Kathleen A. Mandziuk

A number of factors are leading to a paradigm shift in the way that clinical research is conducted. The adoption of EDC technologies that provide real-time access to data and the increasing cost of research has forced the industry to look at optimized methods of conducting clinical research. In addition, several studies have shown that 100% source data verification (SDV) may not result in higher data quality. All of these factors have led to increased interest in risk-based monitoring (RBM) strategies.  

As seen in recent regulatory guidance (i.e., FDA's draft guidance,

), there is growing support for the utilization of multiple monitoring approaches. In addition, industry initiatives such as the Clinical Trials Transformation Initiative (CTTI) and the recent TransCelerate position paper

  have provided preliminary guidance on how to incorporate RBM in clinical research. This growing regulatory support, and industry interest in reduced costs and higher quality, has been the impetus to increased attention toward RBM. 

However, increased enthusiasm for RBM has not yet translated into implementation for all organizations. The recent Industry Standard Research (ISR) survey that examined the attitudes of pharmaceutical and biotechnology professionals found that 73% of the respondents believed that RBM is risky from an operational standpoint, suggesting that although many research professionals are interested in RBM, they are very cautious about its implementation or have a lack of understanding in how best to implement RBM into their studies.  

PRA's Late Phase Services (LPS) team members have been utilizing RBM strategies since the early 1990s, driven by the growth of large-scale post-marketing and Phase IIIb research. For these studies, the large number of sites/prescribers, high volume of patients, long study duration, and accompanying collection required an innovative approach that did not rely on 100% SDV or frequency-based on-site visits to support data quality.  

The key to success of RBM is to incorporate a holistic evaluation of each individual study (Figure 1), beginning with a multi-disciplinary risk assessment and associated plan development. This process is not only conducted at the onset of a study, but also reevaluated and modified as needed due to changes in study design or standard of care.  

There are a number of considerations that should be evaluated during the risk assessment and planning phase. It is especially important to consider the study's critical data points, including the primary study objectives and safety data, as well as the critical processes that impact patient safety and support data quality. The plan should then be developed across functional areas and stakeholders to ensure that all findings of the risk assessment are addressed.  

Since limited onsite visits will occur, there needs to be a centralized monitoring function in-house that supports the prescribers/sites throughout each phase of the study. Central monitoring is critical to the success of RBM, but it has been defined and implemented in many ways throughout the industry. PRA's LPS team has developed a successful approach to centralized monitoring by incorporating a dedicated internal team of Site Management Associates (SMAs) who are trained in optimized start-up and training, ongoing site management, holistic data review, and proactive study support. SMAs utilize customized analytical tools to centrally evaluate the clinical data and site status in real-time. Upon review, the SMA may trigger an escalation action such as site retraining or an on-site visit by the CRA. This ongoing interaction between the SMA and the site staff has shifted the primary relationship and immediate support for the site from the CRA to the SMA.  

During the planning phase of a study utilizing RBM, a variety of functions (such as scientific affairs, therapeutic experts, statisticians, data managers and clinical operations) help the project team define the protocol-specific risks. Specific to these identified risks, a variety of analytical tools to identify site issues and triggers requiring on-site visits are developed. Considering SMAs review a substantial amount of data, these analytical tools are essential to quickly identify and escalate issues and trends that may require an escalation action. Each study is unique and will require customized analytical tools. Examples of on-site triggers may include patient enrollment (e.g., a site that enrolls >50% faster than the overall study average might trigger a visit to determine why the site is enrolling so quickly), serious adverse events (e.g., event rates <30% of the overall average) and large backlog of data entry or query resolution.  

					High-value site monitoring activities				

RBM is an evolution in monitoring as we know it today. RBM is not just a reduction in on-site monitoring, but a paradigm shift towards a different operational approach and organizational structure that focuses on the ongoing holistic review of clinical data, with centralized monitoring supplemented by on-site monitoring visits as needed.  

The ultimate result of RBM will alter site monitoring visit activities that focus on low-value activities (e.g., 100% SDV that allows only minimal time for focusing on critical data variables) towards high-value activities focused on key variables, including time to consult with study staff, review data, and evaluate site processes.  

In addition to promoting high-quality study results, RBM has been shown to reduce the cost of clinical studies by as much as 20-30% in service fees. It has been our experience that in order to be successful in RBM, it cannot be implemented merely through less on-site monitoring. As the industry continues to move towards this approach over the next several years, the role of the CRA will continue to evolve. Organizational structures will therefore need to shift to align with RBM, allowing for processes and analytical tools that shift the focus to central monitoring activities.    

is Vice President of Late Phase Services, 

MPH, RN, is Sr. Scientific Affairs Director, Late Phase Services, and 

 is Scientific Affairs Director, Late Phase Services all at PRA, 4130 ParkLake Avenue, Suite 400, Raleigh, NC 27612, 

1. FDA, "Guidance for Industry: Oversight of Clinical Investigations—A Risk-based Approach to Monitoring," 

2. EMA, "Reflection Paper on Risk Based Quality Management in Clinical Trials,"  

3. MRC/DH/MHRA, "Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products," 

4. TransCelerate Biopharma Inc, 'Risk-Based Monitoring Methodology Position Paper," 

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