What ICH E6 (R2) Means for Investigative Sites, Risk Assessment and Clinical Trial Monitoring


Applied Clinical Trials

The last time the ICH GCP Guideline was updated, the process of conducting a clinical trial, including risk assessment and monitoring, was a largely paper-based affair. Since then clinical trials have evolved substantially as they’ve become more complex, costly, and global in scope.

The last time the ICH GCP Guideline was updated-more than 20 years ago-the process of conducting a clinical trial, including risk assessment and monitoring, was a largely paper-based affair. Since then clinical trials have evolved substantially as they’ve become more complex, costly, and global in scope. At the same time, tremendous advances in technology and data analytics are making it possible to be more effective and efficient at certain aspects of clinical trial monitoring.

To keep up with this evolution, the recent ICH E6(R2) addendum is seeking to modernize GCP by shifting the focus of clinical trial monitoring toward the data and processes that are critical to patient safety and data integrity, while leveraging today’s technologies to increase oversight, quality, and efficiencies. It’s a shift that has major implications for clinical trial sites and sponsors and for their interactions with each other.  

The addendum requires that sponsors and sites implement a risk-proportionate approach in clinical trials. Although this approach includes some of the familiar elements of Risk-Based Monitoring (RBM) such as reduced source data verification, increased centralized monitoring, and the use of data analytics to support on-site monitoring, it also impacts investigational site trial participation and responsibility.

More Focus on What Matters Most

The new approach has several main objectives. First, it is intended to enable more timely “real-time” identification of emerging trends and potential risks that impact patient safety and data integrity. Compared to traditional monitoring methods, current technology provides multiple tools for remotely aggregating data and applying algorithms to flag potential issues for investigation. This allows for early course correction-enabling faster, more informed, decision-making and remediation-before mistakes can become systemic.

Taking a risk-proportionate approach is also intended to enable CRAs, when on-site, to focus more on the activities that best support the site and drive data quality and patient safety. It means CRAs use the information provided by centralized monitoring to increase efficiency and effectiveness, allowing more “quality time” for CRAs to work with sites on processes, GCP and protocol compliance, root cause analysis, and process improvement. When sites are supported at an individual level, they are better able to leverage feedback and solutions in order to provide higher quality care for clinical trial participants, resulting in greater subject centricity and patient safety.

Greater Need for Proactive, Two-Way Dialogue

Another key aspect of ICH E6(R2) is that it reinforces the responsibility that principal investigators have for ensuring adequately skilled/trained personnel and quality process management as part of their oversight of the trial. This, in turn, increases the need for greater communication between sites and sponsors and CROs-and in particular, for sites to more proactively engage with sponsors and CROs during protocol and clinical trial risk assessment.

Experienced sites encounter trials that go poorly for a variety of reasons, including complex protocol procedures (the most commonly cited issue by SCRS webinar participants), difficult inclusion and exclusion criteria, and over-estimated recruitment rate expectations. Sites have the opportunity to provide feedback to sponsors and CROs about these and other potential issues in several ways. They can provide protocol risk assessment feedback on the site information forms (i.e., feasibility questionnaire), at Investigator Meetings, during meetings between the sponsor, sites and advocacy groups, and during site qualification visits by monitors.

But communication needs to be a two-way street. Sponsors and CROs should be prepared to proactively communicate with sites about identified risks and mitigations. Protocol review and training on critical data and processes can take place during investigator meetings. Discussions about on- and off-site monitoring strategies and critical data collection processes can be held during site initiation visits. As part of interim and remote monitoring, sites can be informed about emerging risks, risk mitigation impacts, and early course corrections that have been taken.

The implementation of ICH E6(R2) compliance measures is still a work in progress. As we move forward, it will be important for all to keep in mind that one major effect of ICH E6(R2) has been heightened-the need for shared communication and collaboration between sites, sponsors, and CROs. Improvements in technology may allow timely insight into potential study risks, but the people involved on all sides of the process must participate in the evaluation and response to these indicators in order to achieve what matters most to a successful clinical trial-data quality and integrity, and participant safety and centrality.

To take a closer look at this topic view the on-demand webinar series (sponsored by SCRS and ACRO) we participated in alongside other industry experts titled “A Clinical Trial Odyssey.”


Jill Collins is Executive Director and Sherry Merrifield is Senior Director of Global Operations Management for Syneos Health.

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