Risk-based monitoring in clinical trials

What is risk-based monitoring?

Risk-based monitoring is the process of ensuring the quality of clinical trials by identifying, assessing, monitoring and mitigating the risks that could affect the quality or safety of a study. Guidance from the US Food and Drug Administration (FDA) outlines three steps in a risk-based approach to monitoring:

  1. Identify critical data and processes. To accurately monitor the quality of a study and the safety of its participants, the sponsor must know which elements are most important for each particular study – from informed consent to eligibility screening and tracking of adverse events.
  2. Perform a risk assessment. A risk assessment involves determining specific sources of risk and the effect of study errors on those risks.
  3. Develop a monitoring plan. According to FDA's guidance, a monitoring plan should "describe the monitoring methods, responsibilities, and requirements of the trial." The plan is responsible for communicating risks and monitoring procedures to everyone involved in monitoring the trial.

Why is risk-based monitoring on the rise?

The cost and complexity of clinical trials have grown dramatically in recent years. Up to a third of a study's cost can now be attributed to the traditional on-site review of trial data.

This approach, heavily reliant on exhaustive source data verification (SDV), has proven to be not only resource-intensive, but limited in its ability to identify and prevent issues.

Because efficient monitoring is critical to protecting the well-being of trial participants and maintaining the integrity of final results, it is now generally accepted that the process for clinical trial monitoring needs to change.

A more centralized, risk-based approach is now the preferred method for monitoring clinical trials, according to several regulatory agencies, including the FDA.

Why is it better?

One primary feature of risk-based monitoring is its use of centralized monitoring techniques. As opposed to on-site monitoring based on 100% source data verification, centralized monitoring promises a number of benefits:

  • Fewer errors. On-site monitoring methods, like any manual effort, are limited in scope and prone to error. Risk-based, centralized monitoring uses more automated reviews to determine the need for manual intervention and is more likely to uncover errors.
  • Lower cost. With centralized monitoring, activities like on-site audits can be limited to study sites where problems are most likely occurring, which can dramatically reduce the cost of monitoring.
  • Better analysis. With all data flowing into a central risk dashboard, statistical and graphical checks can much more easily be used to determine the presence of outliers or unusual patterns in the data.
  • Cross-site comparison. Centralized monitoring also allows you to compare data between sites to assess performance, identify potentially fraudulent data, or locate faulty or miscalibrated equipment.
  • More timely results. A dashboard also makes it possible to identify and resolve issues while the trial is ongoing.

The monitoring process

As discussed above, the FDA has provided some detailed guidance on how to prepare a monitoring plan, but once the plan is in place, it's the sponsor's responsibility (or the sponsor's delegate, like a CRO) to execute the plan. While specifics will differ widely between studies, a risk-oriented monitoring program will typically contain the following activities, which all flow through a comprehensive risk dashboard built for your particular study:

  • Data collection and submission. A centralized approach requires a steady and reliable flow of data from each study site to the central monitoring system. This may occur either through manual entry and transfer of relevant data, or through an automated connection between the data entry system and the central dashboard.
  • Dashboard monitoring. The function of the dashboard is to provide, at a glance, information about the status of each study site relative to the specific risk factors in your trial. When a site shows a high risk level, your monitoring plan should help you decide whether further investigation is appropriate, from in-depth statistical analysis to on-site data verification.
  • Statistical analysis. In addition to monitoring your risk dashboard, it can also be useful to perform supplementary statistical analyses to help identify problems. Simple histograms and box plots can be extremely useful for spotting outliers between sites or countries for various risk indicators. More advanced techniques like clustering can also help identify problematic sites or even fraud.
  • Targeted on-site investigation. Dashboard monitoring and further analysis will sometimes signal strongly that in-person investigation is needed at a particular site. In these cases, it may be appropriate to visit and perform a more traditional source data verification activity, depending on the nature of your study. The key is that once a centralized system in place, on-site investigation should be the exception, not the norm.

The risk dashboard

The risk dashboard itself is the center of a risk-based monitoring program. All study data should flow into the dashboard, and the dashboard should be designed to provide obvious visual cues for high-risk trial sites.

To help create those visual cues, a monitoring plan will often define thresholds for certain risk indicators that correspond to mild, moderate or severe risk for that indicator. Using these thresholds, you can color-code your dashboard to summarize risk levels by site or even by country.

Beyond the basic function of the risk dashboard, it should also be possible to customize the display of data and quickly perform further analysis. Analysts should be free to define multiple sets of risk thresholds to assess the sensitivity of their findings. They should also be able to calculate overall risk metrics to help assess overall site or country performance.

Where to begin: dealing with organizational change

Despite lively discussion in the industry – and even growing consensus – about the benefits of a risk-based approach, adoption of these techniques has been slow. Certainly the cost of shifting to more centralized monitoring is significant: Do you have the analytical expertise to monitor data centrally? Do you have the tools to build a useful dashboard? How do you gather and transmit the data from test sites? What happens to the people conducting on-site reviews today?

Ultimately, the move to risk-based monitoring may be easier than you think, and some tools are surprisingly accessible. Here are a few steps to get you started:

  1. Find a champion and an executive sponsor.
    A major organizational shift can’t happen without an internal champion and an executive sponsor. The same person may sometimes fill both roles, but the champion is often a practitioner who sees the need for change, understands its potential and sells the idea to an executive sponsor. The executive sponsor then clears the way for change to occur.
  2. Get the right tools.
    A variety of technologies may be needed to help with centralized monitoring, but it is best to start with tools that offer fast, visual results without the need for extensive database, programming or even statistical experience. Those skills may be helpful eventually, but they should not be necessary to get started.
  3. Start small.
    Once you design a basic monitoring process and get the required tools in place, try to start your risk assessment and centralized monitoring efforts with a single study or small group of studies. This will reduce the resources required and give your organization a chance to warm up to the change.
  4. Scale up organically.
    Starting small also gives you a chance to work out the kinks in your monitoring process. The process should become smoother with each iteration, which will make it easier to scale up to more and more studies. This approach is much less daunting than a single, dramatic shift, and the ability to learn as you go should ultimately yield better processes that scale more effectively.

The shift toward more centralized monitoring presents real challenges, but regardless of where you start or how cautiously your organization approaches the concept, the shift is happening. And it’s better to be on the leading edge than falling behind, especially in an industry where time to market is everything.