Risk-Based Monitoring: A Fundamental Shift In Clinical Trial Conduct, Quality

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

Risk-based monitoring (RBM) is steadily becoming a buzzword in the clinical space. While it may still be awhile before there is a universal standard in place, RBM is nonetheless becoming a key component for quality in the shifting landscape of clinical trials.

To help shed some light on how this practice is being used in the industry today, Clinical Leader reached out to PRA Health Sciences’ RBM Management Team: Alan Simpson, Gareth Adams, and Melissa Nezos.  In this Q&A, the team defines what makes up their RBM strategy and discusses the ways RBM could impact the entire industry.

Anna Rose Welch: As sponsors begin exploring RBM, what best practices have emerged in your business? How do you identify the biggest caveats you will encounter in the course of a clinical trial, and how do you respond to these potential issues?

PRA RBM Team: In our practice of RBM, we’ve come to identify three core elements that form the foundation of Risk Based Monitoring (RBM). For one, there must be a comprehensive, multidisciplinary study risk assessment. This assessment is carried out by expert study team members who review the study protocol from a clinical and operational perspective to identify and determine issues, the likelihood of occurrence, and how these issues could impact patient safety and the integrity of the protocol.         

Alan Simpson, SVP Operations, PRA Health Sciences	Gareth Adams, Senior Director, Data Services, PRA Health Sciences	Melissa Nezos, Director of Clinical Operations, PRA Health Sciences

Once this is completed and the risks are identified, the second component is to understand how we can identify these risks early on and how we can evaluate and provide a framework of analytics and metrics to measure them against. What’s absolutely critical in this process is a suite of data analytics, coupled with any necessary triggers and thresholds — these are integral in identifying areas of concern and any potential impact these might have on quality.

The third element is designing quality operational plans and processes that support an adaptive review and monitoring process fully supported by the analytics. It is important to remember that areas of risk will change during the study and so your plans also need to be flexible to allow for continuous risk assessment to support this. 

Finally, the entire process is supported by documentation, which is completed at the outset and is ongoing throughout the study. This documentation is critical in order to provide an auditable trail for regulatory inspection. For instance, if thresholds for a trigger are met, clear documentation is needed to demonstrate what action was taken, when, by whom, and what the associated outcome was. It is the same for situations where no action is deemed necessary; if this is the case, you still need to document that decision process.

Welch: As you’ve set out to establish and streamline these key components, have you found that the RBM process works best in a particular phase of trial?

RBM Team: We have used RBM for many years on our Phase 4/post marketing studies. These studies can have high enrollment, but the volume of data per patient is small and the majority of site contact and review occurs centrally with onsite monitoring visits happening very infrequently. Of course, there are associated risks in these trials, however, we have found they tend to be less complex because the products are marketed and have already undergone extensive scrutiny in a controlled environment during earlier phases of their development. They just now need to be tested in the real world.

Welch: What role does RBM play in early phase studies? 

RBM Team: Movement of RBM into earlier phase studies has been very gradual with many organizations looking at elements of ‘RBM-like’ data driven models where site visits are based on data volume at the site and less on a routine schedule. We do see a variety of phase 2 studies that are good candidates, though it is important that a proper risk assessment has been performed and that these trials are large enough to warrant consideration.

However, we feel the use of RBM is probably best suited to the larger Phase 3/4 trials where deployment of RBM yields the biggest return on investment.

Welch: Where do you think the industry currently stands in terms of RBM adoption?

RBM Team: Very few organizations have yet to adopt a full-risk based adaptive approach to protocol design and to act on that protocol. We expect that, like the eventual rapid adoption of EDC from paper based studies, the number of RBM-based studies will gradually build until a fulcrum is reached and they will become the ‘standard’.

We have noticed that a significant number of pharma companies are beginning to look at reduced SDV schemas as a form of RBM, primarily to reduce costs. However, what they fail to realize with this is that using reduced SDV schemas alone will increase the risk to quality. There is still a requirement to perform the study risk assessment and deploy adaptive monitoring and data review processes to offset the risks posed by arbitrarily reducing Source Data Verification (SDV) rates.

Welch: Are there any particular obstacles you see that are holding the industry back from wide-spread adoption?

RBM Team: For one, there is no “one size fits all” approach to RBM. There are also significant technology gaps around alternative central monitoring processes that interfere with the ability to manage a truly risk-based, dynamic, monitoring and SDV schema.

Welch: What areas do you feel require the most resources to monitor throughout the process of a study?

RBM Team: For us, the foundation of Risk Based — or as we prefer to call it, Adaptive Monitoring — is the risk management process, and this is the area that is most closely monitored throughout the clinical trial. All operational plans are designed to operationalize strategies and methodologies based upon the findings of the risk assessment. We have found this process is much less intensive in terms of “resource hours” compared to site monitoring or data cleaning activities. That being said, it is definitely no mean feat for the team to apply its expertise and knowledge to ensure the risk management process is deployed accurately, monitored and adapted in response to quality indicators, and that all decisions are properly documented.

Welch: Have sponsors identified any particular triggers to look for throughout a study, and/or have you begun to set up any of your own that help you determine the areas that need the most attention?

RBM Team: Our experience to date is that clients have asked us to undertake the risk assessment on their projects and hence they have not specified any definitive triggers. What we have been seeing typically is that protocols are not yet being designed with specific RBM considerations and that little or no previous risk assessments have been performed.

However, through the course of our own evolution in RBM, we’ve defined 17 core analytics that provide us with a suite of multi-level risk indicators that, with protocol specific triggers, can provide us with a comprehensive and holistic view of the study risks and the areas that may require further investigation. Temporal trending and investigative analysis techniques provide us with more information which helps us identify risk trends and causality and allows for a more proactive approach to potential risks downstream. We are currently looking for innovative technologies to provide even greater and more flexible access to data and increased analytical intelligence.

Welch: What is the financial impact of RBM?

RBM Team: It is hard to say right now what the true financial impact is, and of course, this will vary from project to project depending on the complexity, risk assessment, and sponsor tolerance.

Some sponsors continue to think the progression to RBM is primarily a way of reducing cost. However, they do not necessarily recognize that it is a fundamental shift in how we approach conducting clinical trials. Increasing quality and diversification of monitoring and data review methodologies are the primary goals when implementing RBM. While for certain sponsors, a reduction in overall study budgets and monitoring costs could be realized, this should be an outcome and not the overriding factor in deciding to pursue a RBM approach to study conduct.

Welch: What are some of the ways RBM could save money? What are some of the other benefits that could come from exploring RBM?

RBM Team: In RBM, there is a shift in the resource requirements from an on-site to an off-site model. Therefore, the sponsors save money on the associated service and indirect costs of travel, which, especially on a large phase 3 trial, can be significant.

But beyond finances, there is the benefit of improved focus and targeting of the critical components of the trial that all leads to a better quality deliverable. Improving quality should not be undervalued, although it is hard to equate to a dollar figure.