ICH E6(R3) and the Future of Clinical Trials: A Guide for Biotech Sponsors

Published on: May 21st, 2025

In January 2025, the International Council for Harmonisation (ICH) released a major revision to its Good Clinical Practice (GCP) guidelines—ICH E6(R3) which is set to enter into force in the European Union on 23 July 2025. For biotech companies navigating complex clinical development pathways, these changes are not just regulatory—they’re strategic. E6(R3) reflects a shift toward flexibility, digital readiness, and participant-centered design, and its adoption will significantly affect how clinical trials are designed, executed, and overseen.

This post breaks down the key changes in E6(R3), what they mean for biotech sponsors, and how to prepare.

A Modular, Principles-Driven Framework

Unlike its predecessor, E6(R3) introduces a modular structure:

• 11 Core Principles that apply across all interventional trials, regardless of design
• Annex 1 for traditional trials, with updated guidance on oversight, data governance, and documentation
• Annex 2 (coming soon) for decentralized, adaptive, and real-world evidence trials

Why it matters: This framework enables sponsors to apply GCP in a way that is proportionate to trial risk and complexity, rather than relying on a one-size-fits-all model. It’s a recognition that clinical research has evolved—and regulation must, too.

Risk-Based Quality Management (RBQM) Is Now Central

ICH E6(R3) embeds RBQM across the trial lifecycle, moving beyond risk-based monitoring alone. Sponsors are expected to:

• Identify Critical to Quality (CtQ) factors early
• Design protocols that are fit-for-purpose
• Apply quality principles proactively, not reactively

Implications for biotech sponsors: For small teams with tight timelines, this means building quality into trial design from day one—not leaving it to CROs or post-study audits.

Clearer Oversight of Vendors and Partners

The guideline reinforces the responsibilities of sponsors and investigators, particularly around third-party oversight:

• Sponsors must retain ultimate accountability for trial conduct, even when functions are delegated to CROs
• Investigators are now expected to manage any service providers they engage, such as home health or eConsent vendors

Practical takeaway: Contracts, SOPs, and oversight models must reflect these clarified roles. Good documentation is no longer a best practice—it’s a regulatory expectation.

Data Governance: A Pillar of Clinical Compliance

One of the most important updates is a new focus on data governance in clinical trials. Sponsors and investigators must manage:

• End-to-end data lifecycle, from acquisition to archiving
• Computer system validation for all digital platforms
• Audit trails, metadata, and incident response protocols

Why it matters: As trials become more digital, data integrity and traceability are under increasing scrutiny. A failure in data governance can now trigger compliance risks just as serious as protocol deviations.

A Renewed Focus on Participants

ICH E6(R3) modernizes guidance on participant engagement:

• Informed consent is now viewed as a process—not just a form
• Guidance supports remote and digital interactions with participants
• Participant safety and dignity are emphasized throughout the trial

Implication: Biotech sponsors using decentralized models must ensure that ethics, communication, and oversight are adapted—not just digitized.

Essential Documents: From Checklist to Contextual

Appendix C replaces the static documentation lists of the past with a risk-based, context-driven approach:

• Documentation is aligned with trial purpose, format, and risk
• Supports electronic and decentralized trial models
• Encourages continuous documentation across the trial lifecycle

Key takeaway: This isn’t about keeping more documents—it’s about keeping the right ones, organized for modern audits and inspections.

Looking Ahead: Annex 2 and Non-Traditional Trials

Annex 2, expected in 2025–2026, will expand the GCP framework to include:

• Decentralized clinical trials (DCTs)
• Real-world data (RWD) and evidence (RWE)
• Platform, cluster-randomized, and adaptive designs

For biotech innovators already experimenting with these methods, Annex 2 will provide critical clarity.

Action Steps for Biotech Sponsors

To prepare for the transition from E6(R2) to E6(R3), biotech companies should:

• Conduct a GCP gap analysis across SOPs, quality systems, and training
• Update vendor oversight models to reflect clarified responsibilities
• Build or enhance data governance infrastructure
• Train internal teams on the principles and structure of E6(R3)
• Align protocols and trial designs with RBQM and QbD principles

ICH E6(R3) represents a fundamental update to global clinical trial regulations. It’s more than a regulatory update—it’s a modernization of how clinical trials are expected to operate in an increasingly digital and patient-centered world. For biotech sponsors, it offers an opportunity to modernize operations, improve quality, and align with evolving trial methodologies. While the transition requires strategic effort, early action will ensure readiness and compliance as regulatory expectations evolve.