Navigating the Transition from ICH E6(R2) to ICH E6(R3): Key Changes and Best Practices for Clinical Trial Sites

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 guideline for Good Clinical Practice (GCP) is the global standard for designing, conducting, recording, and reporting clinical trials involving human participants. It ensures the rights, safety, and well-being of trial participants while maintaining the integrity and credibility of clinical trial data [1]. The transition from ICH E6(R2) to ICH E6(R3) introduces significant updates to address the evolving landscape of clinical research, emphasizing flexibility, risk-based approaches, and the integration of digital technologies. This article explores the key changes in the final version of ICH E6(R3) and provides actionable insights for clinical trial sites to adapt effectively.

Overview of ICH E6(R2) and ICH E6(R3)

E6(R2) has been the cornerstone of GCP since its introduction in 2016, providing a robust framework for clinical trial conduct. It emphasized ethical principles, participant safety, and data integrity, ensuring that trials are conducted consistently across global regions. However, as clinical research has evolved—with the rise of decentralized trials, digital health technologies (DHTs), and participant-centric approaches—the limitations of E6(R2) have become apparent.

E6(R3) builds on this foundation, introducing a more flexible, risk-based, and technology-driven framework. Key updates include enhanced guidance on informed consent, investigational product management, quality management, and data integrity. These changes reflect broader trends in clinical research, such as the adoption of decentralized trial models, the use of electronic systems, and a focus on participant-centricity.

For example, while E6(R2) required extensive source data verification (SDV), E6(R3) promotes risk-based monitoring (RBM), allowing sites to focus resources on high-risk areas. This shift not only improves efficiency but also aligns with the growing complexity of modern trials [2].

Informed Consent: Modernizing Participant Engagement

E6(R3) introduces significant updates to the informed consent process, reflecting advancements in technology and ethical considerations. One of the most notable changes is the flexibility to use electronic consent (eConsent) and digital tools, such as video conferencing and interactive multimedia, to obtain consent [3]. This is particularly beneficial for decentralized trials, where participants may not be physically present at the trial site.

For instance, a participant in a rural area can now provide consent remotely using a secure eConsent platform, eliminating the need for travel. E6(R3) also emphasizes the importance of ensuring that consent materials are clear, concise, and tailored to the participant’s level of comprehension. This includes using multiple formats, such as text, images, and videos, to accommodate diverse needs.

In contrast, E6(R2) did not explicitly address the use of digital tools for consent, leaving some sites unprepared for the transition to decentralized models. E6(R3) emphasizes ongoing communication with participants, ensuring they are informed of any new information that could impact their willingness to continue in the trial [3].

If new information arises during the trial that may affect a participant’s willingness to continue (such as emerging safety concerns), the guideline mandates a re-consent process. Revised informed consent materials must be reviewed and approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) before use.

Investigational Product Management: Adapting to Decentralized Trials

The management of investigational product (IP) has undergone important updates in E6(R3). While E6(R2) focused on centralized handling and strict documentation, E6(R3) embraces decentralized trial models, where IP may be shipped directly to participants or managed through local pharmacies.

For example, in a decentralized trial for a chronic condition, participants can receive their medication at home, reducing the burden of frequent site visits. E6(R3) also encourages the use of digital tools, such as electronic patient-reported outcomes (ePRO) and blockchain, to enhance IP tracking and accountability [3].

In contrast, E6(R2) relied on manual or semi-automated systems for IP tracking, which could be time-consuming and prone to errors [4]. E6(R3) introduces a “fit-for-purpose” approach, allowing for flexibility based on trial design and risk level. This includes the use of electronic signatures and remote monitoring tools to simplify accountability in decentralized settings.

Quality Management: A Proactive, Risk-Based Approach

Quality management in E6(R3) shifts from a reactive to a proactive mindset, emphasizing risk-based approaches and continuous improvement. While E6(R2) introduced the concept of risk-based monitoring (RBM), it provided limited guidance on implementation. E6(R3) requires sponsors and sites to adopt a systematic, risk-based approach throughout the trial lifecycle.

