100983.
[2] ICH. Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6(R2). International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). 2016
[3] ICH. ICH Harmonised Guideline: Good Clinical Practice (GCP) E6 (R3). International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). 2023
[4] ICH. ICH Harmonised Guideline: General Considerations for Clinical Studies E8 (R1). International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). 2021
ICH. Final Concept Paper: ICH E6(R3) Guideline for Good Clinical Practice Annex-2 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). 2023