How ICH E6 (R2) Provides a Win/Win/Win through Risk-Based Study Execution


Applied Clinical Trials

The industry-wide shift towards RBx is not only reducing risk, but improving oversight and boosting proactive, predictive decision making, writes Cluepoints' CCO, Patrick Hughes.

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 Pricewaterhouse Coopers, on the progress the industry is making towards implementing the requirements of the ICH E6 (R2) addendum. 

Two years after being ratified, sponsors, CROs and sites have found the industry-wide shift towards Risk-Based Study Execution (RBx) is not only reducing risk, but improving oversight and boosting proactive, predictive decision making.


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, it 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 level, and that metrics on clinical monitoring and data management to 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. Director of Sponsored Research and Research Associate Professor at Tufts CSDDKenneth Getz, 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 towards more agile, flexible and efficient clinical trials,” he added.


Embracing change

These latest discussions, held in Boston in April, found 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, GSK, MCCC, Pfizer, Roche-Genentech, Sage Therapeutics, Takeda and the FDA took part.

After a panel discussion about the state of ICH E6 (R2) compliance, the companies offered up their own case examples before addressing the barriers and anticipated direction of travel. They found that rather than focusing simply on risk-based monitoring, the industry has been working towards improving study efficiency overall, by taking a much broader view of Risk-Based Approaches to Study Execution, or RBx as it is now being known.

“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 the new regulations had compelled companies to move away from a 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 ICH 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

The 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 program-wide view. 

They are making significant investment in analytical capabilities that not only apply to risk-based monitoring 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 are put to use in the clinical trial space.

Achieving this holistic approach isn’t without its challenges and integrating ICH E6 (R2) concepts in 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.”

“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,” explained Getz.

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 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,” she added.


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 on 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-the 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.


Future proofing clinical trials

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 design and conduct of 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, regulators themselves are investing and implementing the same methodologies. For example, FDA is using these techniques to interrogate submission data with a view to selecting sites for inspection based on the results. The data-driven approach detects ‘anomalous’ data in sites that may have previously gone undetected, allowing regulators to focus their attention those sites. 


Patrick Hughes is the Chief Commercial Officer at CluePoints

© 2024 MJH Life Sciences

All rights reserved.