Authors: Frederic Blais, Jelena Pasimisina, Melissa Thomas
ICH E6(R3) provides greater clarity on proactively designing quality into clinical trials, identifying critical-to-quality (CtQ) issues and adopting risk-proportionate approaches. The industry has been encouraged to implement it in the spirit in which it was written, focusing on issues critical to patient safety and trial success.
So, what should you know about ICH E6(R3), and how does it impact Risk-Based Quality Management (RBQM)? Let’s discuss.
Why ICH E6(R3) Was Developed
ICH E6(R3) was officially adopted on January 6, 2025, following extensive industry consultation. The revision was needed to adapt to a rapidly evolving clinical trial ecosystem. While some in the industry perceived ICH E6(R2) as a “one-size-fits-all” approach, ICH E6(R3) incorporates lessons from innovative clinical trial designs and public health emergencies, such as pandemics. The Good Clinical Practice (GCP) guideline builds on concepts outlined in ICH E8(R1), including:
- Fostering a culture of quality
- Integrating quality considerations early in clinical trial and drug planning
- Identifying factors that are critical to trial quality
- Engaging interested parties
- Using a proportionate risk-based approach
Structural Improvements in ICH E6(R3) for Readability & Clarity
The updated structure of ICH E6(R3) is designed to improve clarity and readability. It’s organized into overarching principles, two annexes (with Annex 2 still under public review), and several appendices. Unlike ICH E6(R2), the glossary has been moved to the end. The use of annexes also makes it easier to implement updates more efficiently in the future.
The eleven principles in ICH E6(R3) are designed to stay relevant as technology, methodologies, and trial designs evolve. They include newly introduced principles and restructured versions from ICH E6(R2). For example, Principle 1—focused on ethical considerations in trial design and conduct—consolidates several principles from ICH E6(R2) to emphasize the protection of participants’ rights, safety, and well-being.
New additions to the ICH E6(R3) principles include Principles 7 and 10. Principle 7 reinforces that risk control should be proportionate, aiming to minimize unnecessary burden on both participants and investigators. It promotes fit-for-purpose approaches that align with the importance of the data being collected and the level of risk to participants. Principle 10 emphasizes that roles and responsibilities in clinical trials must be clearly defined and properly documented. This includes the sponsor’s obligation to maintain appropriate oversight, even when services are delegated to external providers.
ICH E6(R3) enhances clarity by aligning its terminology with previous ICH guidance. For example, unlike ICH E6(R2), the updated guideline aligns with ICH E8(R1) on CtQ factors. The notion of monitoring has also been clarified. The concept of monitoring has also been clarified in ICH E6(R3), expanding beyond traditional on-site monitoring to include centralized monitoring. The guideline now features dedicated subsections for each approach: 3.11.4.1 Investigator Site Monitoring and 3.11.4.2 Centralized Monitoring.
ICH E6(R3) Annex 1: Key Updates on Quality, Risk & Data Governance
The annexes are intended to expand on each of the eleven principles by providing specific guidance tailored to different types of clinical trials.
In ICH E6(R3), key topics such as quality management, safety, and data and reporting—which were previously dispersed throughout ICH E6(R2)—have been reorganized and clarified within Annex 1. Reflecting industry feedback, Annex 1 3.10.1.3 Risk Control acknowledges Quality Tolerance Limits (QTLs) as a tool to define pre-specified acceptable ranges and support the control of risks to CtQ factors.
One of the most significant updates is the introduction of Annex 1 4. Data Governance – Investigator and Sponsor. This section provides guidance for responsible parties on managing key processes throughout the entire data life cycle. It emphasizes that these processes should be proportionate to the criticality of the data and must be appropriately documented.
ICH E6(R3) Hones the Focus on Data Quality & Reliability
The updated guidance emphasizes the quality of clinical results, moving the focus from data integrity to data reliability. Data reliability refers to the consistency and dependability of data. It ensures that data can be trusted to provide the same results under consistent conditions. This encourages proactive approaches to build quality into trial design.
Principle 9.2 states that systems and processes used to ensure data quality should be fit for purpose, capture the data required by the protocol, and be implemented to reflect both the risks to participants and the importance of the data collected.
It’s important not to view ICH E6(R3) in isolation. For example, Principle 6 emphasizes that quality should be embedded in the scientific and operational design and conduct of clinical trials. This includes applying Quality-by-Design (QbD) principles to focus on CtQ factors, identify risks that could impact those factors, and safeguard the reliability of trial results. This approach aligns closely with the guidance provided in ICH E8(R1).
RBQM in Practice: The Five Core Elements for Success
ICH E6(R3) ushers in a new RBQM era. It re-emphasizes the need for proportionate risk-based approaches and QbD, shifts the focus from data integrity to data reliability, and encourages critical thinking. There are five key elements to an effective RBQM strategy:
- Risk Identification: Identify which trial factors are CtQ.
- Risk Evaluation: Assess the likelihood, potential impact, and detectability of each risk.
- Risk Control: Develop mitigation strategies, with ongoing updates as needed.
- Risk Communication: Ensure transparent and timely reporting across all stakeholders.
- Risk Review: Continuously monitor, evaluate, and adapt risk strategies throughout the trial.
CluePoints offers a comprehensive suite of tools to support the effective implementation of an RBQM strategy aligned with ICH E6(R3). At the core is our Central Monitoring Platform (CMP), which drives risk-based oversight across trials. The Site Profile & Oversight Tool (SPOT) builds on CMP by delivering targeted, site-specific actions. Additional solutions—including Intelligent Medical Coding (IMC), Medical & Safety Review (MSR), and Intelligent Query Detection (IQD)—further streamline and unify data review. Backed by deep consultative expertise, CluePoints helps you leverage technology to transform data into smarter decisions and stronger outcomes in clinical development.
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