The release of ICH E6(R3) in January 2025 marks the most significant evolution in Good Clinical Practice (GCP) guidelines in over a decade. More than a revision, E6(R3) marks a shift from traditional practices—making participant safety and data reliability not just priorities, but design drivers, and introducing risk-based proportionality as a foundational approach.
With global regulators including the FDA, EMA, and MHRA signaling alignment and implementation in 2025 [FDA, 2025; EMA, 2025; MHRA, 2025], sponsors must act now to align their strategies with the new expectations.
A Quick Refresher: Previous Revisions
The original GCP guideline, ICH E6(R1), was finalized in 1996 and first updated with E6(R2) in 2016 to reflect the growing use of technology and centralized monitoring. Now, E6(R3) represents a major evolution, reframing GCP through the lens of risk-based proportionality, quality by design, and fit-for-purpose oversight.
What’s New in E6(R3)—and Why It Matters
The original GCP guideline, ICH E6(R1), was finalized in 1996 and first updated with E6(R2) in 2016 to reflect the growing use of technology and centralized monitoring. Now, E6(R3) represents a major evolution. It preserves the principles outlined above while reframing them to reflect the realities of modern research—focusing on risk-based decision-making, fit-for-purpose design, and technology-enabled efficiency [ICH, 2025]. The goal is not more complexity, but smarter, leaner operations grounded in relevance and accountability.
Risk-Based Proportionality
- This principle drives the shift in how quality and safety are approached:
- Embed quality by design: Ensure participant protection and data integrity are embedded from the start of trial planning [ICH, 2025]
- Focus on trial-specific risks: Emphasize risks related to study participation—particularly those that go beyond routine clinical care [MHRA, 2025]
- Prioritize critical elements: Identify Critical-to-Quality (CtQ) factors and center controls around them [EMA, 2025]
- Use technology with intention: Apply tools like eConsent or remote monitoring when they enhance trial quality—not just for innovation’s sake [FDA, 2025].
Clear Roles and Responsibilities
- While sponsors and investigators can delegate activities, they cannot delegate accountability. E6(R3) emphasizes:
- Defined oversight structures: Sponsors must maintain appropriate control over CROs, vendors, and technology providers [ICH, 2025]
- Transparent delegation: Investigators and site staff must clearly document and manage task transfers
- Shared responsibility: Everyone involved must understand their obligations under the updated guidance.
What Pharma Sponsors Are Asking
As sponsors prepare for ICH E6(R3), a few common questions have emerged:
- Where do we start? Many pharma companies are unsure how to begin aligning with the new expectations, especially around trial design and quality systems. Our advice is to begin with a thorough review of your documentation, then once the gaps are identified, updates can be planned and implemented.
- What needs to change? Existing SOPs, oversight models/governance, and QMS frameworks are being reassessed for readiness and relevance. Sponsors must be prepared to review roles and responsibilities and how they interface with their vendors and partners.
- What training should we do? Teams need targeted, role-specific training to understand and implement the changes that matter most, and the responsibilities mapped to them.
- Are we ready for inspection? Once documentation and systems have been reviewed and updated, the next step is to prepare your people and sites by conducing mock inspections, so they are always ready for inspection.
E6(R3): A Reset—and an Opportunity
ICH E6(R3) is more than a regulatory update. It’s a strategic reset that challenges sponsors to design and manage trials with greater purpose, proportionality, and accountability. Those who act now will be better positioned to:
- Run leaner, smarter studies
- Strengthen regulatory and site partnerships
- Improve participant safety and data reliability
- Stay inspection-ready in a changing global landscape
Advarra’s GxP Consulting Services team can help you navigate the transition—assessing readiness, refining processes, and embedding quality where it matters most.
References:
- ICH Harmonised Guideline. Integrated Addendum to ICH E6(R1): Good Clinical Practice E6(R3). Final Version, January 6, 2025. https://database.ich.org/sites/default/files/ICH_E6%28R3%29_Step4_FinalGuideline_2025_0106.pdf
- U.S. Food & Drug Administration. FDA Statement on Adoption of ICH E6(R3). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e6r3-good-clinical-practice-gcp
- European Medicines Agency. Reflection Paper on GCP Modernization and E6(R3) Implementation. https://www.ema.europa.eu/en/documents/presentation/presentation-session-1-overview-ich-e6-renovation-peter-twomey_en.pdf
- MHRA UK. Regulatory Expectations for E6(R3) Rollout.
