ICH E6 (R3) is coming at a time when life science organizations are still struggling to adopt ICH E6 (R2). There’s no question that ICH E6 (R3) will impact all organizations engaged in clinical trials. The intent of the forthcoming guidance is to drive efficiencies by enabling the use of modern business methods and technologies. But should organizations wait until these guidelines are ratified to realize the intended benefits?

The recently released ICH E8 (R1), a precursor to this new guidance, provides the answer, specifically calling for establishing a culture that supports critical thinking and open dialogue about quality that goes beyond sole reliance on tools and checklists. ICH E6 (R3) discourages the use of the “standard” checklist approach that is the current practice, in favor of risk-based management approaches that focus the effort on what is truly needed to initialize studies.

On April 19, ICH released the first component E6 (R3) Draft Principles, which confirms that the E8 (R1) concepts will be applied to E6 (R3). The second component E6 (R3) Annex 1, will be released in draft by February 2022 and is currently scheduled to be ratified a year later. By the beginning of 2023, Annex 2 will follow, covering new trial designs, including decentralized clinical trials, artificial intelligence and machine learning. The Clinical Trials Transformation Initiative ICH E6 Guideline for Good Clinical Practice — Update on Progress meetings provide a forum to learn more about the status of these updates.

Applying critical thinking during study startup is pivotal to improving study conduct overall. Proactive planning is essential to identifying what is needed to mitigate risk, ensure regulatory compliance and audit-readiness, and to avoid serious budget and timeline overages. These issues can derail a study, resulting in costly rescue interventions, often due to issues that are preventable.

The regulatory focus on efficiency means that the core value points (e.g., speed, cost and metrics) of operational products will become regulatory requirements as components in risk management of quality, and that quality by design (QbD) and audit readiness has to be built into operational systems.

The guidance will move the majority of work today performed in dedicated compliance and quality management systems into operational systems, ensuring that work is only performed once, as early as possible, and where the ownership and knowledge exist to allow for critical thinking.

E6 was originally released in 1996, creating the first guidance for clinical trial context. In 2016, revisions were made to these regulations for the first time in 20 years, forcing an industrywide shift as it attempted to adjust. With the R3 update to E6 expected this year, there will be a gap of just five years between revisions.

“What we’re seeing is a shrinking timeline of these regulatory guidance revisions, and it’s likely related to the rapid changes in technology’s clinical trial design approaches,” said Crissy MacDonald, vice president of client delivery at WCG Avoca Group. “We need to become more adept at adjusting our internal policies and procedures to comply with these newly changing regulations.”

Nearly 1,400 clinical research professionals registered for a recent webinar on the benefits of starting this transition now before ICH E6 (R3) is released. From webcast polling, 68 percent of clinical research professionals identified ICH E6 (R3) as an opportunity and 56 percent indicated that they wanted to take advantage of the forthcoming guidance recommendations now.

Andy Lawton, consultant at Risk Based Approach — one of the world’s leading experts on the implementation of risk management and QbD in clinical development — highlighted the revisions to E6, as well as the latest revisions to ICH E8, that will encourage greater use of quality tolerance limits. “Quality tolerance limits give us that one perfect gift of avoiding perfection, because we write our plans as if we’re going to achieve perfection,” he said. “We can move away from that definition of perfection to a defined quality basis.”

“Currently, quality is retroactivity assessed and documented after the fact in systems like TMF (trial master file) and quality management system. Ideally, quality should be proactivity assured at the source in operational systems, ensuring documents are correct before they are filed into the TMF,” said Elvin Thalund, director of industry strategy at Oracle. “This would require training operational staff on ICH regulations and implementing quality checks earlier in the process. This way you can design quality (QbD) into your systems and processes,” Thalund said.

MacDonald noted the industry’s tendency to have a reactive approach to new regulations when it should be more proactive. “The industry’s reactive approach drives a decrease in adoption because there’s concerns without a clear understanding of what those regulatory expectations are,” she said.

“Critical thinking is key to proactive transformation management enabling substantiable change. This evolution is ultimately controlled but provides a continuous process for innovation; thus, as you develop and adopt new processes for meeting the requirements of R3, the organization achieves the desired outcome and remains iterative,” said Erika Stevens, principal at Recherche Transformation Rapide.

Although the ICH E6 (R3) revision is fast approaching, these guidances reconfirm the importance and strategic alignment of eClinical technologies capable of providing core operational capabilities, as well as quality and operational excellence, with the objective of making drug development more efficient and ultimately resulting in more cost-effective treatment options for patients.

Morgan is responsible for directing the global marketing strategy and team for the Oracle Health Sciences suite of study startup applications, working with sponsors, CROs, medical device manufacturers and sites to reduce cycle times and improve collaboration and oversight in clinical trials. Morgan is a technology and life sciences management professional with more than 15 years’ experience in the application of informatics and bioinformatics to drug discovery, and eClinical technology associated with starting clinical trials. He holds degrees in analytical chemistry, information systems and business administration, and is a certified project manager with the Project Management Institute.