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We are joined by Valerie Paolella, Associate Director in Clinical Trial Management at Innovaderm, who brings with her a wealth of experience in clinical research. She has dedicated 2 decades of her career to contract research organizations, collaborating with a diverse range of sponsors and sites, from small biotech firms to large pharmaceutical companies.

We will be exploring the topic of risk-based monitoring (RBM), focusing on 3 key areas in our conversation:

1. The various forms of clinical monitoring
2. Best practices and challenges
3. Assembling the RBM A-Team

The risk-based approach to monitoring emerged over a decade ago, guided by directives from the FDA. The onus of its implementation, however, was placed on sponsors and CROs. Observations reveal a spectrum of risk tolerance among sponsors, necessitating a flexible approach from CROs. Despite the diversity in risk-based decisions within the program, the unwavering objective is to ensure the generation of high-quality, reliable data and the safeguarding of patient safety.

Performing Monitoring on a Risk-Based Trial

1. Onsite Monitoring

Onsite monitoring, a well-understood concept, has been in practice for many decades. It necessitates Clinical Research Associates (CRAs) to review data in its original format. Despite the ongoing shift towards electronic data capture, paper still plays a significant role. Onsite monitoring enables CRAs to scrutinize the methods employed by sites to collect data and ensure adherence to regulations and good clinical practices.

For instance, in the consent process, while E-consent is gaining traction, consent is primarily obtained in a paper format. Being onsite allows for the verification of signatures and the timing of events through a medical chart. Thus, onsite presence enables CRAs to confirm the preservation of subject rights.

2. Remote Monitoring

Remote monitoring represents the second type of monitoring. This involves a targeted review of data off-site, complemented by additional checks from data management. Advancements in technology and access to various platforms necessitate an enhanced utilization of real-time data visibility.

Particularly post-pandemic, with restricted site access and travel, remote monitoring visits have proven to be quite beneficial. These visits help resolve site issues and maintain ongoing data cleaning between onsite visits.

3. Central Monitoring

Centralized monitoring constitutes the third type of clinical monitoring that contributes to risk-based approaches. This form of monitoring often gets confused with remote monitoring, but it is distinctly different. Central monitors do not conduct any onsite monitoring. Instead, their focus is on running statistical programs and analyzing data, providing an overarching view of subject data, site data, and study-level data.

Early signals are picked up through the review of data outliers, trends, and duplicates. A standard set of core variables is measured, such as protocol deviations, query aging, and data entry delays. Leveraging dermatology experience, the development of key risk indicators (KRIs) based on study endpoints serves as a crucial factor in determining the success of a trial.

One area frequently cross-checked for discrepancies is when dermatologists attempt to convert their regular practice to study-specific worksheets or questionnaires. Here, transcription errors and other types of mistakes can occur. Central monitoring is a very targeted review that provides clinical trial managers (CTM) with insights into the data. It identifies higher-risk sites that require further follow-up or escalation. When such higher-risk sites are identified, an increased onsite presence with CRAs is a typical response.

KRIs in Central Monitoring

In the context of KRIs, a notable example arises from studies on atopic dermatitis or eczema. The Eczema Area and Severity Index (EASI) score is frequently used, but issues with interrater reliability often surface. Central monitoring mandates the collection and review of rater information and EASI scores across different raters. Significant variances trigger the raising of concerns.

Integrating the 3 Monitoring Techniques

At this juncture, the responsibility falls on the CTM to decipher all the pieces of information from the central monitors, analytics, and observations from the CRAs. The culmination of these efforts results in a targeted decision.

The Key Steps in Executing an RBM Plan

From the onset, medical, scientific, and operational functional teams converge early to identify risks and devise mitigation strategies. This collaboration leads to the development of plans. The first key plan is the monitoring plan, the critical data points that have been highlighted and specifying the data that should be sourced and verified. The monitoring plan also sets the monitoring frequency, allowing some flexibility for adjustments based on risk criteria. These risk criteria are defined by  the initial risk assessment and are tracked against tools on an ongoing basis.

The centralized monitoring plan is a separate document detailing the KRIs that will be reviewed and aggregated. It outlines the recurrence for these inspections, establishes a pattern for trends, and evaluates the limits for reporting. It also highlights the escalation pathway to follow when issues are flagged.

Best Practices in Executing RBM

Maintaining an onsite presence proves absolutely necessary, with infrequent visits to the sites potentially leading to pitfalls. Certain issues may arise, particularly those related to the delivery of an investigational product, whether it be a complex infusion or a seemingly simple topical application. Unseen issues stemming from delivery at the site could impact the primary endpoint of the study. In dermatology studies, specifically, the frequent use of scales or questionnaires often requires as much standardization as possible due to their subjective nature. Face-to-face discussions with CRAs prove crucial in maintaining site engagement and ensuring oversight of data quality.

Challenges in Executing RBM

Resistance to change presents a significant challenge. Sites find themselves overwhelmed with the need to learn new systems and meet with CRAs remotely, necessitating an adaptation to different working methods. Onsite visits have become a well-understood science, but risk-based monitoring lacks standardization. Different implementations by various sponsors can lead to destabilization at the sites. A desire for routine exists, with an expectation that CRAs will visit every four weeks like clockwork.

However, when it comes to risk-based monitoring, uncertainty prevails. Addressing this involves the development of training materials or establishing early rapport with the sites to ensure an clear understanding of the projections. Providing an opportunity for sites to share their experiences with risk-based monitoring, and perhaps their fears, proves crucial. The focus lies in setting clear assumptions.

Assembling the RBM A-Team

The key to working effectively with experienced staff lies in maintaining clear and open communication. Support among onsite monitors, remote monitors, and central monitors proves essential. Asking the right questions and leading to the right areas of concern allows for different roles to address issues appropriately. Constant communication with team members as a CTM ensures that the right information is brought in at the right time.

The introduction of space monitoring brings a level of flexibility to the process, a change that may not sit well with everyone due to the inherent uncertainty in their daily tasks. However, this process is overseen by detail-oriented and diligent individuals who are driven to collect high-quality data. By empowering these individuals to concentrate on their specific roles, we can effectively navigate through these challenges. This involves onsite CRAs who focus on reviewing the process, remote CRAs who ensure the quality of data entry, and central monitors who keep track of trends. This multifaceted approach allows for a comprehensive picture to emerge, ensuring the integrity and success of the trials.

As we conclude another illuminating episode of Phase Forward, we find ourselves at the crossroads of science and progress. Remember that behind the jargon and statistics, lies stories of unwavering commitment, meticulous observation, and the pursuit of evidence that shapes our understanding of health and disease. Stay at the forefront of knowledge and innovation and follow Phase Forward on your preferred platform. My name is Valerie Coveney. Thank you for joining us. Until next time.

Let’s shape the future of research and make a difference in the industry, gain Innovaderm’s support in your upcoming trial and propel your study to new heights. 

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