What is Risk-Based Monitoring in Clinical Trials?

Risk-based monitoring in clinical trials is a vital aspect of any study, ensuring regulatory compliance and the safety of participants, among other benefits. Differing from other types of monitoring which assess studies in a broader way, risk-based monitoring takes place in the early stages of a clinical trial.

In this article, we will discuss what risk-based monitoring in clinical trials is, the strategies, benefits, and challenges, and how it can be applied in real-life examples.

What is Risk-Based Monitoring of Clinical Trials?

Risk-based monitoring (RBM) is used in clinical trials for a number of reasons and is a subset of RBQM (Risk-Based Quality Management), helping to ensure the quality of the study. Using data from previous clinical trials, risk-based monitoring can assist the study sponsor in terms of predicting possible outcomes, such as certain side effects a participant may experience.

The goal of RBM is to identify risks early in the trial’s development so that any potential issues can be mitigated to avoid any serious problems being encountered during the study. Once relevant data has been gathered, cohort analysis is then used to arrange the results into groups based on their risk level.

According to the most recent Good Clinical Practice (GCP) guidelines, RBM extends quality standards to all aspects of the study, adhering to core quality management principles. To be successful, RBM must create considered and simplified processes, utilize smart technology, and maintain a focus on evolutionary change management - the process of making small changes to improve performance in a changing environment.

What is the Difference Between RBM and Traditional Monitoring?

Traditional monitoring such as on-site, centralized, or remote monitoring is reactive, identifying any issues as they arise during the trial. RBM, on the other hand, begins very early in the trial’s development and continues throughout the trial on an ongoing basis.

What is the Difference Between RBM and RBQM?

RBM is a subset of RBQM (Risk Based Quality Management) which is a type of methodology that addresses issues such as research complexity, duration and cost. The vast majority of clinical trials include at least one RBQM component and the rate of adoption by study sponsors and contract research organizations (CROs) has increased significantly in recent years.

Risk Based Monitoring Strategies

According to the Food and Drug Administration (FDA), clinical trials can adopt the following risk-based monitoring strategies:

Centralized Monitoring

Centralized monitoring is a type of integrated approach that considers the expected risk level at each site that is to be used during the clinical trial. Using central statistical analysis, errors and inefficiencies can be detected at each site so measures can be taken to rectify any issue.

Remote Monitoring

This type of RBM does not require any on-site monitoring, instead using technology to monitor trial sites from an external location(s). Remote monitoring was commonplace during the COVID-19 pandemic due to restrictions on site visits, however, its success has seen it adopted frequently ever since.

Reduced Monitoring

Reduced monitoring is often used by CROs to guarantee accurate data, comparing a study’s source data against the final report, referred to as source data verification (SDV). This process identifies any errors before they can become an issue and the final report is published.

Triggered Monitoring

Triggered monitoring is based on a predefined trigger point (e.g. patient enrollment), with actions taken to assess a number of aspects of the clinical trial to confirm protocols are being followed and regulations are adhered to. The well-being of the participants is also evaluated with any serious adverse effects (SAE) reported.

Why Use Risk-Based Monitoring in Clinical Research?

Risk-based monitoring is key to improving safety and identifying potential risks, as well as helping to establish which type of monitoring is the correct option for a specific study. RBM is an essential component in the development of new drugs by safeguarding participants and ensuring data quality, protocol and regulatory compliance, and the quality of conduct.

Thanks to new technology, RBM can provide real-time information to create a proactive risk assessment strategy, and the methodology is included in regulatory guidance in both the US and the EU. Clinical trial regulations in the EU require a risk-based approach to evaluate many aspects of trial conduct.

RBM is also linked to the Quality by Design (QbD) model, enabling ongoing risk assessment and mitigation at an operational level. Both of these models have the same fundamental goal and are designed to increase the success rate of clinical trials in terms of better efficiency, shorter timeframes, and higher-quality results.

What are the Benefits of RBM?

Prioritize Patient Safety

A key benefit of RBM is that it can help to prioritize patient safety, identifying potential risks early in development so any serious health issues can be avoided. This increases the integrity of the trial, removing any bias from the data and correcting any errors.

This type of monitoring also gives trial sponsors a better understanding in terms of whether a new drug should be tested on people who have different levels of health risks, avoiding any potentially dangerous scenarios.

Increased Efficiencies

RBM automates many processes, taking care of straightforward tasks such as form completion and data entry to streamline activities. By automating simple tasks, the clinical trial team can focus on areas that present a higher level of risk or could be prone to error, resulting in safer and more efficient studies.

Reduced Costs

The cost of the study can also be reduced thanks to risk-based monitoring, assessing cost-based risks that may negatively impact the budget or extend the timeframe of the study. Again, thanks to automation, resources can be allocated more efficiently, resulting in further financial savings at each stage of the trial, from the initial development through to the distribution of a new drug.

Using data from previous trials can help recruit the perfect candidates, meaning a smaller number of participants is required to achieve the intended result.

More Efficient Monitoring

An obvious benefit of RBM is that it makes the monitoring process more efficient by combining all activities before, during, and after the trial into a single report.

