How ICH E6 (R2) Offers Wins with Risk-Based Study Execution


Applied Clinical Trials

Applied Clinical TrialsApplied Clinical Trials-11-01-2019
Volume 28
Issue 11

Roundtable gathers industry experts to discuss the guidance update’s early implementation and the shift toward risk-based study execution approaches.

Participant safety is the clinical trial sector’s top priority-and striving to achieve this laudable aim also makes for more agile, flexible, and efficient studies. That’s what we learned from a second executive roundtable discussion, hosted by the Tufts Center for the Study of Drug Development (CSDD), and supported via an educational grant from CluePoints and PricewaterhouseCoopers, on the progress the industry is making toward implementing the requirements of the ICH E6 (R2) addendum.


At the starting blocks

When it was introduced in 2017, ICH E6 (R2) represented the biggest change to international clinical research in two decades. Developed as a response to the rising complexity of studies and the industry’s increasing reliance in electronic data management and reporting systems, the update sought to define good risk management in the modern trial environment. It states that clinical programs should implement risk assessment at both the trial and system levels and that metrics on clinical monitoring and data management should be captured in preparation for clinical study reports.

Following the addendum’s publication, Tufts CSDD held the first roundtable on the updated guidance and found companies in the early stages of a big change. Kenneth Getz, former director of sponsored research and research associate professor at Tufts CSDD, who was recently promoted to research professor and deputy director, organized and facilitated the event with colleague Yaritza Peña, a research analyst at the center.

“Two years ago, companies were in the early stages of interpreting the guidance to translate recommendations into tangible operating practices,” said Getz. “Roundtable participants indicated their initial focus was largely on risk-based monitoring (RBM). They were beginning to implement risk assessment procedures to identify which operating practices were most impacted. Although apprehensive about how the addendum would affect their current standard operating procedures (SOPs), the attendees had all agreed that the revised guidance was a step toward more agile, flexible, and efficient clinical trials,” he added.

Embracing change

These latest discussions, held in Boston in April, found that the organizations had made significant progress on a granular level, and were now taking a more holistic view. A total of 41 participants from organizations including Alkermes, GlaxoSmithKline, Pfizer, Roche-Genentech, Sage Therapeutics, Takeda, the Metrics Champion Consortium (MCC), and FDA took part.

After a panel discussion about ICH E6 (R2) compliance, the companies offered up their own examples before addressing the barriers and anticipated direction of travel. They found that rather than focusing simply on RBM, the industry has been working toward improving study efficiency overall, by taking a much broader view of risk-based approaches to study execution, or RBx.

“Company mindset has progressed from 2017,” said Peña. “Since then, many organizations have incorporated a risk-based framework across end-to-end development processes. Companies are refining the quality management plans developed during the planning and execution stage, and using technology to drive pattern identification, machine learning, and study-specific analysis.”

The discussions found that new regulations had compelled companies to move away from a clinical research associate (CRA)-centric, on-site visit model of monitoring to a data-driven, central statistical approach that improves data quality and contributes to overall trial success. Roundtable participants said that utilizing technological solutions had enabled a risk-based approach, informed by objective data integration, that supported the critical thinking vital to being able to make the right patient safety decision at the right time.

Amanda Hayden, director of global clinical services at Alkermes, said the industry had experienced “significant maturation” with respect to its response to ICH E6 (R2). “While many companies may have approached the update by addressing each subpart separately, the reality is that many of the processes are interconnected. Advancing clinical processes in a holistic fashion and thinking of risk in all facets of study planning, execution, and analysis creates synergies and efficiencies, and allows for better use of time, resources, and study data.”

Challenges and opportunities

Companies chalking up success in this area are those that have recognized the opportunity and have since worked to reorganize SOPs and pathways to allow for a portfolio, rather than a program-wide view. They are making significant investment in analytical capabilities that not only apply to RBM and oversight, but also to operational outcomes such as enrollment and protocol feasibility. Advanced data visualization, for example, can automatically detect trends and anomalies, and automated query management systems assist with the reconciliation of serious adverse events.

Study optimization is a natural consequence of utilizing these metrics, which allow companies even more sophisticated ways to distinguish between reliable and potentially unreliable data, and to avoid unnecessary protocol complexity. These opportunities are only set to increase as analytical techniques, including machine learning, natural language processing, and other types of artificial intelligence  (AI) are put to use in the clinical trial space.

Achieving this holistic approach isn’t without its challenges, and integrating ICH E6 (R2) concepts into study planning and implementation is proving difficult for some sponsors. “Part of the challenge depends on the creation of an efficient interface between a proactive quality planning process and a risk-based monitoring process,” said Getz. “Another daunting task is shifting company culture to adapt to the necessary changes to study processes when anticipating risk and performance issues.”

Getz further explained: “Since risk management is not currently a core operational competency, employees require training and monitoring to understand concepts such as data quality vs. data integrity, site monitoring vs. trial monitoring, and data reliability vs. trial results reliability.”

According to the panelists, the companies currently embracing the opportunities of RBx have fundamentally changed the way data are verified, reviewed, analyzed, and managed within their organizations. This has taken commitment from senior leadership and a wholesale change both in company structures and culture. Strategies employed have included robust change management training and the digital upskilling of staff. Clinical study teams, tasked with examining ICH E6 (R2) requirements to ensure the right data quality oversight tools are being used, have also been set up.

Some industry players have developed teams of subject matter experts (SMEs) with the responsibility to ensure the updated guidance is implemented. These SMEs are able to take an overarching view of risk identification, reporting and evaluation, cross-functional sharing of risk, and the monitoring of risk control measures across studies and protocols.

“This horizontal view that rises above separate protocols and sites to take in the bigger picture, is the key to realizing the potential of RBx,” said Hayden. “The main drivers in successfully implementing a risk-based approach to study execution is to consider the interconnected nature of risk identification and analysis throughout the entire lifecycle of the clinical program.”

What’s next?

While many of the companies at the roundtable said the project had increased operating costs, they also said these were offset by the benefits in terms of risk mitigation and proactive decision-making. As clinical trials become ever more complex and fragmented, RBx systems can be used to continue to consolidate and streamline studies while allowing for strategic oversight. In fact, many of the roundtable companies said they believed they were better placed to drive effectiveness and optimize performance in the next three to five years.

Those with the framework of RBx in situ appeared best placed to leverage the rich data that will be generated by ever-advancing analytics. While AI utilization is still in its infant stages, for example, the roundtable participants expect it will soon play a role in efficiently identifying areas of risk and be able to guide stakeholders to the best possible solutions. They are also in the best position to respond to expected regulatory changes-FDA is currently looking at revisions for E8 as well as a proposal regarding the next iteration of E6, for example.

“Drug development sponsors are being encouraged to partner with regulators, take more innovative risks, and amplify their concerns and ideas in terms of clinical trial quality and compliance,” said Peña. “With more time to process learnings from new technological implementations, the industry will begin to see additional standards for proactive clinical trial planning, execution, and quality-by-design.” In the long-term, companies will save time and expense from identifying anticipated risks early on through the refinement of current processes, she added.

RBx is about investing in the future by improving quality and effectiveness. Roundtable attendees agreed that while holistic ICH E6 compliance has led to a modest increase in short-term operating costs, they expected to see substantial savings over time.

Investing in the risk-based approach to the design and conduct of clinical trials is about the intelligent use of data to make informed decisions. It’s not only sponsors and CROs that are adopting risk-based approaches, but regulators are as well.


Patrick Hughes is Chief Commercial Officer, CluePoints

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