For example, a site conducting a Phase III trial can use risk matrices to identify critical data and processes, focusing monitoring efforts on high-risk areas. E6(R3) also promotes the use of real-time data monitoring and analytics to detect issues early, enabling quicker resolution [3].

In contrast, E6(R2) often relied on periodic site visits and 100% SDV, which could delay issue identification [4]. E6(R3) also emphasizes the importance of root cause analysis and corrective actions, fostering a culture of continuous improvement.

Data Management: Ensuring Integrity in a Digital Age

Data management in E6(R3) reflects the growing reliance on digital technologies and the need for robust data integrity practices. While E6(R2) referenced the ALCOA principles (Attributable, Legible, Contemporaneous, Original, and Accurate), E6(R3) expands these to ALCOA+ (adding Complete, Consistent, Enduring, and Available) [4].

For example, a site using electronic data capture (EDC) systems must ensure that data is not only accurate but also complete and enduring. E6(R3) also mandates the use of audit trails to track changes to electronic records, ensuring transparency and accountability [3].

In contrast, E6(R2) did not provide detailed guidance on electronic systems, leaving some sites unprepared for the transition to digital record-keeping. E6(R3) also encourages the use of interoperable systems, enabling seamless data sharing across platforms [3].

Regulatory Impact & Compliance Considerations

The transition to E6(R3) has significant implications for regulatory compliance. Sites are encouraged to adapt to decentralized trial models, integrate digital tools, and implement risk-based approaches to remain compliant.

For example, a site conducting a hybrid trial must ensure that remote monitoring tools are validated and comply with regulatory standards, such as 21 CFR 11. E6(R3) also requires sites to maintain detailed training records and conduct internal audits to prepare for regulatory inspections [3].

In contrast, E6(R2) did not explicitly address the regulatory challenges of decentralized trials, leaving some sites struggling to adapt.

Best Practices for Adapting to ICH E6(R3)

To successfully adapt to E6(R3), sites should [5,6]:

• Conduct risk assessments and develop risk management plans.
• Integrate digital health technologies (DHTs) and ensure staff are trained on their use.
• Adopt ALCOA+ principles and transition to electronic systems for data management.
• Implement proactive quality management practices, such as early issue detection and root cause analysis.
• Prepare for regulatory inspections by conducting internal audits and mock inspections.

The Future of GCP Compliance

The transition from GCP E6(R2) to GCP E6(R3) is more than just a regulatory update; it is a leap into the future of clinical research. With its emphasis on flexibility, risk-based approaches, and digital innovation, E6(R3) is perfectly poised to address the complexities of modern trials while keeping participant safety and data integrity at the forefront. From streamlined informed consent processes to decentralized trial models and proactive quality management, the updates in E6(R3) empower clinical trial sites to operate more efficiently and effectively in an increasingly digital world.

As sites navigate this transition, the key lies in embracing change with a spirit of adaptability and curiosity. By integrating new technologies, adopting risk-based strategies, and fostering a culture of continuous improvement, clinical trial sites can not only meet the demands of E6(R3) but also set new standards for excellence in clinical research. After all, the future of clinical trials is not just about compliance; it is about innovation, collaboration, and, ultimately, better outcomes for participants.

References

1. European Medicines Agency (EMA). n.d. “ICH E6 Good Clinical Practice: Scientific Guideline.” Accessed March 1, 2025.

2. Bhatt, Arun. 2023. “The revamped Good Clinical Practice E6(R3) guideline: Profound changes in principles and practice!” Perspectives in Clinical Research 14(4):167-71.

3. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). 2025. “ICH Harmonised Guideline: Guideline for Good Clinical Practice E6(R3).” Accessed March 1, 2025.

4. U.S. Food and Drug Administration (FDA). 2023. “E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1).” Accessed March 1, 2025.

5. Sam, Leslie. 2025. “Embracing the Future: Reflections on the Release of ICH E6(R3).” The Association of Clinical Research Professionals (ACRP) Blog, January 17.

6. GCP Central. 2024. “Preparing for ICH GCP E6 (R3 Update: What Learners Need to Know).” Accessed March 1, 2025.