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Good Clinical Practice E6 (R3) Guidance and Implementation

Feb 10, 2025 | Blog

Understanding the Updated ICH GCP E6 (R3) Guidance

Good Clinical Practice (GCP) is the internationally recognised standard for designing, conducting, recording, and reporting clinical trials. It ensures the protection of participants’ rights, safety, and well-being while maintaining the integrity and credibility of trial data. The International Council for Harmonisation (ICH) Good Clinical Practice E6 R3 guidance represents the latest revision to these standards, replacing E6 R2 with important updates aimed at improving the quality and efficiency of clinical research.

This article explores the key changes in the ICH GCP E6 (R3) guidance, the reasons behind these updates, and what they mean in practical terms for professionals working in clinical research.

Key Changes

1. Modernisation to Reflect Advances in Clinical Trials

Clinical trials have evolved significantly in recent years, with new methodologies such as decentralised trials (DCTs), remote monitoring, and digital data collection becoming more common. E6 R3 accommodates these modern approaches by offering greater flexibility in trial design while ensuring the core principles of GCP remain intact.

Unlike E6 R2, which did not explicitly address decentralised trials, E6 R3 provides guidance on using digital technologies such as electronic informed consent (eConsent) and Data Acquisition tools to remote data capture while maintaining data integrity and participant safety.

2. Risk-Based Quality Management

One of the major shifts in E6 R3 is the emphasis and additional guidance provided on risk-based approaches to trial quality management. While E6 R2 introduced the concept of risk-based monitoring, the new guidance expands this by encouraging sponsors to focus on critical to quality (CtQ) factors, ensuring that trial activities prioritise aspects most important to participant protection and data reliability.

3. Emphasis on Investigator Responsibilities

E6 R3 clarifies and strengthens the role of investigators, particularly regarding oversight of delegated tasks. While E6 R2 required investigators to ensure proper delegation and supervision, the new revision highlights the need for clear delegation plans and effective training of study personnel. It also aims to reduce some of the unnecessary burdens on the investigator by giving the sponsor more autonomy to contact the ethics committees directly and by only requiring study-specific training on aspects of the trial that are not part of the investigators’ teams standard of care.

A principal investigator (PI) delegating responsibility for informed consent must ensure that the delegated staff member is adequately trained and that documentation supports their competency in obtaining consent.

4. Enhanced Flexibility for Diverse Trial Designs

E6 R) acknowledges that a “one-size-fits-all” approach does not suit all clinical trials. It encourages proportionality in trial design and execution, meaning that trials with lower risk profiles may require different approaches compared to high-risk studies. E.g. A low-risk observational study may not require the same level of monitoring intensity as a first-in-human investigational medicinal product (IMP) trial.

5. Greater Focus on Participant Protection and Ethical Considerations

While GCP has always prioritised participant safety and well-being, E6 R3 reinforces ethics as a central pillar. It promotes participant-centred trial designs and increased transparency in informed consent procedures, ensuring that patients fully understand trial requirements and potential risks. Studies involving vulnerable populations, such as paediatric trials, require additional safeguards, which E6 R3 emphasises through enhanced requirements for ethical oversight and participant comprehension.

6. Discusses the concept of Reference Safety Information (RSI)

RSI is a cumulative list of Adverse Drug Reactions (ADRs) that are expected for the IP being administered to participants in a clinical trial. In E6 R3 they recommend RSI should be aligned with ICH E2F (Developmental safety update report). It also advises periodic review of the RSI and also that the RSI should be separate from other safety sections of the IB to avoid confusion.

Why Were These Changes Necessary?

The updates in E6 R3 were driven by several key factors, including:

  • Advances in technology: The increasing use of digital tools, electronic records, and decentralised methodologies needed clearer regulatory alignment.
  • A need for more efficient trials: Risk-based approaches reduce unnecessary burden, improving trial efficiency without compromising participant safety.
  • Greater global harmonisation: Regulatory bodies worldwide are striving for consistency in clinical trial expectations to support multinational research efforts.
  • Evolving ethical and participant considerations: Ensuring that clinical trials remain ethical and participant-centred was a major driver of these updates.

Practical Implications for Clinical Research Professionals

For those working in clinical research—whether as investigators, sponsors, CROs, or monitors—the E6 R3 guidance means adapting to a more risk-based, flexible, and technology-driven trial environment.

Some key points that you will need to be aware of are:

  • The need to adopt risk-based quality management: Focus on what truly impacts trial outcomes rather than applying uniform procedures to all studies.
  • How to leverage technology responsibly: If using remote monitoring or electronic consent, ensure compliance with regulatory expectations for validation and security.
  • The requirement to strengthen investigator oversight: Document delegation of responsibilities clearly and ensure proper training for all trial personnel.
  • Focus on enhancing participant engagement: Use improved informed consent processes to prioritise transparency and comprehension.

How can we help?

As the implementation of E6 R3 approaches, now is the time to update your knowledge and ensure compliance with the latest guidance. Our brand-new ICH GCP E6 R3 online training course is designed to provide you with everything you need to understand, apply, and implement these changes effectively. Our courses are:

  • Fully interactive and engaging – Real-world scenarios, case studies, and practical applications.
  • Designed for all learning styles – Videos, activities, and knowledge checks using some of the latest technology to reinforce key concepts.
  • Developed for flexible access – Take the course anytime, anywhere, on any device.
  • Created by clinical experts – Created by professionals with over 35 years of experience in clinical research.

Have a look at our course today using this link: Good Clinical Practice E6 R3 Online Course

References

  1. International Council for Harmonisation (ICH) – ICH E6(R3) Good Clinical Practice (Draft Version)
    • ICH Official Website: https://www.ich.org
    • Provides the official draft guidance and rationale for updates from E6(R2) to E6(R3).
  1. European Medicines Agency (EMA) – Good Clinical Practice and Clinical Trials Regulation
  1. U.S. Food & Drug Administration (FDA) – Guidance for Industry: E6(R2) Good Clinical Practice
    • FDA Website: https://www.fda.gov
    • Discusses how regulatory bodies apply GCP principles and the importance of compliance.
  1. Medicines and Healthcare products Regulatory Agency (MHRA) – GCP Compliance and Inspections
    • MHRA Website: https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
    • Covers GCP compliance expectations within the UK.
  1. TransCelerate BioPharma Inc. – Risk-Based Monitoring Methodology
  1. World Health Organization (WHO) – Handbook for Good Clinical Research Practice (GCP)
    • WHO Website: https://www.who.int
    • Offers global perspectives on GCP implementation and ethics in clinical trials.

These references provide reliable information on ICH GCP E6 R3 and its implementation across regulatory frameworks.

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