ICH E6(R3) reinforces a proactive, risk-based approach to clinical trial quality, placing greater emphasis on Quality by Design (QbD), Critical to Quality (CtQ) factors, and structured risk management.
In this article, we provide a brief overview of the changes introduced in ICH E6(R3), focusing on the foundational principles of QbD, CtQ factors, and risk management.
Early January 2025, the International Conference of Harmonisation (ICH) Assembly approved the final version of ICH E6 revision 3. Following this finalization, regulatory agencies around the world have begun determining enforcement dates.
As of February 2026, the European Medicines Agency (EU), Swissmedic (Switzerland), and the HSA (Singapore) have begun enforcing ICH E6(R3), with other ICH participants expected to follow.
Compared to its previous version, ICH E6(R3) includes an overall structure change, containing fewer principles that have a broader impact. The revision promotes practical and flexible solutions with an increased focus on removing participant burden.
R3 also contains more considerations for technology and digital solutions as well as improved roles and responsibilities.
Perhaps most widely discussed, ICH E6(R3) includes a focus on quality by design and enhanced risk management.
Quality by Design is an approach that encourages proactively focusing on the data and processes that are most important to ensuring trial quality (“critical to quality factors”) in order to maximize the likelihood of the trial meeting its objectives.
QbD requires establishment of a process for the identification and review of critical to quality factors at the time of design and planning of the study and throughout its conduct, analysis, and reporting.
QbD is not new – in fact, ICH E6 R3 refers us to ICH E8 R1, “General Considerations for Clinical Studies,” (published in 2021) where QbD is outlined in more detail.
Critical to quality (CtQ) factors refer to the data and processes that are critical to ensuring trial quality and the risks that threaten the integrity of those factors. Ultimately, these factors can impact the reliability of trial results.
Common examples of CtQ factors might include:
Prior to trial initiation and throughout trial conduct, a sponsor must identify risks that have a meaningful impact on CtQ factors.
CtQ factors are identified by evaluating trial objectives, design elements, participant characteristics, and data criticality. Sponsors then apply a risk-based, proportionate approach to manage those factors through the trial lifecycle. In practice, this typically involves a collaborative risk assessment or operational review in addition to a framework that allows their continuous monitoring and management.
How is risk management defined in R3?
Risk management means continuously identifying, evaluating and controlling risks as well as regularly communicating and reviewing them. ICH E6(R3) requires reporting of major risks and their mitigations.
Ultimately, ICH E6(R3) formalizes a shift toward proactively designing quality into clinical trials.
PharPoint Research is a collaborative contract research organization (CRO) that helps sponsors meet study milestones. To learn more about our approach to quality – or to speak with a QA consultant about preparing for ICH E6(R3) – reach out to our team.
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