Monitoring of Clinical Investigations: A Risk-Based Approach

17. April 2023: Monitoring of Clinical Investigations: A Risk-Based Approach

Wien, 17.04.2023 – Text: Catarina Carrão

The U.S. Food and Drug Administration (FDA) has just released an extension to the guidance “A Risk-Based Approach to Monitoring of Clinical Investigations”, previously published in 2013. The new guidelines are intended for clinical investigations regarding human drug and biological products, medical devices, and combination products; and it offers recommendations on planning a monitoring approach, developing the content of a monitoring plan, and addressing and communicating monitoring results.

Sponsors of clinical investigations are required to provide oversight, including ensuring proper monitoring of the investigation. Such oversight helps to ensure adequate protection of the rights, safety, and welfare of participants in the study and the integrity of the data submitted to the FDA. Therefore, sponsors should implement a system to manage, throughout all stages of the clinical investigation, both risks to participants (e.g., a safety problem) and to data integrity (e.g., incomplete and/or inaccurate data). This should be done by focusing on the design of efficient clinical trial protocols, tools for identifying and tracking potential risks, and procedures for data collection and processing. 

This tailored risk-based approach should be abreast of the sponsor’s overarching quality management activities and should be adjusted throughout the conduct of the investigation as needed. As such, at the protocol design stage, sponsors need to identify the critical data and processes necessary for human subject protection and maintaining data integrity throughout the investigation.

Once these are identified, sponsors should perform a risk assessment and determine whether risks to critical data and processes may be mitigated through revisions of the protocol and investigational plans. When risks cannot be resolved through such revisions, sponsors should determine how remaining critical risks will be identified, tracked, and managed via the sponsors’ monitoring plan or related study oversight plans. Furthermore, if throughout the clinical investigation not-anticipated additional risks are detected, those should be promptly addressed. 

In terms of risk-assessment methodologies the can be used, the new FDA guidance indicates the ISO/IEC 31010:2019 Risk Management – Risk Assessment Techniques has a tool that can be applied to clinical trials. Furthermore, the guideline recommends that the monitoring plan be organized to account for both the overall investigation and site-specific risks – recognizing that some mitigating activities may not be relevant for all investigational sites. With this in mind, the guidance indicates that the use of electronic data capture (EDC) systems with the capability to assess quality metrics in real time (e.g., missing data, data error rates, protocol violations) could help identify potentially higher risk sites that need more intensive monitoring. 

Furthermore, statistical and analytical methods to monitor critical data in a centralized manner may be particularly advantageous for overarching clinical investigation monitoring activities. As such, incorporating centralized monitoring as a part of a risk-based approach may help ensure the quality of a clinical investigation by allowing sponsors to aggregate and compare site data, and detect potential anomalies more quickly. Sites with multiple issues detected through centralized monitoring, such as delays in assessments or missing assessments, may also provide an early signal that the sponsor should promptly determine whether there is a need for a site visit and further corrective actions, in order to minimize the likelihood of similar issues occurring during the remainder of the clinical investigation. 

For investigations that include blinding of interventions and/or outcome assessments, ensuring that the blinding of the investigation is maintained is a critical process that sponsors should consider in their risk assessment. In a blinded investigation that requires the site staff personnel dispensing the test article to know whether the test article is the investigational product or the placebo, the adequacy of maintaining the blinding for the remainder of the site staff should be regularly monitored.

The guidance clarifies that focusing more monitoring activities on risks to the most critical data elements and processes should enable sponsors to achieve the objective of conducting a quality clinical investigation without necessarily having to conduct frequent routine visits to all clinical sites and extensive Source Data Verification (SDV). With that in mind, the guideline advises to schedule early monitoring visits (e.g., soon after the first few trial participants are enrolled), so that sponsors can ensure early in the investigation that the protocol is being followed and procedures are being correctly performed. If early monitoring identifies issues, then corrective actions can be implemented sooner avoiding further problems down the road.

Further info

Link 2013 RBM guidance:

Link 2023 RBM Q&A:

Link ISO/IEC 31010:2019 Risk Management – Risk Assessment Techniques:

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