ICH GCP E6(R3) Compliance: 6 Key Changes for Clinical Trial Teams

Oct 22, 2025 | Pinar Bérénice Benét

The ICH GCP E6(R3) guideline took effect on 23 July, 2025, ushering in a new era of proactive, risk-based approaches with an unwavering focus on data quality. For sponsors who rely on outsourcing, this is more than a regulatory update. It underscores the industry’s move away from manual tools toward fit-for-purpose clinical trial oversight management systems and eTMF solutions.

Here are six key changes for fully and heavily outsourced sponsors to consider as they navigate R3:

1. Essential records vs. documents

R3 requires sponsors to capture and maintain “essential records,” rather than solely focusing on “essential documents.” Essential records encompass a broader range of information beyond formal documents, including electronic data, communication logs, and other process-related materials.

This expanded definition requires a more comprehensive approach to operational data management and oversight within an outsourced setting. Sponsors must ensure their contracts with CROs clearly define ownership, access, and retention procedures for all essential records throughout the trial lifecycle.

Sponsors also need their own clinical oversight systems, such as an eTMF and CTMS, to document and demonstrate continuous oversight processes. This includes study documentation and operational data.

2. Direct access to essential records

R3 mandates that sponsors and investigators have direct access to all essential records, regardless of format or location. Sponsors must be able to trace their end-to-end data lineage across all their systems – including CRO and vendor technology – and maintain real-time visibility of essential records like audit trails.

3. Focus on the process beyond final study documentation

R3 requires more than the final documented outcome of a process. Instead, sponsors are expected to capture their rationale, decision-making processes, and actions taken to manage risk throughout the trial.

4. Proactive quality by design

While R2 advocated for a risk-based approach to quality management, R3 promotes a more proactive “quality-by-design” philosophy. This enhanced approach integrates quality considerations into the trial’s design, execution, and oversight.

Sponsors working with CROs must foster partnerships that prioritize quality from the outset, ideally beginning with protocol design.

A final eTMF quality review at study closeout is no longer sufficient for inspection readiness. Instead, sponsors must embed quality oversight processes from the start, recording key decisions and actions within validated, audit-trailed systems.

5. Strengthened risk-based sponsor oversight

R3 increases the sponsor’s responsibility for ensuring quality throughout the trial, particularly when activities are outsourced. The guideline mandates clear documentation and oversight of all delegated activities. Sponsors will need to reinforce their oversight capabilities by:

• Investing in qualified sponsor personnel like sponsor oversight managers or site engagement managers
• Establishing robust risk management plans
• Implementing rigorous CRO and vendor oversight practices
• Investing in technology to execute the study risk management plan

Two critical principles that result from these activities are direct ownership and proportionality. Direct ownership mandates that data managers need direct access to data on demand without navigating through multiple groups, eliminating the game of telephone. Proportionality requires a risk-based approach, meaning the rigor of quality management, monitoring, documentation, and data oversight should be directly proportional to the risk and importance of the data (Critical-to-Quality or CtQ), eliminating unnecessary work and focusing controls where they are most impactful.

At the same time, sponsors must also invest in direct sponsor-site relationships to build trust, accelerate issue resolution, and maintain visibility. Although CROs can facilitate operational execution, they may not maintain staffing continuity or fully support investigator engagement. This is especially relevant for sponsors operating in Europe’s highly diverse small- and medium-sized biopharma landscape, where relationships and reputation can influence investigator retention and patient enrollment.

6. Expanded role-based training and training oversight requirements

R3 brings a new focus on training programs, requiring that sponsors ensure their personnel – as well as personnel at sites, CROs, and other functional service providers – are adequately trained on GCP compliance, trial protocols, and their specific responsibilities. The guideline also places new responsibilities on investigators to provide training oversight. Previously, investigators were responsible for their site’s oversight. Under R3, they must also maintain documentation of appropriate training, especially for tasks that fall outside of the standard of care, to:

• Ensure patient safety
• Improve data integrity
• Reduce principal investigator burden
• Speed trial execution

Investigators who manually track tasks, training, and training completion will be at greater risk of regulatory findings. This can jeopardize both their professional reputation and the sponsor’s compliance. It may even invalidate data collected at that site.

Sponsors can mitigate these risks by supporting sites with technology that streamlines training assignments and tracking in validated systems, providing real-time oversight. Embracing these principles and leveraging modern clinical trial technology will empower outsourced sponsors to meet evolving regulatory expectations with confidence.

Learn five ways to adapt your clinical trial oversight processes for ICH GCP E6(R3) compliance