Improving Clinical Trial Efficiency: Centralized and Risk-Based Monitoring

The problem: Monitoring clinical trial data using SDV

With clinical trials becoming increasingly complex over the past decades, the costs of clinical trials have reached new heights.

On-site review of clinical trial documents, classically taking the form of source data verification (SDV), together with investigator site management, represent a significant portion of total clinical trial expenses. A major drawback of indiscriminately applying exhaustive (100%) SDV is that it is costly and time-intensive.

Although SDV in clinical trials has often been considered standard protocol, it has also been shown to have limitations in terms of identifying and correcting issues. Especially with recent developments in clinical trial monitoring solutions, many of which include alternative data validation tools, SDV is now considered by some to be unnecessary at best, and wasteful at worst – particularly for studies or parts of studies wherein the data is already of high quality or when minor issues would not be detrimental to the study results nor patient safety. Complete SDV was also shown to be only marginally better than partial SDV in one study.

Solution: Centralized and risk based monitoring (RBM)

It is becoming widely accepted that the limited resources in a clinical trial would be better spent by focusing solely on vital tasks, which explains the rise of centralized monitoring and risk-based monitoring (RBM).

In centralized and risk-based monitoring approaches, monitoring tasks are prioritized according to the relative risks and severity of potential consequences in the various aspects of clinical trial operations. Monitoring is conducted in a coordinated manner, from centralized locations, according to the highest risk areas.

If problems or potential issues are identified, then site-specific or more thorough investigations can be conducted. This prevents the spending of limited resources on indiscriminate monitoring of data or operations where the potential benefit (and potential risk) is minimal or even null.

Numerous major regulatory bodies, including the FDA, have formally recognized and put forth guidelines for centralized and risk-based monitoring as effective strategies for monitoring clinical trial data.

In this article, we will further define centralized monitoring and risk-based monitoring (which often overlap or are combined into one approach), explore their advantages and drawbacks in comparison to traditional monitoring methods including SDV, and go over some considerations for transitioning smoothly to a centralized RBM strategy. At the end of the article, we include links to 3 trusted RBM providers.

Centralized Monitoring

Centralized monitoring describes the tracking and assessment of clinical trial operations and data by dedicated staff (who may be trial monitors, investigators, statisticians) at locations separate from the clinical trial sites.

This lies in contrast to on-site monitoring, where separate clinical trial monitors may visit trial sites in-person to monitor operations and validate data, which necessitates more personnel, more travel time and logistical considerations, and more complex oversight. In centralized monitoring, monitoring is coordinated and executed from a centralized location in order to streamline monitoring operations and optimize resource allocation, and is usually assisted by technological solutions integrating the various trial sites. Nonetheless, on-site monitoring may still be needed to further investigate specific instances or high-risk aspects, so the two approaches are not mutually exclusive.

Centralized monitoring enables the possibility of performing statistical analysis to identify trends, both within and between trial sites, and thus is useful for assessing the performance of different trial sites and identifying potential issues such as data outliers or improperly functioning equipment (indicated by unexpected values) and noncompliance.

Risk Based Monitoring (RBM)

Risk-based monitoring, or RBM, refers to the concept of identifying the principal risk areas in a clinical trial, and prioritizing the monitoring of these aspects to assess and mitigate issues that could cause problems in terms of the safety and/or the quality of the trial. It can also be thought of as a method of centralized monitoring based on a risk-based approach.

Risk-based monitoring aims to make the monitoring process more efficient and aligned with the goal of ensuring the safety and quality of the study by using statistical indicators and thresholds to quickly identify errors where they are most likely to occur and/or have relevant consequences.

The design of a risk-based monitoring approach requires 3 steps:

1. Identify which operations and data are most critical to the trial, in terms of patient safety, regulatory affairs, and trial quality. Designate these factors as the indicators which will be monitored in the central dashboard.

2. Conduct a risk analysis to predict the potential risk posed by the main potential sources of error in the study. Establish thresholds which would indicate the severity of risk represented by different values, which will enable you to set up a “traffic-light” system or other visually obvious cues for alerting the monitor to any potential issues.

3. Design the monitoring plan based on these risk areas, indicators, and thresholds, which should include details and clear instructions on the monitoring methods, clarify who is responsible for which aspects of monitoring and responding to issues, and how risks and errors will be communicated between the various actors involved.

RBM and its relation to Risk Based Quality Management (RBQM)

RBM is closely related to another concept, risk-based quality management (RBQM), which is a broader clinical trial quality management framework that was described by the EMA as “the identification of the risks on a continuous basis for risk-bearing activities throughout the design, conduct, evaluation and reporting of clinical trials.” RBM can be thought of as a key component of a RBQM strategy.

Risk-based monitoring focuses on data, using statistical approaches and software, to determine potential risk to trial safety or quality and encourage rational decision-making by enabling sponsors and investigators to recognize and address issues as they emerge. Such an approach can allow investigators to save costs, optimize data quality and integrity, and ensure patient safety. RBQM, in a broader sense, refers to a quality management system that governs the entire clinical trial through a risk-based focus. ICH Good Clinical Practice (GCP) guidelines from 2016 suggest the application of a risk-based approach to all aspects of clinical trial quality management systems.

What are the benefits and drawbacks of risk based monitoring?

Risk-based monitoring offers several advantages for clinical trials; let's take a look at the main benefits in more detail.

