The ICH E6(R3) Guideline: A Major Update to Good Clinical Practice

As anticipated, the International Council for Harmonization (ICH) published the Good Clinical Practice (GCP) guideline E6(R3) Principles and Annex 1 on January 6, 2025. While ICH E6(R3) was still in the development phase, the FDA released a draft guidance in May 2023 in the form of the draft ICH E6(R3).  No word yet on whether FDA will issue guidance endorsing the final ICH E6(R3). The European Medicines Agency (EMA) has adopted  E6(R3) Principles and Annex 1 to take effect on July 23, 2025, and other ICH member nations and regions are still in the process of adopting E6(R3). Meanwhile, Annex 2, which provides guidance on pragmatic and decentralized clinical trials as well as trials incorporating real-world data, is expected to be finalized by ICH later in 2025.

This Revision 3 has been a long-awaited update and modernizes clinical trial conduct by  integrating evolving technologies and emphasizing a Quality by Design framework along with Risk Proportionality. E6(R3) specifically acknowledges the rise of innovative trial designs such as adaptive and decentralized methods, while also encouraging the use of electronic informed consent and remote monitoring. The guideline expands its focus on data governance and clearly defines the roles and responsibilities of sponsors, investigators, and service providers.  Ultimately, the guideline encourages a risk-based and proportionate approach to clinical trials that prioritizes the safety and rights of study participants while ensuring robust data quality.  Below, we explore some of the key themes seen in the changes.

Quality by Design

One of the most significant shifts in E6(R3) is its endorsement of a Quality by Design approach, requiring sponsors to proactively identify and mitigate risks throughout the trial lifecycle. This aligns with the broader trend toward risk-based monitoring and oversight extending risk-based principles to trial planning, design, conduct, monitoring, and reporting.

Risk Proportionality

A new Risk Proportionality section has been added under Principles, emphasizing that “[c]linical trial processes, measures, and approaches should be implemented in a way that… avoids unnecessary burden on participants and investigators.”

More Varied Clinical Trial Designs

To address a “one-size-fits-all” approach to clinical trials, E6(R3) expanded the approach to trial design to allow for more varied trial designs including adaptive designs and recognition of technological advances in trial design and conduct such as remote monitoring.

Clarification of Roles and Responsibilities

The Roles & Responsibilities section was added to provide clearer expectations for all trial stakeholders. Notably, sponsor oversight and accountability is enhanced with investigators required to be qualified through education, training, and experience and they must demonstrate sufficient resources and facilities to properly conduct the trial, reinforcing ethical standards and patient protections through strengthened oversight for the clinical trial and documentation.

Patient Safety

Annex 1 also includes more detailed sections outlining  the responsibilities and functions of the  Institutional Review Board/Independent Ethics Committee (IRB/IEC), sponsor and investigator with an emphasis on the rights and safety of trial participants.

Focus on Data Integrity

The Data Governance section of Annex 1 provides comprehensive guidance for investigators and sponsors on managing data integrity, traceability, and security throughout the clinical trial lifecycle recognizing the increasing complexities and importance of data security. It emphasizes that “the quality and amount of the information generated in a clinical trial should be sufficient to address trial objectives” and emphasizes that systems and processes must be designed and implemented in a way that is proportionate to the risks to participants and the reliability of trial results. Key processes include ensuring the protection of trial participants’ data confidentiality, managing computerized systems appropriately, safeguarding critical trial elements (such as randomization and blinding), and supporting key decision-making steps like data finalization and unblinding. Additionally, the guidelines require robust procedures covering the entire data life cycle—from data capture, with appropriate metadata and audit trails, to data correction, transfer, and eventual finalization for analysis.

Implications for Future of Clinical Research

R3 represents an important evolution in GCP, shifting away from a prescriptive model toward a more flexible, risk-based approach. By integrating modern trial methodologies and technologies, it provides a framework for conducting clinical research more efficiently while maintaining the highest standards of ethics, data integrity, and patient safety.

As stakeholders begin implementing R3, many questions remain regarding its practical application. How regulators will interpret and enforce its provisions may not become clear for some time. Until then, sponsors and investigators should carefully review their trial protocols, monitoring strategies, and data management systems to align with this new landscape and take advantage of the new approaches.