Improved Patient Experience

The experience of all participants is crucial to a successful trial and the patient’s well-being and satisfaction can be significantly increased by real-time data collection. Wearable devices can send important information at any point during the trial, and from any location, with these insights available to view on mobile devices or on a web portal.

How Risk-Based Monitoring is Implemented in Clinical Trials

The FDA has provided guidance on a risk-based approach to monitoring which is outlined in three steps.

Detect Critical Data and Processes

The first stage of implementation is detection. Critical data must be evaluated and flagged if there is a potential risk. To do this, the sponsor must first identify the expected and acceptable values and parameters to act as a benchmark.

Perform a Risk Assessment

Step two is the risk assessment itself and once the risks have been flagged, they can then be visualized using a ‘traffic light system’ for clinical operations, ranking risks in terms of their likelihood to happen and their severity.

Develop a Monitoring Plan to Incorporate a Risk-Based Approach

Finally, a clinical/ trial monitoring plan (CMP/TMP) must effectively describe the monitoring methods, responsibilities, and requirements of the trial.

What Key Risk Indicators are Important in Risk-Based Clinical Trial Monitoring?

Key risk indicators (KRIs) are a measurement that indicates the level of risk that is associated with a process, procedure, or activity. In terms of clinical research, KRIs are an important aspect of a monitoring plan during a clinical trial’s preparation.

Based on FDA guidelines, KRIs do not need to be included in a clinical monitoring plan unless deemed necessary during the risk assessment phase.

KRIs may include:

• Safety - Relating to the potential of adverse event scenarios that may occur during the trial, this may include how any safety information is collected during the study.
• Investigational Product – This indicator relates to a new drug or treatment that is being tested, focusing on accountability, dosage, and compliance with drug administering protocols. 
• Recruitment/ Discontinuation - All participants need to be monitored to assess their safety and the efficacy of the medical intervention. To manage resources effectively, the enrollment phase should also be monitored. 
• Issue Management - Problems may arise during the trial which could result in a deviation from the study protocol, while there may be other general issues or problems that have been left unresolved. Any issues must be rectified in the correct manner and in a timely fashion.
• Data Quality - Abnormal trends may be identified in the data, impacting its overall quality. These inconsistencies must be corrected to maintain data integrity, The data quality KRI also encompasses the Case Report Form (CRF) completion level.
• Staffing, facilities, and supplies - The training needs of any staff need to be monitored and the delegation of responsibilities should be evaluated to determine if it is the most optimal solution. In addition, facilities also need to be assessed to ensure they have undergone proper maintenance, storage is sufficient, and that the calibration of supplies and equipment has been maintained.

Real-Life Examples of Risk-Based Monitoring in Clinical Trials

There are many examples of the real-life applications of risk-based monitoring, two of which are the ACRO study and COVID-19, highlighting the benefits of RBM components such as remote monitoring.

ACRO Study

In 2019, the Association of Clinical Research Organizations (ACRO) conducted a landscape survey among its member companies across 6,513 clinical trials. Of these, 22% included at least 1 of the 5 RBM components which are:

• Key risk indicators (KRIs)
• Centralized monitoring
• Off-site/remote-site monitoring
• Reduced source data verification (SDV)
• Reduced source document review (SDR)

Implementation rates for each component ranged between 8%-19%, with centralized monitoring the most frequently used and SDR the least frequently used. The survey also showed that the RBM adoption rate prior to the COVID-19 pandemic was below the expected level despite the clear benefits of this approach.

A small number of trials implemented several or more RBM/RBQM components, highlighting that an important aspect of the broader trial management framework is underutilized. However, the survey also showed that there was a clear shift to remote monitoring and that the effectiveness of monitoring was not reduced despite difficult circumstances.

COVID-19

COVID-19 has had a significant and disruptive impact on clinical research but also created its own natural experiment, forcing clinical trial sponsors to transition to remote practices, including remote monitoring. The pandemic effectively led to a widespread trial of remote site monitoring, showing how it can be successfully implemented going forward.

COVID-related protocol deviations were easily differentiated from non-COVID-related deviations, with the minor change in the monthly totals of no-COVID deviations clearly seen despite on-site monitoring being prohibited.

The data collected during the pandemic suggested that remote monitoring was effective and had no major drawbacks when compared to on-site monitoring pre-COVID. However, to maintain a high level of effectiveness, RBM principles needed to be established, as well as the increased reliance on technology.

A risk-based approach and centralized, remote monitoring assured data quality despite external disruption, while also ensuring regulatory consistency and a clear direction. This example helped monitoring activities to be swiftly resumed once COVID-19 restrictions were lifted, while also highlighting the benefit of only monitoring critical data.

On April 16, 2020, the FDA released information regarding remote monitoring, stating that sponsors should carefully evaluate technologies and favor a risk-based approach when collecting data from clinical trial sites and making changes to documents.

Conclusion

As a subset of RBQM (Risk RBQM-based quality Management, risk-based monitoring (RBM) is necessary to safeguard participants, maintain data quality, and provide accurate results during a clinical trial. The benefits of RBM include a more efficient allocation of resources, prioritized patient safety, and a better patient experience.

During the COVID-19 pandemic, remote monitoring, a risk-based monitoring strategy, became the norm, helping trial sponsors to meet their objectives in a safer and more cost-efficient way.