U.S. FDA's Adoption of ICH E6(R3) Good Clinical Practice: Key Takeaways for Sponsors and Investigators

The U.S. Food and Drug Administration (FDA) has officially adopted the International Council for Harmonisation (ICH) E6(R3) Good Clinical Practice (GCP) Guidance¹. This long-awaited revision reflects the most significant modernization of GCP over the past three decades. For sponsors, investigators, and other clinical trial stakeholders, E6(R3) introduces a comprehensive, risk-based framework that emphasizes trial quality, participant protection, and data integrity in a rapidly evolving technological and scientific environment.

A Modernized GCP Framework

 First adopted in 1996, the original ICH E6 provided the foundation for global GCP standards. The new ICH E6(R3)2², endorsed in January 2025, integrates lessons from decades of clinical research experience and responds to innovations such as decentralized clinical trials, digital health technologies, and data-driven oversight models using a risk-based approach. At its core, E6(R3) continues to safeguard the rights, safety, and well-being of participants while ensuring reliable results for regulatory decision making. The updated guidance expands its scope by

• promoting quality by design, requiring sponsors to identify and mitigate risks to trial quality from the earliest stages

• encouraging flexible, proportionate oversight, tailoring trial processes to participant risk and data criticality

• incorporating technological advances, including wearables, remote monitoring, and computerized systems, into trial governance

• strengthening data integrity and transparency, with detailed expectations for metadata, audit trails, and secure record retention

Key Principles for Industry

 E6(R3) establishes a series of interdependent principles that must guide every clinical trial. Notably:

• Ethics and Informed Consent: Clinical trials must align with the Declaration of Helsinki. Informed consent processes must be clear, concise, and adaptable to remote or electronic formats while safeguarding voluntariness and comprehension.

• Risk-Based Design and Conduct: Sponsors must proactively identify “critical-to-quality” factors and implement proportionate controls to protect participants and ensure reliable outcomes.

• Oversight and Accountability: While sponsors may delegate activities to contract research organizations and service providers, ultimate responsibility for trial conduct remains with the sponsor. Clear agreements and robust oversight are essential.

• Data Governance: Comprehensive standards are outlined for managing data across its lifecycle, from capture to archiving, with explicit requirements for computerized systems validation, security, and user accountability.

Practical Implications for Sponsors and Investigators

 From a compliance perspective, E6(R3) imposes heightened expectations in several areas:

• Documentation and Records: Sponsors and investigators must ensure that “essential records” including and not limited to informed consent, source records, case report forms, monitoring reports, serious adverse event reports, and data management documentation are readily available for regulatory inspection.

• Use of Technology: Digital platforms for data capture and remote monitoring must undergo rigorous validation and security checks (i.e., access controls, traceability). Cybersecurity and data privacy will be under increasing scrutiny.

• Global Harmonization: By aligning standards across ICH member countries, E6(R3) facilitates multinational trials and requires sponsors to manage complex jurisdictional requirements consistently.

• Participant Engagement: Incorporating patient and community perspectives in trial design is encouraged to improve feasibility, inclusivity, and the real-world relevance of results.

Sidley’s Perspective

For clients, the adoption of E6(R3) represents both opportunity and challenge. It provides a harmonized framework that can streamline global trial operations but also demands significant investment in compliance systems, training, and risk management protocols. Early alignment with E6(R3) principles will be critical, particularly as regulators begin to integrate these standards into enforcement and inspection activities.

Sidley Austin is closely monitoring FDA’s implementation and stands ready to advise on compliance strategies, risk assessments, and documentation frameworks to ensure clinical trial readiness. Our multidisciplinary team spanning FDA regulatory, data privacy, and international GCP compliance is uniquely positioned to help clients navigate this new era of clinical trial governance.

ICH E6(R3) is a technical update and a paradigm shift in how clinical trials are designed, conducted, and overseen. By embedding quality, ethics, and data integrity into every stage of the trial lifecycle, the guidance aims to accelerate innovation while maintaining the highest standards of participant protection. For industry stakeholders, now is the time to operationalize these principles and practices in line with FDA’s evolving expectations.