Contributed commentary by Karen Harvey and Michelle Webb, WCG

July 3, 2025 | In the intricate tapestry of clinical trials, collaboration ensures quality and streamlines processes vital for advancing medical science and discovering new treatments. The recent update to the International Council of Harmonisation (ICH) E6(R3) guidance features collaboration as the invisible thread that is seamlessly woven throughout the key changes, even though the term itself is never explicitly mentioned. Over the past three decades, the ICH E6 guidance has provided a robust framework that upholds unified standards in clinical trials and remains one of the few ICH guidance frequently referenced in regulatory documents. While the recent updates to ICH E6(R3) may not be revolutionary, they introduce changes that enhance the ability to respond to rapid technological advancements, innovative trial designs, and more efficient approaches to conducting clinical trials. More significantly, this updated guidance strengthens the crucial role of collaboration among all stakeholders, including sponsors, investigators, and providers.  

Building Quality Together: Quality by Design (QbD) & Critical to Quality Factors 

ICH E6(R3) builds on the concepts outlined in ICH E8(R1), which highlights the need to design quality into clinical trials from the earliest stages and the identification of critical-to-quality factors to ensure participant safety and data reliability. ICH emphasizes that E6(R3) should not be leveraged independently, but rather in conjunction with other ICH guidance, further reinforcing the importance of collaboration. Strong collaboration is essential when multifunctional teams, both internal and external, come together to prospectively identify critical-to-quality factors, assess potential risks, and establish mitigation activities. The development of the protocol and the corresponding risk assessment must incorporate diverse perspectives including input from site staff, clinical operations, diversity experts, participants, and providers. The more diverse and greater expertise included, the higher likelihood of uncovering and addressing hidden risks. Ultimately, the goal is to create an operationally feasible trial that reduces the unnecessary burden on participants and investigators. This begins by using proactive multidisciplinary collaboration to build design quality from the start. 

Tailored Trials: Proportionality & Fit-For-Purpose Approaches 

Adopting proportionate and fit-for-purpose approaches in the design and conduct of clinical trials encourages sponsors and investigators to focus their resources on the most critical aspects of the trial. This strategy supports efficiency without compromising quality. Similarly, ICH recognizes that one size does not fit all, encouraging greater flexibility and innovation to adapt to the evolving landscape of clinical research. Tailoring procedures based on risk/benefit analysis highlights ICH E6(R3)’s flexibility in managing varying levels of participant risk from different trial types. This helps to mitigate unnecessary burden by allowing for more agile and adaptive practice in clinical research. Much like QbD, collaboration is intrinsic to successfully implementing proportionate and fit-for-purpose approaches. Stakeholders working together enable more accurate risk assessment and decision-making, ensuring all trial aspects are calibrated to their specific context, leading to more effective and patient-centric research.  

Creating a Quality Culture: The Power of Collaboration & Critical Thinking 

One notable change in the revision of ICH E6 is the explicit reference to “quality culture.” Establishing a successful quality culture acknowledges the value of soft skills within an organization, recognizing that effective communication, openness, and proactive critical thinking are crucial. ICH E6(R3) encourages an environment where individuals feel comfortable voicing both successes and concerns, where addressing issues in an open and proactive manner is the norm. Prioritizing transparency across key stakeholders promotes critical thinking and allows for the shift from a checkbox mentality to a more proportionate approach, ensuring balance between elevating quality and avoiding undue burden.  

Innovation Unleashed: Collaborative Approaches in Today’s Clinical Trials

Fostering an environment which welcomes innovations in trial design, technology, and operational approaches requires collaboration with all stakeholders. ICH E6(R3) Annex 2 has been drafted to encourage sponsors and investigators to embrace alternative types and approaches to clinical research, emphasizing ICH’s acceptance of new technologies to enhance trial efficiency and effectiveness. Moreover, the meticulous crafting of ICH E6(R3) ensures that no language impedes innovation. For instance, the guideline maintains media neutrality throughout, thereby eliminating any potential barriers. By promoting innovative trial designs and technological advancements, the guidance aims to enable the inclusion of a wider and more diverse population in clinical research. Ensuring clinical trials are more inclusive and reflective of diverse participant populations requires engagement from all stakeholders—sponsors, providers, and sites—ideally from the earliest stages. This is crucial, especially when exploring novel ways of working, so that participant and site burden remains a primary consideration. 

