Guidance Breakdown: E6(R3) Good Clinical Practice (GCP) Guidance for Industry
The FDA’s adoption of ICH E6(R3) marks a major shift in GCP, moving from checklist compliance to risk-based, quality-by-design oversight.
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The FDA has just formally adopted the E6(R3) Good Clinical Practice (GCP) Guidance for Industry, the most substantial update to the global GCP framework since the E6(R2) addendum in 2016.
Finalized at Step 4 of the ICH process in January 2025, this new standard reshapes expectations for sponsors, investigators, and ethics committees in how clinical trials are designed, conducted, and overseen.
E6(R3) builds on the principles introduced in ICH E8(R1) and represents a clear shift: away from compliance-by-checklist and toward embedding quality into trial design from the start. It also modernizes GCP to account for digital technologies, decentralized elements, and broader participant inclusion, while reinforcing ethics and transparency as central pillars of clinical research.
We've distilled the key points below.
From “compliance” to quality by design
Where E6(R2) focused on adding oversight mechanisms, E6(R3) calls for a deeper integration of quality principles into trial planning itself.
As the guidance puts it:
“quality by design should be implemented to identify the factors…that are fundamental to the protection of participants, the reliability and interpretability of the trial results, and the decisions made based on those trial results”
This requires sponsors to prospectively identify “critical-to-quality” factors—such as protocol design elements, participant selection, blinding, or investigational product handling—and develop proportionate risk controls. Tolerance limits must be set in advance, with procedures in place to evaluate and address deviations that may point to systemic issues.
In other words, regulators are now asking sponsors to prove not only that monitoring and quality checks exist, but that trial design itself has been stress-tested against foreseeable risks.
An embrace of flexibility and technology
E6(R3) explicitly recognizes that trials no longer happen solely in traditional clinic settings. The guidance calls itself “media neutral,” opening the door for wearables, sensors, and electronic health records to be integrated when validated and fit for purpose.
Remote consent and digital modalities (text, images, video, phone/video visits) are permitted where appropriate, so long as the process ensures clear, comprehensible information and adequate understanding, with identity assurance per regulations.
Very importantly, the guidance stresses that new technologies must be adapted to participant characteristics and trial context—not the other way around. This obviously reflects the broader cultural shift: innovation is encouraged, but participant protection remains paramount.
A higher bar for transparency
The new principles strengthen expectations around public accountability.
Sponsors are reminded that essential records must be retained securely and made available for regulatory inspection, but E6(R3) goes further by requiring “timely registration on publicly accessible and recognized databases and the public posting of clinical trial results.”
The guidance also encourages sponsors to consider communicating results directly to participants in an “objective and nonpromotional” manner. This marks a pretty meaningful evolution in transparency—moving beyond data disclosure to active engagement with trial participants and the public.
Oversight (still) cannot be delegated
This point touches on one of the perennial problems we encounter in our own GCP audit work for clients across the clinical space: passing oversight responsibility that can’t be passed.
Both sponsors and investigators may delegate activities to CROs/service providers, but responsibility remains non-transferable. Roles must be documented in agreements, and the sponsor/investigator must maintain appropriate oversight of delegated activities. This extends to subcontractors, too!
Expanding data governance
One of the most notable updates in E6(R3) is the detailed expansion of data governance requirements. The guidance introduces a full “data life cycle” model, covering capture, metadata, corrections, transfers, retention, and destruction.
Sponsors and investigators are expected to validate computerized systems, secure user access, maintain tamper-proof audit trails, and plan for risks to blinding. Audit trails may not be disabled, and any unplanned unblinding must be documented and assessed for its impact on trial results.