The article highlights the key points related to monitoring clinical investigations as prescribed by the applicable legislation.
The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a questions-and-answers document dedicated to a risk-based approach in the context of monitoring clinical investigations. The document is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be followed by medical device manufacturers and other parties involved in order to ensure compliance thereto. At the same time, provisions of the guidance are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with existing legislation and has been agreed with the authority in advance.
The present document is intended to provide additional information regarding the way risk-based approaches should be applied in terms of monitoring the conduct of clinical investigations related to medicines, medical devices, biological and combination products. According to the guidance, clinical investigation monitoring is a quality control tool for determining whether investigation activities are being carried out as planned. In particular, the document provides recommendations regarding the specific way such monitoring should be carried out. It is important to mention that similar matters are addressed in another document issued already by the FDA – a guidance document named Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring – while the purpose of the present guidance is to elaborate more on the most important aspects.
Under the general rule, parties responsible for clinical investigations (sponsors) are obliged to conduct the proper oversight, which includes monitoring described herein. The main purpose of the said oversight is to ensure adequate protection of the rights, safety, and welfare of participants in the clinical investigation and the integrity of the data submitted to the FDA. Hence, study sponsors are responsible for developing and implementing a system to be applied to manage both risks to study subjects (participants) as well as the data integrity (its accuracy, reliability, and completeness) throughout the entire period of clinical investigation. As a part of this process, attention could be paid to clinical trial protocols or the tools used to identify and track potential risks that are relevant to the specific trial. The authority states that effective implementation of risk-based monitoring, including the prioritization of monitoring and other oversight activities directed at processes and procedures critical for human subject protection and maintaining data integrity, should help maximize the quality of a clinical investigation.
At the same time, the authority acknowledges that even though the appropriate requirements are set forth by the relevant legislation, they are missing details on how exactly this should be performed by the parties involved. In this respect, the authority encourages study sponsors to apply a risk-based approach when developing monitoring plans and making changes thereto if necessary. It is mentioned that this risk-based approach should be informed by the sponsor’s overarching quality management activities undertaken in the development of the protocol and associated investigational plans and should be adjusted throughout the conduct of the investigation as needed.
In accordance with the initial guidance document mentioned herein above, study sponsors are encouraged to identify the data which is critical for the trial, as well as key processes necessary to ensure the protection of study participants at the early protocol design stage. The said assessment should also cover the aspects related to maintaining data integrity for the investigation. Upon completion of this process, a risk assessment should be conducted in order to determine if the risks identified could be duly mitigated by making necessary changes to protocols and investigational plans. Should it appear that some of the risks cannot be resolved, an additional determination is to be performed with respect to the way these risks should be identified, tracked and managed in the course of the study. This process should be carried out by the team members dealing with conducting and monitoring clinical investigations. However, it would also make sense to consider the patient’s perspective.
The study monitoring itself should be carried out in accordance with the respective plan developed before commencing the study, while all the important issues identified in the course of the study should be duly addressed. The said plan should also provide a procedure for escalating important issues to make sure they are addressed properly. Apart from this, the authority encourages study sponsors also to add details on the way monitoring activities should be adjusted based on the findings. As an example, the document describes a situation when important issues are identified in the course of monitoring a clinical site where an investigation takes place – in such cases, it would be reasonable to increase the duration and/or frequency of visits for that specific site.
According to the guidance, the processes related to risk management should continue as long as the investigation takes place. The authority also encourages sponsors to use the information gained from each investigation, including the monitoring experience, to inform, as appropriate, the conduct of other ongoing investigations, future clinical investigations, risk assessments, and monitoring plans.
The elements to be covered by the risk-based quality management are expected to include, inter alia, the study-level monitoring plan, and relevant monitoring activities. These elements are vitally important for ensuring the issues are properly identified and addressed. Furthermore, the aforementioned guidance highlights the key factors to be taken into consideration by the parties responsible for clinical investigations when developing a monitoring plan and ensuring it meets the needs of the investigation. The said document also provides several examples of methods and techniques to be used for monitoring clinical investigations.
In summary, the present FDA guidance outlines the most important aspects to be considered with respect to the risk-based approach to be applied in the context of monitoring clinical trials. The document describes the main principles and indicates the key points study sponsors should pay attention to when developing a monitoring plan.
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