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Centralized monitoring is a suitable way in which sites can identify and control investigational risks while improving performance. This new approach can not only help sponsors to monitor site performance, but also facilitate proper oversight resulting in good ROI.
It has been seen that very often performance of investigational sites poses major challenges to study conduct and reporting. The performance of sites related to patient recruitment, data quality, patient safety and protocol compliance affects the clinical trial investments and the achievement of expected quality, timelines and budgets. Poor performance by the sites not only increases budgetary burden but affects clinical trial cycle times and overall drug development objectives.
Risk-based centralized monitoring offers innovative solution in tracking and controlling sites performance almost real time basis which is otherwise intricate with only traditional on-site monitoring approach. Centralized monitoring offers many of the capabilities of on-site monitoring as well as additional capabilities. Using right process, analytical technology and relevant e-clinical tools, one can build efficiencies in sites performance management and at the same time fulfills the overall objectives of monitoring and oversight also.
As far as right implementation of centralized monitoring is concerned, there are few steps one needs to take into consideration such as below.
Identification and Assessment of Investigational Sites’ Risks
Pre-identifying key risks that need to be monitored at the site during central monitoring is very important. This process should be done after all sites are selected for the study. Based on feasibility and site selection process, one can identify the risks related to sites performance that are critical for study success. Similarly, identification of right KRIs will allow correct representation of the risks that one wants to monitor throughout the study during centralized monitoring. The KRIs should be measurable, comparable, and predictable to provide early warning signals. For example, if “protocol compliance” is one of the risk areas identified for a study then to track and control this risk effectively, the KRI “protocol deviation/violation per subject per site” that needs to be monitored during study conduct.
Once the right KRI is identified, the next step is to define the threshold value to trigger the action when that specific value of any KRI reaches. The threshold for KRIs should be defined in such way that it will allow timely/proactive action planning if a particular risk triggers reaches during the conduct. Based on the criticality of KRIs for a study, different threshold levels can be planned which allow different escalation levels and further close monitoring of KRIs to deploy proactive actions whenever needed. If completing subject recruitment on time is vital for a study, it would be advisable to have different levels of threshold, for example first level could be “>5% to 15% of sites below expected recruitment rate” (yellow indicator) and then second level would be “ >15% sites below expected recruitment rate” (red indicator). Of course, the threshold value will vary study to study depending on the criticality of the KRI for that specific study.
Identification of Data Sources, Data Points for Risk Report
In order to monitor the identified risks, the data source and the right data point that will reflect the risk/KRI appropriately also needs to be identified. For example, to monitor risk related to patient safety, such as the number AE or SAEs per patient, the relevant data points on the AE page on an eCRF should be captured into analytical tool to get the relevant risk reports related to real time safety status on the study. As far as identifying data points is concerned, it is also important to design the eCRF in such way that it will allow capture of an appropriate single data point, which reflects the risk that needs to be monitored during the study. Apart from EDC, other data sources such as IRT, CTMS and eDiaries can be used to capture relevant data points.
Analytical & Visualization Technology
This technology plays a crucial role in successful implementation of central monitoring. The tool should be able to integrate with various data sources and collate and analyze the data from various sources like EDC, CTMS, eDiary, IRT etc. It should produce the graphical/visual representations of analyses and identify trends, patterns, and outliers on an ongoing basis to assess performance of the sites at country and patient level. It should proactively generate alerts when risk indicator values meet thresholds values that are predefined. It is also important that the tool allow modifications to new risk indicators, thresholds, and alerts, if needed.
Ongoing Monitoring by Central Monitors
The centralized monitoring process flow shown below with dedicated central monitors based at one place works well when there are good number of sites for local study or for a regional or global study with multiple countries and sites. The central monitor or central monitoring team will be reviewing the risk reports periodic basis and look for risk alerts and issues. The study level risk alerts will be escalated to the study manager, whereas site related risk alerts will be escalated to relevant on-site monitors for further action and/or site contact to manage those risks/issues. The relevant feedback from on-site monitors will come back to the central monitoring team. This process will also ensure that there is a complete tracking of all the issues identified till their close out.
Issue Tracking and Controlling
It is important that all risk alerts or issues that are identified during central monitoring or onsite monitoring should be logged in one place for tracking and for resolution/closure purpose. This kind of issue log is helpful in getting complete status of the issues in term of issue raised/escalation date, ownership, action planned, review date, status, closed date etc. The provision to filter these issues sites-wise or CRA-wise is helpful for better tracking and closure of the issues. With the proper communication and coordination between central and on-site monitors these investigational sites risks can be proactively managed and issues can be resolved on time.
Centralized monitoring appears to be a suitable approach available today to proactively identify and control investigational sites’ risks effectively and improve performance of sites. Even regulators encourage greater use of centralized monitoring techniques, wherever appropriate. With effective processes, right technology and with trained central monitors, this new approach will not only help sponsors to monitor performance of sites almost real time basis, but also facilitate proper oversight to ensure good ROI.
Ashok Ghone, PhD, is Vice-President, Global Services at MakroCare and member of the Applied Clinical Trials Editorial Advisory Board.