Risk-based monitoring in clinical trials: Implications for sponsors, investigators
‘Risk-based monitoring in clinical trials’ was originally published by Becker’s Hospital Review.
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Monitoring risk is certainly not a new concept in healthcare. There are countless treatment protocols and care pathways designed to mitigate risks for patients and making their treatment safer.
More recently, many of these risk management discussions are increasingly focused on clinical trials. Components of risk-based monitoring (RBM) in clinical trials go by many different names, including strategic monitoring, centralized monitoring, remote monitoring, and statistical monitoring. In short, RBM refers to the identification, prevention, mitigation and management of risks in clinical trials.
Risk-based monitoring has increasingly garnered attention over the past few years driven by the ICH E6 (R2) regulatory guidance requiring Sponsors to develop a targeted, risk-based approach to monitoring their clinical trials. It has been over a year since the ICH E6 (R2) final guidance was issued by the FDA, and pharmaceutical/biotechnology/device companies continue to adapt their internal processes.
As with blood glucose, INR or ambulatory blood pressure monitoring, the intent of RBM is the same: use data or clinical indicators to mitigate risk. All of the above could, in fact, be used as key risk indicators for a clinical study (depending on patient population and endpoint). Also, patient data is monitored centrally, using statistical algorithms to detect other outliers that may not be readily apparent during normal on-site monitoring activity.
This is a significant departure from the traditional model of on-site monitoring, in which all of the site’s source data are verified and monitored on-site. This approach is not only labor-intensive, but it also does not factor risk into which sites are monitored, applying the same monitoring frequency uniformly to all sites. It may seem that risk-based monitoring is just another methodology to analyze data; however, one of the primary goals of this new approach is to enhance the safety of patients in clinical trials by identifying any risks as early as possible. Understanding this goal will help both Sponsors and Investigators not only better prepare for RBM but also genuinely embrace it.
Implications for Sponsors
While TransCelerate BioPharma Inc (a consortium of biopharmaceutical organizations) has provided useful guidance recommendations for RBM, there certainly is not a “one-size-fits-all” approach to risk-based or centralized monitoring across the industry. Fiscal constraints and company culture can limit the extent or speed at which changes can be implemented. This is likely due to a combination of legacy procedures coupled with a level of risk averseness that is pervasive in such a regulated industry.
Many software and technology companies have promising products to assist in a centralized monitoring model, and these solutions are often cost-prohibitive – especially for small and medium-sized companies with a limited portfolio. Instead of spending their dollars on tech, some companies with limited resources simply opt to create their own risk-based process and solution. After all, they have access to the most important element of any risk-based methodology – their data.
Assessing how mature a company is from a data accessibility and usability perspective is a critical first step in initiating a risk-based monitoring process. Companies are still revising their operations to comply with the guidance and determine what data (and tool) will be used to prioritize a monitoring visit. They also include company infrastructure questions around new roles that may need to be created vs. expanding the responsibilities of current roles in clinical operations, data management, and biostatistics.
Implications for Investigators
The first hurdle for Investigators and other personnel at a clinical site is understanding that the monitoring landscape is changing. Since Sponsors will be adopting RBM in different ways, it is important for the Investigator to clearly understand what the expectations will be for each clinical trial. Some more conservative companies may elect to continue on-site monitoring with 100% source document verification and additional targeted visits based on risk indicators, whereas others may significantly decrease their on-site presence and elect to prioritize a centralized monitoring model.
Decreasing on-site presence can have both positive and negative effects. Sites may genuinely prefer to eliminate the logistic disruption that accompanies hosting a monitor. Either space limitations or real-time demands on staff may render targeted visits the preferable monitoring approach. Conversely, the traditional on-site model may be preferred if the Investigator and Study Coordinator rely on-site visits as opportunities to ask questions, review quality and even develop rapport (this is a partnership after all). In short, Investigators should be prepared in advance for vastly different monitoring frequencies and methodologies across Sponsor companies – and the reasons why.
With more emphasis on managing risk centrally, Sponsors may require more aggressive data entry timelines. Of course, data is the critical element in RBM – the sooner it is available, the earlier it can be analyzed for risk. An increased focus on data entry could adversely impact a site’s resources. Potential new headcount may be required for data entry, and current resources at the site could be increasingly challenged. As such, Investigators should be considering how their budget will be impacted prior to executing the clinical trial agreement. When a site is being considered for participation in a trial, Investigators should be equipped with relevant questions around the monitoring model to be used so they can negotiate the budget accordingly.
Lastly, Investigators should understand that centralized monitoring also detects data differences across participating sites. Data points that are statistically deemed outliers (or too similar) will be further reviewed, and the site could be targeted for an on-site visit. This will be another variable to consider for sites with unique patient populations or in large global studies, where the standard of care and practice patterns vary.
The Technology Variable
It is no coincidence that technology heavyweights (e.g., Apple and Oracle) recently announced the development of new technologies related to electronic health records and patient data collection. As clinical trials increasingly become more virtual, technologies that make the data collection process easier and faster will continue to play a critical role. While ensuring patient confidentiality will always be a top priority for these solutions, the potential to streamline the clinical trial process is very attractive for both companies and patients. Data can be available immediately for analysis, resulting in much faster drug development cycle times and lead to more treatment options available for patients.
With any data-driven process, more data is not necessarily a good thing. Filtering the signal through the noise will continue to be critical whenever RBM is implemented. Statistics, modeling, and analytics will significantly assist with data analysis, but thoughtful safety data review and interpretation will continue to serve as the backbone of successful risk identification.
Both Sponsors and Investigators can expect to work through the necessary growing pains as risk-based monitoring is implemented. From a Sponsor’s standpoint, it will be important for Investigators to understand and adopt any new data entry requirements. From an Investigator’s standpoint, it will be important for Sponsors to understand that these additional requirements may be associated with additional costs. Transparently working through the direct and indirect effects of RBM together, will not only increase efficiency and data quality, but it will, more importantly, help shape a safer future for the clinical trial participant.