Benefits of RBM

• Ensure participant safety: Risk-based monitoring allows researchers to focus on aspects of a clinical trial that may pose or represent greater risks to patient safety, and the centralization of monitoring and related statistical capabilities allow for quick identification of outlying or concerning data, even at the level of individual patients.
• Efficient and targeted monitoring: The risk-based approach improves the efficiency of clinical trial monitoring by focusing resources on higher-risk aspects of the trial and organizing all data in one place from where it can be analyzed and validated for quality.
• Reduced monitoring costs: Clinical trial monitoring represents a significant proportion of overall trial costs. Centralized risk-based monitoring streamlines monitoring operations and maximizes efficiency, usually leading to sizeable savings compared to traditional monitoring methods.
• Enhanced statistical analysis capabilities: Combining study data from across study sites allows for more powerful statistical analysis of trial data and results, and can even allow for assessment of performance between the clinical trial sites involved in the study.
• Early identification of errors or adverse events: By knowing which high-risk aspects to monitor more closely and establishing risk thresholds for the various indicators, investigators can be alerted very quickly to address any potential errors or adverse events indicated by study data. For example, if one site is producing outlier data for a given metric but this continues over a series of patients, it could indicate that a piece of equipment is miscalibrated. A single extreme outlier for a health endpoint could notify investigators to a potential adverse event, and the central monitor could notify the trial site in real-time.
• Optimized data quality: The centralized management of data enables real-time data validation and clean-up, improves consistency of data collected at separate sites, and can assist with regulatory affairs by maintaining up-to-date records of study data.

Although risk-based monitoring strategies offer several advantages, there are also certain drawbacks associated with the transition to such a strategy.

Drawbacks of RBM

• Requires foresight and planning: A risk-based monitoring strategy can only be effective with thorough planning prior to the start of the trial. Indicators, thresholds, and warnings must be set up according to the specific trial parameters, and central monitors must be trained in using the software and regarding the procedure to follow when errors arise or problematic data is flagged.
• Initial investment costs: With the transition to new technologies, there may be costs associated with the initial setup, whether this involves contracting a solution offered by a vendor or setting up your own systems. Nonetheless, the initial investment is likely to pay off via the subsequently enhanced efficiency and decreased costs of monitoring operations.
• Transition and training: Sponsors, investigators, and any staff involved in the trial review and monitoring processes must be trained so they are familiar with the centralized or RBM system. These approaches represent a transition from traditional methods and the transition may require some time and certain adjustments, so plan accordingly.

How do you implement risk based monitoring?

Numerous organizations have provided guidance and considerations for designing and implementing a risk-based monitoring strategy, including the FDA, ACRO’s CRO Forum, and TransCelerate. You can find the initial design of an RBM strategy in an earlier section of this article under the heading “Risk-Based Monitoring”. After the trial begins, implementation of the monitoring strategy generally involves the following aspects:

• Assembling and submitting data: Individual study sites must input and connect the trial data they collect into the centralized system. This can be done either through manual data entry or automated processes. In either case, clear guidelines and instructions should be put in place to maximize data consistency right at its source.
• Dashboard monitoring: The “dashboard” is the name given to the main “overview” panel in the central monitoring operation. The dashboard should have easily visible pre-defined cues to alert the central monitor when any established threshold for an indicator is approached or exceeded, which would be indicative of potential problems. The procedure for addressing the specific issue should be clearly described in the monitoring guidelines, so that when any high risk is flagged by the system, the responsible person can be notified and make an informed decision about next steps to take.
• Statistical assessments: You may establish other periodical statistical analyses to be performed on the trial data as it is collected, to further help identify potential issues in data quality or adverse events. These can be automated or their execution may be specified in the monitoring plan.
• On-site investigations when necessary: As mentioned previously, centralized monitoring does not necessarily exclude the need for on-site monitoring. When any risk event is identified in the centralized monitoring operation, monitors should assess the data presented to determine if further on-site investigation of the issue is warranted. Some issues may still warrant in-person investigations to uncover the cause and/or rectify the problems.

Bonus: Trusted RBM Vendors

If you are intrigued and curious about ready-to-use RBM solutions, here are some trusted RBM vendors to get you started on your search for a partner:

• TransCelerate: The TransCelerate risk-based monitoring solution consists of extensive and detailed guidelines for implementing their model RBM framework which can be adapted to any type or phase of clinical trial. The guidelines are offered for free, and include step-by-step instructions and considerations for making the transition to RBM approaches to enhance patient safety and ensure data quality.
• JMP Clinical: JMP offers a robust clinical data analysis software designed to facilitate easy statistical analysis, identification of safety issues, validation of data, and medical monitoring for all stakeholders involved in a clinical trial’s review.
• IQVIA: The risk-based monitoring approach offered by IQVIA combines technology and automation with their extensive experience in clinical monitoring to offer flexible and customizable solutions that improve patient safety and reduce the costs of trial oversight, with 300 studies already completed across over 39,000 sites.

Conclusions

Centralized and risk-based monitoring approaches are becoming increasingly recognized as effective methods for monitoring clinical studies, with major regulatory bodies such as the FDA and EMA already having stated their approval and publishing guidelines for adopting such strategies. As compared to traditional alternatives like exhaustive SDV and pure on-site monitoring, centralized RBM can streamline monitoring operations and maximize resource efficiency, enable rapid detection of errors, enhance participant safety, and improve trial data quality. Sponsors have the option of contracting a partner to undertake the monitoring or developing their own tools and methods for integrating such an approach into their operations.