Collaborative Data Governance: A Unified Approach

The newly introduced section on data governance underscores the shared responsibility and collaboration opportunities for both investigators and sponsors in maintaining robust data governance frameworks. While data governance and data integrity have always been fundamental to clinical research, these concepts were previously included only within the sponsor section in ICH E6(R2). By elevating data governance to its own section and designating both investigators and sponsors as responsible parties, the guidance provides clearer expectations for the appropriate management of data integrity and computerized systems. Sponsors, providers, and sites will need to align on how to meet these standards to allow for accurate reporting, verification, and interpretation of clinical trial-related information.  

Collective Oversight

One of the most notable changes is the increased focus on oversight. Although proper oversight was always expected, the concept is now explicitly woven throughout the document. The new sponsor oversight section consolidates all expectations previously scattered in ICH E6(R2), offering greater clarity and shifting the perspective from the traditional focus on providers and investigators to a more comprehensive approach that covers all aspects of trial design and execution. Effective oversight requires close collaboration among all parties to ensure a balanced approach. 

Similarly, the responsibilities for investigator oversight have been significantly expanded. Historically, investigator oversight focused primarily on “trial site” activities, but R3 has replaced “trial site” with a more comprehensive definition that includes staff provided by other parties. For instance, the sponsor can assist the investigator in identifying service providers for activities that ultimately fall under the investigator’s oversight responsibility. As investigators adjust to these new expectations, there will likely be challenges during implementation. This broadened scope may explain why the 2024 Avoca Industry Survey results suggest that this increased responsibility could potentially increase the site burden. Strengthening partnerships, especially during the implementation phase, will enable each stakeholder to fulfill their own responsibilities while enhancing the overall oversight of the clinical trial.  

Threads of Unity: The Collaborative Future of Clinical Trials 

Collaboration emerges as the invisible thread intricately woven through the recent updates to ICH E6(R3), highlighting its vital role in advancing clinical trials. Although not explicitly mentioned, the essence of collaboration is ever-present, underpinning the guidance's key changes and ensuring that the principles of quality and efficiency are maintained in the evolving landscape of clinical research. As we move toward widespread implementation of ICH E6(R3), it is collaboration that is the crucial element to enable the successful navigation of the changes brought about by ICH E6(R3).  

The clinical research landscape is continuously evolving, and fostering strong long-term partnerships built on collaboration among all stakeholders will be crucial. This approach will allow us to balance quality without imposing unnecessary burden on stakeholders, most notably the participants. Ultimately, collaboration will continue to be the cornerstone for advancing the quality and efficiency of clinical trials in the future. 

Michelle Webb is Vice President, Avoca Quality Consortium, WCG. Michelle has more than 25 years of experience in the pharmaceutical, biotech, and CRO industries, as well as Academia. As the Vice President of Quality Solutions and Strategic Partnering, Michelle drives strategy for the Avoca Quality Consortium, focusing on building strong client relationships, guiding content creation, and expanding client knowledge of Avoca solutions. Prior to joining Avoca, Michelle held professional roles in diverse areas in pharmaceutical development including leadership roles in Quality Assurance and Quality Management Oversight. Michelle has also co-authored several scientific journal articles. She received her bachelor’s degree from McMaster University in Hamilton, Ontario. She can be reached at michelle.webb@wcgclinical.com.  

Karen Harvey is Senior Director, Avoca Quality Consortium, WCG. Karen has 25 years of experience in healthcare and in the clinical research industry. As the Senior Director of the Avoca Quality Consortium, Karen has a focus on building strong client relationships, content creation, and expanding client knowledge of Avoca solutions. Prior to joining Avoca, Karen’s previous professional roles included work as a Registered Nurse and then diverse roles within the clinical research industry at the site level and at CROs in Quality Assurance and Quality Management Oversight with focus on Sponsor/CRO oversight and strategic relationships. She can be reached at karen.harvey@wcgclinical.com.