The E6(R3) Guideline for Good Clinical Practice revises ICH E6(R2) and is expected to go live in 2025. To understand the potential impacts of this guideline on clinical research, Outsourcing-Pharma spoke with TransCelerate BioPharma Inc. member Madeleine Whitehead, RBQM Product and People Lead at Roche, and ACRO Forum member Nicole Stansbury, senior vice president of Global Clinical Operations at Premier Research.
Can you provide an overview of the ICH E6(R3) guideline and its significance in the landscape of clinical research?
Certainly! The ICH E6(R3) draft guideline represents a pivotal update in Good Clinical Practice (GCP) standards. GCP sets foundational guidelines to help ensure clinical trials are conducted in ways that prioritize safety, integrity, and reliability. This revision, while building on key E6(R2) themes, establishes a more flexible and collaborative framework. This framework, in turn, will hopefully facilitate the adoption of the guideline and give it more durability in the dynamic drug development landscape.
The revision also supports continua.l innovation by reinforcing “risk-proportionate” and quality-first approaches. It’s crucial to note that E6(R3) is designed to be a resource for the global clinical trial community, not just those operating in the US.
How does this latest revision differ from E6(R2), and what are some of the most important updates or additions in the revision?
E6(R3) acknowledges that certain aspects of E6(R2) are unnecessarily rigid and challenging to implement. In fact, the industry has perceived some of E6(R2)’s more prescriptive requirements as a regulatory demand to achieve “perfection.”
In comparison, E6(R3) tries to remove undue burdens and complexity and move toward more dynamic, agile, and flexible clinical trial processes. It emphasizes risk-proportionate approaches to quality management, which marks a significant shift.
By leveraging a risk-based quality management (RBQM) framework, E6(R3) shows that regulators are not seeking perfection. Nor do they want the industry to lose sight of the forest for the trees. Instead, E6(R3) urges stakeholders to eschew “check-box” processes in favor of concentrating on the activities and data that are most impactful to patient safety and study outcomes. It is a sizable adjustment in how all stakeholders are expected to think about clinical trials.
Another hallmark addition to E6(R3) is a comprehensive section dedicated to data governance. This section introduces sustainability measures to address the swiftly evolving technology and abundance of data now common in clinical trials.
Are there any specific changes that you believe will have a significant impact on the conduct of clinical trials?
E6(R3)’s focus on RBQM will affect many aspects of the clinical trial process. However, two noteworthy examples are the new concepts of 'Acceptable Ranges' and 'harms/ hazards':
Acceptable Ranges is a more flexible—yet no less rigorous—expansion of E6(R2)’s 'Quality Tolerance Limits' (QTLs). It permits readjustments within broader ranges of control measures rather than demanding accountability each time a trial strays outside of narrow, predefined QTLs.
'Error(s)' are now 'harms/hazards.' This subtle yet meaningful change in wording recognizes that all errors are not equally impactful. Although all errors still must be accounted for, E6(R3) allows us to prioritize our time and resources on those errors that rise to the level of causing “harms/hazards” to patient safety or data quality. It is another example of E6(R3) adopting a risk-proportionate mindset.
What are some of the potential benefits that stakeholders can expect to derive from the implementation of the ICH E6(R3) guideline?
E6(R3) truly is “the thinking person’s GCP,” which means we will all shoulder more responsibility for critically considering each study’s potential risks and protecting what matters most. However, in exchange, it also gives us much greater flexibility and reduces superfluous constraints. In that way, it should be easier to adopt than E6(R2). It sets the stage for faster decision-making capabilities and greater collaboration among stakeholders.
Even better, perhaps the biggest potential benefits of E6(R3) will come from its ability to cultivate more innovation, efficiency, and patient-centricity. The RBQM construct should enable more agility throughout the drug development lifecycle and make the guideline more adaptable as the industry evolves. Moreover, we expect this new framework to help lessen the burden on sites and improve the patient experience.
What are some of the key areas where the ICH E6(R3) guideline presents opportunities for innovation and improvement in clinical research practices?
The guideline spotlights several areas ripe for innovation and improvement. These include enhanced flexibility in trial design, greater integration of data collection and management technologies, faster decision-making, and further emphasis on patient engagement. Much of this is due to the strategic shift to RBQM, which encourages more tailored risk assessment and mitigation plans and empowers stakeholders to utilize resources more effectively, concentrating efforts on areas with the greatest impact on patients and outcomes.
How can sponsors and CROs leverage these opportunities to enhance the quality and efficiency of clinical trials?
