Navigating the new ICH E6 (R3): Key changes for sponsors

The final ICH E6 (R3) Good Clinical Practice (GCP) Guidelines were published on 6^th January 2025, updating the framework for clinical trials to reflect modern trial designs, technology, and data management practices. For trial sponsors, particularly those working with Contract Research Organisations (CROs), understanding these changes is essential for efficient, compliant trial conduct.

These new regulations for running clinical trials in the UK will be a legal requirement from 28^th April 2026, giving sponsors a defined but limited window to adapt trial design, oversight, and governance models.

What’s new in ICH E6 (R3)?

The guideline introduces several structural and content changes:

1. Proportionality & fit-for-purpose

ICH E6 (R3) places proportionality at the heart of trial conduct. Sponsors are expected to scale trial activities, documentation, and oversight according to the risks posed to participants and the importance of the data being collected.

This marks a clear shift away from a “one‑size‑fits‑all” approach. For example, whilst a first-in-human study involving a novel mechanism of action will require intensive safety oversight, a late-phase pragmatic study using an established therapy may justify a lighter monitoring and documentation approach. The guideline makes clear that applying the same level of oversight to all trials, regardless of risk, is no longer appropriate.

Importantly, ICH E6 (R3) clarifies that data does not need to be error-free. Instead, data must be sufficiently reliable to support trial conclusions. This change supports more focused data review and reduces the burden associated with resolving low-impact discrepancies that do not affect participant safety or data integrity.

2. Quality-by-design (QbD)

Quality-by-design (QbD) moves from being a recommended best practice to a clear expectation. Sponsors are required to identify critical-to-quality (CtQ) factors early in trial planning and to proactively manage risks that could affect participant safety or the reliability of results.

In practice, this means focusing attention on aspects such as eligibility criteria, primary endpoints, safety monitoring processes, and data collection methods that are essential to trial success. Rather than relying on retrospective quality checks, ICH E6 (R3) encourages sponsors to design protocols and operational processes that prevent issues before they occur.

This approach aligns closely with risk-based monitoring strategies and supports more efficient trial delivery, particularly in complex or innovative study designs.

3. Expanded data governance & computerised systems

ICH E6 (R3) introduces a dedicated section on data governance, reflecting the increasing complexity of data sources and systems used in modern trials. Sponsors are expected to maintain oversight of data integrity, traceability, and security across the entire trial lifecycle, including systems deployed by investigators or third-party vendors.

For example, where electronic data capture, wearable devices, or remote monitoring tools are used, sponsors must ensure that responsibilities for data control, access, and validation are clearly defined. The guideline also provides greater clarity on expectations for system validation, documentation, and user training, helping sponsors demonstrate that computerised systems are fit for purpose.

This expanded focus recognises that data quality is not solely a technical issue, but a governance responsibility that must be actively managed.

4. Modern trial designs

ICH E6 (R3) explicitly recognises trial designs that were previously addressed only indirectly, including decentralised, pragmatic, adaptive, and real-world evidence studies. This is a significant development for sponsors seeking to incorporate innovative approaches into their clinical programmes.

The guideline also introduces greater flexibility in safety reporting, including acceptance of selective safety reporting in later-stage trials, provided that participant safety remains appropriately protected. For example, in large phase III studies with well-characterised safety profiles, sponsors may justify a more targeted approach to adverse event reporting, rather than comprehensive collection of all events.

This flexibility supports efficiency while maintaining the core objective of safeguarding participants.

5. Participant-centric updates

Participant focus is strengthened throughout ICH E6 (R3). Sponsors are encouraged to support representative recruitment, inclusivity, and transparency, recognising that trial populations should better reflect the patients who will ultimately use the medicinal product.

The guideline also emphasises the importance of clear, concise informed consent. Electronic consent (eConsent) is formally recognised, alongside appropriate assent processes for minors. These updates aim to improve participant understanding and engagement, while maintaining ethical and regulatory standards.

6. Refined sponsor & investigator responsibilities

ICH E6 (R3) provides greater clarity around the respective responsibilities of sponsors and investigators, particularly in complex trial delivery models involving multiple service providers.

Sponsors are expected to ensure adequate resourcing, fit-for-purpose agreements with CROs and vendors, and proactive oversight of critical trial processes. Investigators, meanwhile, retain final responsibility for participant safety and data integrity at the site level and maintain decision-making authority over service providers operating under their responsibility.

This clarification supports accountability while recognising the practical realities of modern trial conduct.

7. Updated principles of GCP

The original 13 principles of GCP have been consolidated into 11 more detailed principles, reinforcing key themes that run throughout ICH E6 (R3). These include building quality into trials, proportionate trial conduct, reliable and transparent results, and clearly defined roles and responsibilities.

Rather than introducing new concepts, the updated principles provide greater clarity on how GCP should be applied in practice.

8. Trial transparency & reporting

ICH E6 (R3) also encourages greater transparency, including sharing trial results with participants and, where appropriate, providing information on treatment allocation in blinded studies once the trial is complete. This reflects growing expectations around participant engagement and trust in clinical research.

Implications for sponsors & CROs

For sponsors, these changes translate into practical considerations:

• Trial planning: Incorporate QbD and proportionality principles from the start. Engage stakeholders, including patients, during protocol development.
• Data management: Ensure robust systems for data integrity, traceability, and security, with defined responsibilities across sites and sponsors.
• Monitoring & oversight: Implement risk-based, centralised monitoring strategies. Classify deviations appropriately and escalate critical issues promptly.
• Participant safety & experience: Reduce unnecessary burdens, provide clear and concise information, and facilitate inclusion.
• Regulatory compliance: Adapt safety reporting and documentation processes to align with updated expectations, while leveraging flexibility for novel trial designs.

ICH E6 (R3) reflects the evolution of clinical trials into a more flexible, technology-enabled, and patient-focused landscape. Sponsors working with CROs must embrace quality by design, proportionality, and robust data governance to stay compliant and efficient. This update is not just a regulatory requirement, it’s a roadmap to safer, more reliable, and transparent trials.

About the author

Dr Lisa Campbell is director of regulatory strategy at Richmond Pharmacology, where she oversees early engagement with the MHRA, EMA, and FDA to align clinical trial designs with regulatory and market access requirements. With more than two decades of experience spanning both global pharmaceutical companies and CROs, Dr Campbell has a deep understanding of how clinical programmes must adapt across jurisdictions. She specialises in designing regulatory roadmaps that anticipate regional complexity, helping sponsors achieve approvals faster and with greater clarity.