The adoption of risk-based monitoring (RBM) has been led by regulatory agencies and continuously driven by the pharma industry, as well as organizations such as TransCelerate Biopharma.
Different pharma companies are implementing this approach in different ways, stages and time points. The first documents regarding RBM were written in 2011, initially as a guidance (EMA Draft Reflection Paper & FDA Draft Guidance on RBM). However, the ICH E6 Addendum was recently finalized, where additional RBM guidelines were outlined. Interestingly, there was an added emphasis on central monitoring, which was clearly defined (section 5.18.3). Updates to this document reflect changes indicative of the ongoing progress of RBM and Central Monitoring throughout the pharma industry.
Although there are several recommended RBM core principles, it is vital to focus and place trust in new areas such as central monitoring, allowing for a fair assessment in the effectiveness of new functionalities in support of RBM.
But first, let us remind ourselves of the core principles of RBM:
- Focus monitoring on the most critical data and processes
- Share responsibility for subject safety, data quality
- Customize monitoring approach to each trial/site based on risk assessment
- Monitoring as a cross-functional responsibility
- Use of technology to monitor study conduct
- Adapt monitoring approach in response to findings
- Rely more on offsite and central monitoring
There is an immediate opportunity for industry to benefit from following the last principle, ’Rely more on Offsite and Central Monitoring.’ Although the objective of this article is to focus on central monitoring, I would encourage the full implementation of this core principle in order to obtain clear results reflecting the value-add on the data quality of a clinical trial.
We can understand the importance of this last principle since it includes two of the four key elements of RBM studies:
- RACT (Risk Assessment and Categorization Tool)
- Strategic On-site Monitoring
- Off-site Monitoring
- Central Monitoring
If we turn our attention to central monitoring, the goal is to perform holistic assessments of clinical trial data, utilizing analytics and visualizations to detect trends, outlier data, and areas of emerging risks.This can lead to early issue detection, resolution, as well as a targeted review of sites that need the most attention, resulting in enhanced patient safety and improved data integrity.
Central monitoring provides a unique analysis of data across sites, countries and studies to allow for early detection and targeted intervention. It is not a fully automated process; it relies on individuals who have effective communication skills, strong critical thinking capabilities, technical abilities, as well as knowledge of clinical operations, data management and GCP.
The main responsibilities of a Central Monitor include:
- Remote assessment of key risk indicators (KRIs)
- Early identification of issues/emerging risks in study specific critical variables observed as a trend or outlier indicative of poor performing sites
- Support risk mitigation and global monitoring of processes that align with company’s programs and protocols
We can summarize the way both RBM and central monitoring processes are implemented with the following questions and answers:
- What are our risks? Risk Assessment Categorization Tool (RACT)
- What can help us to mitigate risks? Key Risk Indicators
- How will we know when to take action? Thresholds and Central Monitoring Review
- How will we respond? Actions and follow-up with the cross-functional study team
When breaking down the above consignments, it’s important to emphasize the main challenges of implementing central monitoring:
- Monitoring trends and outliers for ALL primary endpoint data including data from all sources (including variety of external data, commonly critical data)
- Ensuring timely and accurate issue management
- Ensuring study teams understand the differences between central monitoring review vs. data cleaning
- Generating central monitoring performance metrics
Although we can propose recommendations to overcome these challenges, sometimes we need the aid of technology.
As a result of central monitoring assessments and the use of new analytics software, we can manage findings and identify issues early in a trial that help us prevent the recurrence of duplicate issues and help mitigate risks.
In addition, with the implementation of the central monitor function, as well as offsite review activities, it is anticipated the number of required onsite visits will potentially decrease. Moreover, the duration between visits will likely increase, allowing site monitors to truly focus more on specific sites that require additional support.
Although some people would consider this shift in monitoring activities to be driven by economic reasons, I trust this new monitoring approach will be a key factor in obtaining better results potentially in terms of fewer audit findings and early detection of safety and efficacy issues.
Therefore, I strongly believe this methodology will contribute to improving our overall data monitoring efficiencies, resulting in an enhanced monitoring methodology.
Ultimately, there are numerous benefits and recommendations for adopting a RBM approach, some of which can be summarized as below:
- RBM addresses greatest risks impacting subject safety and data quality
- Recent ICH Addendum supports how RBM is being implemented across industry
- Use of technology to identify issues is key
- Targeted onsite and offsite monitoring focuses on early issue intervention at poor performing sites
- Central monitoring provides a new lens to view clinical trial data for outliers and trends, resulting in early issue detection and targeted intervention
- RBM is a cross-functional collaboration
- Communication within study team is crucial
Substantial effort is being applied by clinical research organizations to improve clinical research activities as a whole. The ongoing evolution in important areas such as technology is leading to significant progress in developing our clinical research expertise. Also, the development of special tools and systems adapted for the collection of clinical data are key advances we should take advantage of. RBM and central monitoring are examples of increasing value and efficiency in the monitoring of clinical trials, enhancing patient safety and ensuring the quality of the data. We have the opportunity to demonstrate this monitoring approach is a success, so let’s do it.