Clinical trial sponsors for pharmaceutical products (drugs and/or biologics for human use, medical devices, combination products etc) are required to provide the oversight for monitoring a clinical trial to help make sure that the rights, safety, and welfare of trial participants are protected. For this, sponsors are required to implement a system that manages safety risks and data integrity for participants throughout all stages of clinical trials- be it through trial protocol design, tools for identifying risks, and data collection processes. Ideally, the system should also include a risk-based approach for monitoring the clinical trial to further support and enhance the overall quality of the clinical trial.
Risk-based monitoring has recently emerged as a strategic and targeted approach that incorporates real time data analytics for monitoring clinical trial. This helps trial investors in addressing errors, identifying risks, and mitigating them effectively so that they do not compromise on trial quality. More simply put, risk-based monitoring aims to ensure the quality and safety of a clinical trial by identifying, evaluating, monitoring, and reducing the risks that could potentially impact the quality or safety of the study.
Clinical trial costs (and complexities) are increasing. A significant part of the trial costs includes the traditional on-site review of clinical trial data, which relies on source data verification (SDV) which can be resource-heavy and limited in identifying and mitigating risks . Thus, a more centralized and risk-based approach to monitoring trials is preferred by regulatory authorities for efficient monitoring to safeguard the welfare, safety, and data integrity. Some of the advantages of risk-based monitoring include lower costs and errors, improved data comparison and analysis, and more accurate and/or timely results .
US FDA: Perspective on Risk-Based Approach to Monitoring Clinical Trials
The US FDA requires clinical trial sponsors to monitor how a trial is being conducted and the progress it is making. They recommend sponsors to implement a risk-based approach when developing and/or revising their trial monitoring plans as per their guidance that was released in 2013 .
In April 2023, the US FDA issued a guidance document that additionally provides recommendations on preparing a monitoring approach, developing monitoring plans, and communicating results. The guidance emphasizes the importance of study-level monitoring plans and activities for identifying and addressing risks during trials. It recommends a three-step approach, including identifying critical data and processes, performing a risk assessment to determine specific sources of risk, and developing a monitoring plan that outlines monitoring methods, responsibilities, and requirements for the trial .
A)- Monitoring Approach
Purpose of risk assessment in clinical trials : Risk assessment in clinical trials is essential to identify and minimize potential hazards to human subjects’ safety and data reliability. While designing the protocol, sponsors should evaluate risks to critical data and human subject protection. The risk assessment should inform the development of the investigational plans, clinical trial protocol, and, monitoring plan, and should be recorded and updated throughout the investigation. Information on identified risks and how monitoring methods will address them should be included in the monitoring strategy. The FDA may require documentation of the sponsor’s initial risk assessment and any pertinent updates if a risk-based monitoring approach is being used.
Consider new risks : In clinical trials, sponsors are required to monitor not only the identified risks but also any new risks that may arise during the investigation. The monitoring plans should be comprehensive and address all potential risks that could impact the safety of participants and the quality of the investigation. Sponsors must adjust the monitoring plans as needed to address any new information about risks that becomes available during the investigation.
Making monitoring plan considering specific factors : The FDA recommends that sponsors create a monitoring plan that considers factors such as the clinical investigation infrastructure, electronic data collection, stage of the study, and staffing. The plan should address both overall and site-specific risks and be modified as needed based on any additional issues identified during the investigation. Early monitoring visits can help ensure that the protocol is being complied with accurately and procedures are being carried out correctly, especially for complex studies.
Centralized Monitoring : The document discusses centralized monitoring, which involves an evaluation of study procedures across multiple clinical sites by sponsor personnel. This allows sponsors to review data from the entire study, perform data checks, ensure documents are current, and determine which sites require on-site review. Including centralized monitoring as part of a risk-based monitoring approach may improve the quality of a clinical investigation by allowing sponsors to identify potential anomalies more quickly. Sites with multiple issues detected through centralized monitoring may signal the need for a site visit and corrective actions.
Maintenance of blinding : The maintenance of blinding in clinical trials is crucial and should be included in the risk assessment. Sponsors should take steps to mitigate risks to blinding maintenance that are discovered during risk assessment before the study begins. Deviations that could lead to unintentional unblinding should be found and recorded during the study, and adequate blinding should be maintained at clinical sites and by the sponsor. The DMC Charter outlines how Data Monitoring Committees can access unblinded data.
B)- Monitor plan content
Monitor plans based on risk assessment : The FDA recommends that monitoring plans for clinical trials be created based on a risk assessment that considers study-specific and site-specific risks, prioritizes critical risks, and manages both expected and unexpected risks. In addition to the components suggested in the 2013 RBM guidance, the monitoring plan should describe the study design, procedures for verifying randomization, a sampling plan, and a method for determining whether an issue is present at other clinical sites. The plan should also include an approach for issue escalation based on specific issues detected through monitoring.
C)- Follow-Up and Communication of Monitoring Results
Immediate assessment of significant issues : The document suggests that if significant issues are detected during monitoring, they should be immediately assessed and addressed through root cause analysis and appropriate preventive and corrective actions to minimize their impact on participant safety and data integrity. The risk assessment and monitoring plan should be reviewed and updated to reduce the risk of recurrence. Possible actions include improving training, suspending enrollment at clinical sites, revising investigational plans, and modifying vendor service agreements. All significant issues and actions taken should be communicated and documented to the relevant parties, such as sponsor management, clinical sites, DMCs, regulatory agencies, and, institutional review boards, as needed.
Documentation of Monitoring Activities : The 2013 RBM guidance suggests that monitoring activities in clinical trials should be documented, including the date, individuals involved, a summary of reviewed data or activities, identification of any issues, and actions taken. This documentation should confirm compliance with the monitoring plan and be submitted to relevant management for examination and follow-up. The clinical investigator should be informed of significant findings. Monitoring should include on-site and remote monitoring, as well as centralized monitoring across clinical sites.
The FDA’s guidelines on risk-based monitoring for clinical trials involves identifying and reducing potential risks that may impact the quality or safety of the study. The process involves a three-step approach, including identifying critical data and processes, performing a risk assessment, and developing a monitoring plan. Sponsors are encouraged to implement a system to manage risks, use a risk-based approach to monitoring, and revise their plans as needed. The monitoring plan should consider factors such as infrastructure, electronic data collection, stage of the study, and staffing. The maintenance of blinding and documentation of monitoring activities are also essential components of risk-based monitoring. If significant issues are detected, they should be addressed immediately and communicated to relevant parties.
References and Further Reading
 Tudur Smith C, Stocken DD, Dunn J, Cox T, Ghaneh P, Cunningham D, Neoptolemos JP. The value of source data verification in a cancer clinical trial. PloS one. 2012 Dec 12;7(12):e51623.
 Barnes B, Stansbury N, Brown D, Garson L, Gerard G, Piccoli N, Jendrasek D, May N, Castillo V, Adelfio A, Ramirez N. Risk-based monitoring in clinical trials: past, present, and future. Therapeutic Innovation & Regulatory Science. 2021 Jul;55(4):899-906.
 US FDA. Oversight of Clinical Investigations- A Risk-Based Approach to Monitoring. United States Food and Drug Administration. 2013
 US FDA. A Risk-Based Approach to Monitoring of Clinical Investigations: Questions and Answers. United States Food and Drug Administration. 2023