An Overview of ICH E6(R3)

ICH E6 was the first harmonized guideline on Good Clinical Practice (GCP). The first iteration of this guidance, ICH E6(R1), was released in May 1996 by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ie, the ICH). ICH E6 is focused on ensuring the protection of study participants and the reliability of study results by covering topics that include investigator and sponsor responsibilities, conduct of Institutional Review Boards and Independent Ethics Committees, and essential documentation. While ICH E6 has been updated twice since it was originally released, the overall purpose of the guidance has not changed. Modifications have been made to address technological advancements in how studies are conducted and documented, to acknowledge the increasing complexity of clinical studies, and to incorporate new and evolving requirements in the industry.

The first update wasn’t made until 20 years after the initial release of ICH E6. This integrated addendum – ICH E6(R2) – was released in November 2016. Briefly, the updates in ICH E6(R2) incorporated: a risk-based monitoring approach; more proactive risk-based quality management; more details on Sponsor oversight; increased requirements for Investigators on oversight, documentation, and delegation; and more details on the identification and mitigation of protocol deviations.

Recently, the guidance was updated again, with release of the final version of ICH E6(R3) in January 2025.

Major changes were incorporated to:

1. Address new requirements and standards on study transparency,

2. Place a greater emphasis on flexibility and adaptability in study design, and

3. Acknowledge the importance of building quality into every step of the clinical trial process.

The first main section of the guidance, Principles of ICH GCP, is more detailed and better organized in the updated ICH E6(R3). The main (Level 1) principles are the key facets of GCP, with more details on each principle beneath (Level 2). Unlike previous versions of ICH E6, I feel like you can read this section of ICH E6(R3) and have a solid understanding of GCP.  

The section includes the following language in its introduction:

“[…] Careful consideration of factors relevant to ensuring trial quality is needed for each clinical trial.

The principles are intended to support efficient approaches to trial design and conduct. For example, digital health technologies, such as wearables and sensors, may expand the possible approaches to trial conduct. Such technologies can be incorporated into existing healthcare infrastructures and enable the use of a variety of relevant data sources in clinical trials. This will aid in keeping clinical trial conduct in line with advancing science and technological developments. The use of technology in the conduct of clinical trials should be adapted to fit the participant characteristics and the particular trial design. This guideline is intended to be media neutral to enable the use of different technologies.

The design and conduct of the clinical trial may be supported by obtaining the perspectives of interested parties, such as patients and their communities, patient advocacy groups and healthcare professionals. Their input can help to reduce unnecessary complexity, improve feasibility and increase the likelihood of meaningful trial outcomes. The use of innovative trial designs and technologies may enable the inclusion of a wider and more diverse population of participants and thereby broaden the applicability of trial outcomes.”

Some key additions within this section of ICH E6(R3) that were not included in or were substantially updated from prior versions of ICH E6 are shown below.

Quality

• (6) Quality should be built into the scientific and operational design and conduct of clinical trials.

  • (6.1) Quality of a clinical trial is considered in this guideline as fitness for purpose.

  • (6.2) Factors critical to the quality of the trial should be identified prospectively. These factors are attributes of a trial that are fundamental to the protection of participants, the reliability and interpretability of the trial results and the decisions made based on those trial results. Quality by design involves focusing on critical to quality factors of the trial in order to maximise the likelihood of the trial meeting its objectives.

  • (6.3) Strategies should be implemented to avoid, detect, address and prevent recurrence of serious noncompliance with GCP, the trial protocol and applicable regulatory requirements.

• (7.3) Risks to critical to quality factors should be managed proactively and adjusted when new or unanticipated issues arise once the trial has begun.

• (9) Clinical trials should generate reliable results.

  • (9.1) The quality and amount of the information generated in a clinical trial should be fit for purpose and sufficient to provide confidence in the trial’s results and support good decision making.

  • (9.2) Systems and processes that aid in data capture, management and analyses, as well as those that help ensure the quality of the information generated from the trial, should be fit for purpose, should capture the data required by the protocol and should be implemented in a way that is proportionate to the risks to participants and the importance of acquired data.

  • (9.3) Computerised systems used in clinical trials should be fit for purpose (e.g., through risk-based validation, if appropriate), and factors critical to their quality should be addressed in their design or adaptation for clinical trial purposes to ensure the integrity of relevant trial data.

Efficiency and Flexibility of Clinical Trials

• (1.4) When designing a clinical trial, the scientific goal and purpose should be carefully considered so as not to unnecessarily exclude particular participant populations. The participant selection process should be representative of the population groups that the investigational product is intended to benefit, once authorised, to allow for generalising the results across the broader population. Certain trials (e.g., early phase, proof of concept trials, bioequivalence studies) may not require such a heterogeneous population.

• (7) Clinical trial processes, measures and approaches should be implemented in a way that is proportionate to the risks to participants and to the importance of the data collected and that avoids unnecessary burden on participants and investigators.

  • (7.4) Trial processes should be operationally feasible and avoid unnecessary complexity, procedures and data collection. Trial processes should support the key trial objectives. The sponsor should not place unnecessary burden on participants and investigators.

Transparency

• (9.6) The transparency of clinical trials includes timely registration on publicly accessible and recognised databases and the public posting of clinical trial results. Communicating trial results to participants should be considered. Such communication should be objective and non-promotional.

These concepts are also weaved throughout other sections of the guidance.

In ICH E6(R2), the word “quality” is used 23 times in the Sponsor section alone and 43 times in the entire guidance. In IHC E6(R3), it is used 43 times just in the Sponsor section and 82 times in the entire guidance.

Reflecting the adaptability built into ICH E6(R3), the term “fit for purpose” is used 14 times. This term is used to refer to the information being collecting in a clinical trial, the systems/processes used for collecting such data, operational documentation, and study oversight. This term is not used at all in ICH E6(R2).

Another major change to ICH E6(R3) is the addition of an entirely new section (Section 4) titled “Data Governance – Investigators and Sponsor”. This section describes requirements for systems and processes for ensuring data integrity, traceability and security – again coming back to the concept of quality!

This section includes subsections on “Safeguard Blinding in Data Governance” (an important topic not addressed in prior versions of ICH E6), details on data handling throughout the entire data life cycle, and important details on security and validation of data.

Finally, ICH E6(R3) now uses the term “participant” instead of “subject”. While this change may not be substantive, it's still worth noting in my opinion, as the "patient" versus "subject" versus "participant" debate seems to never end. The use of "participant" has been used in every iteration of the TransCelerate protocol and CSR templates. Now that ICH E6 has adopted this term, I think we can no longer argue against "participant" being the most universally accepted and best term to use when describing individuals enrolled in clinical trials.

An update to ICH E6 was very much needed, and I'm happy to see improved organization of content within the document. In my opinion, the guidance is more thorough, yet also easier to read and comprehend. If you haven't gone through this updated guidance yet, check it out here. There are additional resources from ICH regarding the updates to ICH E6(R3) also at this location, including an explanatory video.

Upcoming virtual events discussing ICH E6(R3) are linked below:

• The Association of Clinical Research Professionals webinar: 13 Feb 2025

• Accelerating Clinical Trials in the EU (ACT EU) Live broadcast of a workshop on ICH E6(R3): 19 Feb 2025 and 20 Feb 2025

• TransCelerate Biopharma Inc. webinar - Navigating ICH E6(R3): Tools & Resources for Understanding Changes and Supporting Adoption: 04 Mar 2025

You can also find a ton of contract research organizations (CROs) with their own summaries and videos explaining ICH E6(R3) if you do a simple Google search.