Sponsors and CROs can start by reevaluating their existing processes and identifying areas where flexibility and risk-based strategies could be implemented. E6(R3) may also enable more adaptive and responsive trial designs, including decentralized trials, remote monitoring, and other tech-enhanced modalities. Leveraging these opportunities could potentially improve patient engagement and reduce the overall time and cost of bringing new therapies to market.
Furthermore, by advocating for even greater collaboration and patient-centricity, E6(R3) could help foster a more inclusive research environment that results in better patient recruitment and retention, as well as richer study data. Collectively, such efforts could enhance the quality and efficiency of clinical trials, ultimately improving the speed and quality of the drug development process.
What challenges might stakeholders face as they try to implement and comply with the ICH E6(R3) guideline—particularly in terms of resource allocation, training, and process adaptation?
Shifting to an RBQM mindset could certainly create some challenges for stakeholders. It’s not simple. It requires every stakeholder, at every step, to stop and think critically about how to protect what matters most—patient safety and study outcomes.
Considering this, understanding and applying the revised principles will likely involve a learning curve. Practically speaking, sponsors and CROs will need to align their operational and management practices with risk-based approaches. Re-evaluating existing risk management strategies and ensuring they support the principles of RBQM, Acceptable Ranges, etc., will require thoughtful planning and execution.
All stakeholders, including external partners and vendors, will need to be adequately trained on E6(R3). Therefore, another challenge to implementation may be the time and resource investment necessary to educate stakeholders and align processes. Ongoing support and updates may be needed as the guideline evolves.
How can sponsors and CROs effectively address these challenges to ensure smooth implementation, widespread adoption, and compliance with the updated guidelines within their organizations?
Sponsors and CROs can take a proactive stance toward implementation and compliance. Start now! Consider ways to move toward more risk-proportionate models. This could include conducting a thorough gap analysis to identify areas within current processes that don’t align with RBQM, and then developing a strategic plan to simplify processes and address the gaps.
Nurturing a culture of collaboration and critical thinking will also be essential to adoption and compliance. Sponsors and CROs will want to reevaluate how to strike the appropriate balance between flexibility and agility on the one hand, and patient safety and trial integrity on the other. But no one organization needs to go it alone. E6(R3) encourages sponsors, CROs, sites, patients, and other stakeholders to embrace opportunities to work together to design trials effectively, define critical quality factors, identify and mitigate risks, etc. By doing so, sponsors and CROs are more likely to smooth the implementation and adoption of E6(R3), as well as capitalize on the opportunities it presents.
Looking ahead, how do you envision the future of clinical research evolving considering the ICH E6(R3) guideline and other emerging trends or developments?
Good question! Appreciating how E6(R3) fits within the larger industry jigsaw puzzle is important. For example, it dovetails nicely with other standards like ICH E8(R1), which revises the General Considerations for Clinical Studies. E6(R3) and E8(R1) complement each other and help ensure that clinical trials can be planned and executed using the same core principles.
We can’t overlook how E6(R3) fits into the greater technology and data picture, either. Studies now routinely generate around three million to six million data points, and technological advances will only increase the volume and complexity involved. Can we really expect humans to find every error among six million data points? Of course not! We must be able to rely on technology to make clinical trial processes more accurate and efficient. So, E6(R3) tries to set a foundation that enables us to harness the benefits of technology as it evolves while preserving scientific rigor. Overall, the hope is that the flexibility and agility built into
E6(R3) will make it easier for the industry to embrace current and future innovations.
In conclusion, what key messages or advice would you like to leave our audience with regarding the ICH E6(R3) guideline and its implications for clinical research?
First, we’d like people to understand that RBQM isn’t theoretical. It’s what sustained the swift development of COVID-19 vaccines, so we know that it works. Therefore, there’s little doubt that E6(R3)’s emphasis on RBQM, data governance, and collaboration will help provide a solid foundation for future improvements and innovations.
Still, to successfully navigate the transition to E6(R3), all stakeholders will need to evaluate their current processes. It is a terrific opportunity to eliminate unnecessary complexity and focus on what matters most. It will be essential to create clear pathways for oversight and figure out how to take a risk-proportionate approach to identifying, reporting, and remediating any issues that arise.
We’re not suggesting that the new guideline will be easy to get used to; some concepts may be a significant departure from the environment many stakeholders currently work within. Nevertheless, it’s tremendously exciting to consider how the RBQM philosophy embedded in E6(R3) will help ease, speed, and strengthen drug development in the future.
