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Given FDA's new guidance on risk-based monitoring (RBM), there has been a lot of interest on identifying critical data points, drafting RBM plans, and executing RBM.
Given FDA’s new guidance on risk-based monitoring (RBM), there has been a lot of interest on identifying critical data points, drafting RBM plans, and executing RBM. TransCelerate, which is a consortium of biopharmaceutical industry personnel, issued a position paper to assist biopharmaceutical Sponsors/CROs with defining RBM activities; nonetheless, due to the level of subjectivity in clinical trials, clinical operations personnel seem to exhibit a level of confusion, particularly around interpreting risk and executing centralized monitoring.
What is Centralized Monitoring?
According to FDA’s guidance, centralized monitors conduct remote and high-frequency evaluations to assess data quality and uncover factors affecting patient safety through statistical analyses of clinical datasets. Moreover, the FDA suggests in its guidance that centralized monitoring is better at detecting fraud than on-site monitoring. Centralized monitors ultimately identify high-risk clinical sites and critical data points through trend and outlier analyses. The FDA encourages that study teams implement a mix of both on site and centralized monitoring practices, which transforms our existing monitoring activities. I will speak about the differences between Source Document Verification and Source Data Review in a future blog.
How Do We Operationalize Centralized Monitoring?
The figure below demonstrates the centralized monitoring process.
Firstly, centralized monitors will need to have access to real-time data in order to conduct centralized monitoring activities; this requires a solid IT infrastructure. Secondly, centralized monitors carry out statistical assessments on factors (predefined in RBM plans) affecting patient safety and data integrity; unusual findings should be documented in CAPAs. Lastly, once centralized monitors identify issues, on-site monitors are sent out to study sites in a targeted manner to investigate why these trends exist and finalize findings in CAPAs.
To demonstrate, a centralized monitor identifies an unusual analytical trend with a critical data point affecting study primary endpoints (i.e., NIHSS score), then on-site monitors investigate the unusual trend in the data point (i.e., was there a transcription error? was the administrator certified in NIHSS?). This targeted approach is meant to boost quality, significantly enhance efficiency, and yield cost savings in clinical monitoring operations. Additionally, this approach will especially benefit study sites, as they will not need to spend resources on unnecessary and repetitive monitoring visits.
The Considerable Gap in Skillsets
There were extensive discussions on RBM at CBI’s Risk-Based Monitoring in Clinical Studies Summit, and discussions revealed that there was a clear gap in the skill sets that are necessary to conduct centralized monitoring. Centralized monitors not only need to understand GCP and have a background in life sciences, but should also be equipped with advanced statistical, analytical, and business skill sets in order to interpret risk (both qualitatively and quantitatively) and strategically conduct centralized monitoring activities. Further, Sponsors/CROs are required to demonstrate appropriate training for centralized monitors, according to the FDA. Moreover, due to the current state of IT systems in clinical operations (which are oftentimes disconnected and not integrated), centralized monitors need to understand how to plan required datasets for analysis, and mine/analyze data from a variety of databases.
Optimizing Business Operations
The FDA released its guidance on RBM in order to encourage Sponsors/CROs to find scientifically valid ways to cut costs and boost productivity. Feedback from study personnel, nonetheless, suggests that conducting centralized monitoring could be more expensive and resource exhaustive if not done properly. Study teams should establish RBM infrastructures and optimize their protocols early on, continually measure their monitoring activities from a financial perspective and optimize their resource allocation models in order to improve budgetary forecasts and minimize variances.
Moe Alsumidaie, President & Chief Scientific Officer, Annex Clinical. Moe Alsumidaie can be reached here. If you are interested in joining the discussion, apply to the Breakthrough Solutions in Clinical Trials & Healthcare Group.