New approaches are required to comply with the International Council for Harmonization’s (ICH‘s) E6(R3) guideline for Good Clinical Practice (GCP), intended to drive a culture of quality. These include new ways of working, use of proportionate risk-based methods, and a culture that favors quality and rewards critical thinking.
“E6(R3) shifts us from checklists to critical thinking,” says Leslie Sam, BA, CSSBB, CQIA, President of Leslie Sam and Associates. Compared to the previous ICH E6(R2) guideline, E6(R3) adds new principles: proportionate risk and the need for clarity around roles and responsibilities.
E6(R3) discourages excessive burdens on participants and investigators
“The updated guideline requires clinical trial processes, measures, and approaches to be implemented in a way that is proportionate to the risks to participants and to the importance of the data collected,” states Sam. “At the same time, E6(R3) discourages excessive burdens on participants and investigators, saying that these should be avoided using operationally feasible trial processes. In addition, complex procedures should be minimized and excessive data collection avoided.”
E6(R3) also specifies that roles and responsibilities in clinical trials should be clear and documented appropriately, including within agreements. Under the updated guidance, the sponsor and principal investigator (PI) have distinct but complementary roles, retaining overall responsibility, including oversight of delegated tasks.
“Change management is key to the success of E6(R3) implementation,” according to Sam. “This goes beyond processes to stakeholder engagement, ensuring that teams have the right tools and enabling research professionals to adopt new ways of working. To drive sustainable change, organizations must embed quality by design (QbD) in protocol development and across site operations, overseeing service providers, making data governance actionable, and appropriately identifying ‘important’ protocol deviations.
“Proportionality is the thread across design, conduct, oversight, and documentation under E6(R3),” concludes Sam. “While QbD concepts are not new, they must be applied in an intentional manner. Readiness begins with understanding, but only action achieves real impact.”
Workforce education prepares clinical researchers to fulfill responsibilities
“As a manager responsible for workforce education and training, my focus for ICH E6(R3) has been ensuring that PIs understand their roles and responsibilities, the importance of adhering to ICH Good Clinical Practice, and U.S. Food and Drug Administration and institutional review board requirements,” says Emma Pinto, BS, MBA, Manager of Clinical Trial Education and Communications at Kaiser Permanente. “Through our PI education program, we provide resources that support current investigators and prepare new and prospective PIs to meet responsibilities described in E6(R3) Principles and Annex 1.
“In parallel, we strengthen research staff readiness via competency frameworks that clarify roles across the research lifecycle,” notes Pinto. “We also ensure that PIs and staff complete the updated Collaborative Institutional Training Initiative (CITI) Program’s GCP training aligned to E6(R3). Structured training and easy-to-find resources function as key risk controls within risk-based quality management, helping reduce variability, reinforce compliance, and enable proactive issue management.”
“From the perspective of onboarding new research staff, this means we aren’t just teaching new hires what the rules are, but also how to think critically about data integrity and participant safety from day one,” says Jennifer Tugwell, MSN, RN, ACRP-CP, Senior Manager of Clinical Trials Education, Training, and Policies for System Clinical Trials at City of Hope. “Instead of overwhelming new staff with every possible standard operating procedure (SOP), ICH E6(R3) encourages focusing on the factors that are critical to the study’s success. For example, rather than teaching ‘how to fill out a case report form,’ we teach ‘why this specific data point is vital to the primary endpoint.’”
Driving a more unified and quality-focused culture
“In the year since the release of E6(R3), I’ve witnessed firsthand how its introduction has sparked waves of change throughout our daily work in clinical research,” says Katherine Mary Marangio, Learning Program Consultant, EMEA Regional Lead, at Parexel Academy. “We’ve adapted to new requirements and have seen how incremental improvements in practice and mindset can trigger a chain reaction across teams, departments, and organizations. This is shaping a more unified and quality-focused culture. The far-reaching impact on GCP from ICH E6(R3) is evident in the way we’ve updated training, reviewed SOPs, and reimagined trial design. Each adjustment, whether big or small, has influenced others—prompting open discussions about risk, flexibility, and practical solutions tailored to each study. This interconnectedness means that progress in one area often inspires positive momentum elsewhere, reinforcing the importance of collaboration and shared learning.”
The Ripple Effect: Making ICH E6(R3) Real Across Clinical Research
Join Katherine, Emma, Leslie, and Jennifer at ACRP 2026 [April 24-27; Orlando, Fla.] as they discuss how critical thinking supports better choices, where risk-based approaches add the most value, and lessons learned in leading the cultural mindset shift needed for sustainable quality practices. View complete schedule.
Marangio explains that communication and ongoing education have become central to this process. “E6(R3) isn’t just for clinical teams; its influence extends to information technology, finance, human resources, and beyond. By sharing knowledge and encouraging questions, we’ve seen waves of understanding and engagement that strengthen our foundation for quality and efficiency.”
For those still navigating the transition, Marangio’s advice is to embrace this momentum. “Take small steps, use available resources, and focus on how changes in your role can influence the broader team and patient outcomes. There’s no single approach that fits all, and that’s part of the beauty of this evolution. The goal is to make the guideline work for your team and your patients, knowing that every action can spark further progress. Looking back, I’m proud of how these waves of change have grown into real improvements.”
Edited by Jill Dawson
