ICH E6 (R2) was first introduced in 2017. It signified the greatest change in two decades to international clinical research. Intended to outline good risk management in the modern trial environment, it was formulated as a reaction to the rising complexity of studies and the industry’s increasing reliance in electronic data management and reporting systems. The guidelines outline that clinical programs ought to implement risk assessment at both trial and system level, and that metrics on clinical monitoring and data management are captured in preparation for Clinical Study Reports.
ICH E6 (R2) modernized the ICH Good Clinical Practice (GCP) Guideline and resulted in companies either developing or purchasing new risk-based monitoring (RBM) technology to meet the guideline’s requirements and help mitigate risk in clinical trials. The updates ensure that sponsors undertake risk assessment during pre-study start-up, implement risk controls and corrective action during study conduct, and keep a full, auditable log of everything that has been done, by who, when and why.
Then and Now
Following the ICH E6 (R2) publication, the Tufts Center for the Study of Drug Development (CSDD) held a roundtable in 2017 on the updated guidance and discovered that companies were in the early stages of immense change. Associate Professor and Tufts University founder, Kenneth Getz, organized and facilitated the event with colleague, Yaritza Peña, a research analyst at the center. The 2017 roundtable found that companies were in an initial period of decoding the guidance and establishing risk assessment procedures. This primary phase of interpretation was predominantly about translating recommendations into something tangible.
It was interesting to discover that roundtable participants were initially focusing on risk-based monitoring (RBM). They were beginning to implement risk assessment procedures and identify which operating practices were most impacted. It was clear that the participants were apprehensive about how the addendum would affect their current Standard Operating Procedures (SOPs). However, there was no doubt that the revised guidance was a step towards more agile, flexible and efficient clinical trials. It heralded the biggest paradigm shift in the industry in decades.
Fast-forward over two years and the clinical trials industry is now beginning to transition from a risk-based monitoring (RBM) approach to risk-based quality management (RBQM). Another roundtable was needed to assess the landscape, and key industry executives welcomed the opportunity to take part in a second Tufts CSDD follow-up discussion aimed at investigating the progress the industry is making towards implementing the requirements of the ICH E6 (R2) addendum. A total of 41 participants from organizations including Alkermes, GSK, MCCC, Pfizer, Roche-Genentech, Sage Therapeutics, Takeda and the FDA took part.
In the 2019 roundtable, companies reported that they have made significant progress in responding to the ICH E6 addendum. Kenneth Getz commented, “Company thinking has evolved and matured, and many organizations have incorporated a risk-based framework and mindset across end-to-end development continuum including organizational design, technology use, development execution, training, data management and analytics.” Benefits are now being realized and sponsors, contract research organizations (CROs) and sites are embracing an industry-wide shift towards Risk-Based Study Execution (RBx), which is not only reducing risk, but improving oversight and boosting proactive, predictive decision making. With so many interconnected processes, synergies and efficiencies can easily be gained by thinking of risk across all aspects of study planning, execution and analysis. The result is better use of time, resources, and study data.
Opportunities and Threats
Companies that are 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 comprehensive 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.
Getz commented, “Shifting company culture to adapt to the necessary changes to study processes when anticipating risk and performance issues is a daunting task. Since risk management is not currently a core operational competency, employees require training and monitoring to understand existing concepts, such as data quality versus data integrity, site monitoring versus trial monitoring, data reliability versus trial results reliability. Additional guidance on data management tools is critical for recognizing potentially unreliable data.”
Companies triumphing in this area 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 ever 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 utilized in the clinical trial space.
“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,” said Getz.
Clinical trials are becoming more complex and fragmented and there is a need to consolidate and streamline studies while allowing for strategic oversight. RBx systems are ideally suited to help companies drive effectiveness and optimize performance as a team to address these challenges.
ICH E6 (R2) Provides a Win/Win/Win
Undoubtedly, participant safety continues to be the clinical trial sector’s top priority. Yet it is possible that while striving to achieve this steadfast aim, studies can also become more agile, flexible and efficient. Investing in the risk-based approach to design and conduct of trials is about the intelligent use of data to make informed decisions. Not only does this protect participant safety, but it optimizes all study elements, streamlining processes and, ultimately shortening the road from target discovery to market access.
The spring 2019 executive roundtable held in Boston in April 2019, found that organisations were embracing change and had made substantial headway on a practical level. The next stage will see them take a more holistic view. Yaritza Pena noted that “achieving this holistic approach isn’t without its challenges, though, and integrating ICH E6 (R2) concepts in study planning and implementation is proving difficult for some sponsors.”
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. This goes above and beyond risk-based monitoring. “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 2019 roundtable 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. Pena clarified, “To apply RBx, companies will need to completely move away from a CRA-centric, site visit model of monitoring to a more data-driven, statistical approach. Implementing oversight and QMS internally enables companies to have control over the clinical trial data captured in real time. Establishing quality lead teams to oversee study teams will ensure processes are done more efficiently and effectively.”
Roundtable participants said that utilizing these technological solutions had enabled a risk-based approach, informed by objective data integration, that supported the critical thinking so vital to being able to make the right patient safety decision at the right time.
Where to Next?
The key to realizing the potential of RBx is down to adopting a“horizontal view”. One that rises above separate protocols and sits to take in the bigger picture. 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. However, companies worry that this will increase budgets, and many of the companies at the roundtable stated that projects had increased operating costs. While roundtable attendees agreed that holistic ICH E6 compliance has led to a modest increase in short-term operating costs, they expected to see substantial savings over time. “Costs were offset by the benefits in terms of risk mitigation and proactive decision making. In the long-term, companies will save time and expense from identifying anticipated risks early on through the refinement of current processes,” clarified Getz. RBx is about investing in the future by improving quality and effectiveness.
A crucial future benefit that RBx stands to offer is 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,” said Pena. They are also in the best position to respond to expected regulatory changes, such as FDA E8 revisions and E6 iterations, for example.
Roundtable participants agreed that technology solutions are essential to enabling a risk-based approach informed by objective data interrogation routinely conducted. ‘Intelligent Data Surveillance and Oversight’ allows sponsors and CROs to do what they do best by supporting critical thinking to make the right decisions at the right time for patient safety and improve data quality and overall trial success. 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 order to reap the benefits well into the future, companies need to stop viewing the updated ICH guidance as an exercise in meeting regulations. Sponsors and CROs must look beyond simple compliance and towards the transformational improvements they can achieve across their clinical development franchise. The solution is here to fundamentally alter how clinical research is managed. Quality management will, undoubtedly, be an essential component of the future clinical research landscape for decades to come. We look forward to the next roundtable discussion to see just how far we have come.