The International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines received a major facelift in a global effort to adapt to modern and post-pandemic changes in clinical trial design and conduct with the introduction of ICH E6(R3). ICH E6 is the blueprint for clinical trials, helping to ensure participant safety and data quality. It also specifies the processes needed for study conduct and documentation to comply with industry guidelines and regulatory requirements. In this piece, we dive deeper into these revisions and provide insight into how to prepare for ICH E6(R3) and the future of clinical trials.

The Need for Updated GCP Guidance

Prior to the COVID-19 pandemic, ICH recognized that the current guidelines weren’t fully designed to address the future of clinical trials, failing to consider factors such as emerging technologies, diversity of data sources, and innovative trial designs. But it was during the COVID-19 pandemic when many clinical research professionals – who were unprepared with little systematic training and had to quickly adapt to an innovative way of clinical trial conduct – experienced ethical challenges and major deviations, such as inadequate study oversight, missed important protocol deviations, lack of source documents, and inaccurate or incomplete collected data, all of which could have serious consequences for the protection of participants and the integrity of data. These occurrences and operational challenges prompted the updated guidance for GCP.

Today, there’s an urgent need for all clinical research professionals (CROs, Sponsors, Investigators, etc.) to develop competence in trial conduct procedures, recommended by updated GCP guidelines, to ensure compliance in the post-E6(R3) era and future clinical trial execution.

What is ICH?

The International Council for Harmonisation (ICH) is an international non-profit association and a legal entity under Swiss Law founded in 1990. The FDA, a founding member since 1990, has helped to encourage the implementation of all ICH guidelines by pharmaceutical regulatory authorities globally.

At the first ICH Steering Committee Meeting in the early 1990s, topics for harmonization were divided into three areas: Safety, Quality, and Efficacy. In the years to follow, the ICH would introduce and finalize other guiding principles, including E6 – Good Clinical Practice (1996) and E8 – Clinical Trial design (1997). In more recent years, ICH introduced two other key guidelines: E6(R2) – Risk-Based Approach to Quality Management (2018), and E8(R1) – Quality by Design (2022).

Draft Guidance for Good Clinical Practice E6(R3), a revised version of ICH E6(R2), along with ICH E8(R1) – Clinical Trial Design, have both been undergoing revisions as part of the GCP Renovation Initiative. The revised guidelines will interplay to support innovative clinical trial design, risk-based approaches to conduct and data quality, and more clear, flexible, and modern Good Clinical Practice principles in clinical trials.

ICH E6(R3) – What’s Changed?

ICH E6(R3) places a strong emphasis on risk and also emphasizes the importance of quality assurance throughout the clinical trial process. With ICH E6(R3), there are a few notable differences from R2. Those changes include:

• The Sponsor section saw a number of changes. R3 pushes for a proactive, forward-thinking approach to quality where it’s in the very fabric of trial design and operation. Principle 6, for example, takes the quality focus of R2 and builds on it with a quality-by-design approach, as seen in E8.
• The R2 Principles aren’t ‘deleted,’ but instead, they’ve been combined and moved into 11 new Principles of GCP (We look forward to addressing these 11 Principles in a future piece – stay tuned!). The two new principles to ICH E6(R3) are Risk Proportionality, focusing on the participants’ safety and reliability of results and considering the risks beyond those associated with standard medical care; and Roles and Responsibilities, clarifying the transfer of activities by the sponsor and delegation by the investigator to maintain appropriate oversight.
• The Glossary has been moved back and includes modifications to E6(R2) definitions and new additions, including:
  • The GCP Definition has been modified.
    • In E6(R2), GCP is a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.
    • In the E6(R3) GCP definition, the description of clinical trial processes and aspects to be assured is changed. GCP is a standard for the planning, initiating, performing, recording, oversight, evaluation, analysis, and reporting of clinical trials that provides assurance that the data and reported results are reliable and that the rights, safety, and well-being of trial participants are protected.
  • New terms added to the glossary include: assent, audit trail, data acquisition tool, metadata, Reference Safety Information, signature, and Suspected Unexpected Serious Adverse Reactions (SUSAR).
  • Subjects are now referred to as Trial Participants.
  • Clinical trial has been updated to any interventional investigation.
  • Source records, which replace source documents and data, are original documents or data (that include relevant metadata) or certified copies of the original documents or data, irrespective of the media used. This may include trial participants’ medical/health records/notes/charts; data provided/entered by trial participants (e.g., electronic patient-reported outcomes [ePROs]); health-care providers’ records from pharmacies, laboratories, and other facilities involved in the clinical trial; and data from automated instruments, such as wearables and sensors.
• Annexes have been introduced, making it easier to add information as new innovations emerge. R3 adds four new sections, including one on data governance, and for the first time, it mentions Assent for minors.
• Appendices were also added.

Key Takeaways for ICH E6(R3)

E6(R3) was drafted as a response to how modern clinical trials are operated today, taking into consideration the use of electronic systems, data, and documents; complex trials (e.g., personalized medicine); protecting patient safety and data integrity; and the rise of decentralized and pragmatic clinical trial elements.

As we think through ICH E6(R3) and the key takeaways for those in the clinical trials space, here are our quick thoughts to take into consideration as your organization transitions into the future of clinical trials:

• Cultural Shift. The shift to more flexible, risk-based approaches might be at odds with traditional, more rigid clinical trial structures. Changing organizational or professional cultures can be one of the most challenging aspects of this transition.
• Potential Resistance. Change often faces resistance. There may be stakeholders who are comfortable with older methodologies and might resist transitioning to the updated guidelines.
• Technology and Infrastructure. ICH E6(R3) emphasizes a more risk-based approach to monitoring; investment in new technologies or systems to effectively manage and assess risks may be needed.
• Implementation Effort. Existing processes and SOPs (Standard Operating Procedures) might need to be revised.

What Can You Do to Prepare for ICH E6(R3)

If you’re a clinical trial investigator, CRO, sponsor, or other key stakeholder in the design and execution of clinical trials, what should you be doing now to prepare for ICH E6(R3)?

1. Review Draft Guidance. It’s important to review the ICH E6(R3) draft guidance carefully and understand the key changes that have been made so that you know what action needs to be taken to prepare – particularly since the guidance is still under development.
2. Implement Change Management Initiatives. Begin to foster a culture of innovation, openness, and collaboration. You might ask yourself, “Where do we have siloed departments?” Think about ways to encourage cross-functional collaboration and information sharing to break down the so-called silos. It’s also important to get your leaders involved from the start; leading by example enables employees to experiment, take calculated risks, and embrace continuous learning to drive cultural change.
3. Plan Ahead. Whether implementing a quality-by-design approach, employing risk management, or even simply defining roles and responsibilities, you need to plan ahead. Consider your people, process, and technology: What gaps exist, and what are your steps to address them? Do you have a technology strategy roadmap in place? Is it time to bring an outside expert in for help?

If you work in clinical trials, it’s important to be familiar with ICH E6(R3) and to ensure that your work complies with the guidelines. This will help to protect the rights, safety, and well-being of trial participants, and to ensure that the results of your trial are credible and reliable. If you’re looking for further guidance on ICH E6(R3) – including how to get started with change management or establishing a roadmap – our team at Clarkston can help.