Risk-based monitoring (RBM) represents a significant departure from traditional monitoring, where clinical research associates (CRAs) conduct routine on-site monitoring with 100% data verification. With RBM, the goal is to enhance human subject protection and clinical trial data quality by focusing sponsor oversight on the most important aspects of study conduct and reporting. Moreover, a risk-based approach to monitoring is dynamic and responsive, enabling evaluation of monitoring findings in real time to determine whether additional actions are required to ensure patient safety and data quality across all investigative sites.
Recent changes to the ICH E6 R2 guidelines emphasize the need for improved, more efficient approaches to clinical trial design, conduct, oversight, recording, and reporting. The updated guidelines take the U.S. Food and Drug Administration (FDA)’s guidance on risk-based monitoring approaches one step further by making risk-based quality management a requirement, rather than a recommendation.
Rationale for Centralized Monitoring in RBM
A growing body of research supports the idea that risk-based approaches to monitoring, which focus on risks to the most critical data elements and processes necessary for achieving study objectives, are more likely than routine visits to all sites and complete source data verification to ensure human subject protection and overall study quality.2 Numerous publications have suggested that centralized monitoring may be more effective that on-site monitoring for detecting certain data anomalies. In fact, one review of on-site monitoring findings collected during a multi-center international trial found that centralized monitoring activities could have identified more than 90% of the findings identified during on-site monitoring visits.
Adopting a statistical approach to centralized monitoring can help improve the effectiveness and efficiency of on-site monitoring by guiding and prioritizing site visits based on risk signals and real-time site performance. Moving from scheduled site visits to signal-driven site visits can not only improve patient safety and data quality, but also save time and expense.
Criteria for Effective Centralized Monitoring
To truly enable an RBM approach, the central monitoring process utilized must identify problems continuously from the outset and provide a basis for immediate action in response to emerging issues.
The key success factors of a continuous centralized monitoring approach include the ability to:
- Identify as many potential problems as possible, in advance
- Establish processes for detecting such problems
- Maintain continuous vigilance for signs of any developments or event that might compromise patient safety and/or data quality
Continuous centralized monitoring may include rules-based analytic checks, cross-case report form (CRF) consistency comparison, and outlier checks, to name a few. The types of monitoring activities and the extent to which centralized monitoring practices can be employed in a study depend on various factors, including the use of electronic systems, access to subjects’ electronic records, timeliness of data entry, and even investigator or site experience.1
Finding the Right Monitoring Mix
Neither the FDA guidance nor the updated ICH E6 R2 guidelines dictate how a sponsor should implement a risk-based approach to monitoring clinical trials. However, the ICH E6 R2 update does require sponsors to clearly define the rational and justification for the strategies chosen.2 Monitoring may involve a combination of techniques and the optimal mix of on-site, remote, and centralized monitoring may vary from study to study. In some cases, centralized monitoring techniques are best used to supplement or reduce the frequency and extent of on-site monitoring, rather than replace it.
In an increasingly complex and competitive landscape, sponsors must leverage the best of modern clinical trial management and computing technologies to reap the full benefits of risk-based monitoring. This requires a foundational shift to management based on real-time metrics, with a precise focus on the information most critical to study success and predictive elements that allow anticipatory, rather than reactive or even proactive, management techniques.
 U.S. Food and Drug Administration. Guidance for Industry: Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring. Available at https://www.fda.gov/downloads/Drugs/Guidances/UCM269919.pdf.
 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Guideline for Good Clinical Practice E6 (R2), November 9, 2016. Available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4_2016_1109.pdf.
 Bakobaki JM, et al. The potential for central monitoring techniques to replace on-site monitoring: findings from an international multi-centre clinical trial. Clin Trials 2012;9(2):257-264.