Recent years have witnessed a surge in clinical practice data generation outside of trials, driven by advanced signal detection technologies and expanded database capabilities. The integration of real-world data (RWD) with artificial intelligence (AI) tools is reshaping regulatory and medical decision-making. Various user-generated practice data types are stored in centralized databases, offering valuable longitudinal observations for disease insights. Thus, validating RWD for specific clinical contexts is crucial. Translating RWD into real-world evidence (RWE) is seen as pivotal for expediting clinical development. The US FDA defines RWD as “data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources”, and RWE as the “clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of RWD”. Emphasis is placed on bridging the reasoning gap between data and evidence, emphasizing the need for interpretative context to make data actionable.
US FDA- Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices
The U.S. Food and Drug Administration (FDA) has recently issued a draft guidance document aimed at providing clarity on the evaluation of real-world data (RWD) for the generation of real-world evidence (RWE) in the regulatory decision-making process for medical devices.
The preliminary guidance document establishes RWE as clinical evidence obtained through the analysis of RWD, encompassing a variety of information related to patient health and healthcare delivery from sources such as electronic health records, registries, and medical claims. A crucial aspect is the fit-for-purpose assessment, where the FDA rigorously evaluates the pertinence and dependability of RWD in the context of specific regulatory decisions. The guidance underscores the significance of sponsors engaging with the FDA for discussions on alternative approaches, and it recognizes a potential 60-day implementation period for both the FDA and industry following the finalization of the guidance.
This draft guidance serves as a revision to the FDA’s 2017 guidance, significantly broadening its scope. While the original guidance focused on Humanitarian Device Exemption, Premarket Approval Application (PMA), and De Novo submissions, the updated version now includes considerations under the Clinical Laboratory Improvement Amendments (CLIA). Mandated by the 2022 Food and Drug Omnibus Reform Act (FDORA) and the Medical Device User Fee Amendment (MDUFA V), this revision is a proactive response to the industry’s demand for more explicit guidelines regarding the utilization of RWE in regulatory decisions.
Key Considerations for RWE Use in Regulatory Submissions
The guidance provides general considerations for the use of RWE in supporting regulatory decision-making for medical devices. These considerations include –
Fit-for-Purpose Assessment: The FDA emphasizes the importance of a fit-for-purpose assessment when considering RWE for regulatory decision-making. This assessment involves evaluating both the relevance and reliability of the underlying RWD. Sponsors are encouraged to understand the strengths and limitations of the RWD, acknowledging potential biases, and communicating limitations effectively.
RWD Sources: The draft guidance recognizes various sources of RWD, including electronic health records (EHRs), registries, administrative claims data, patient-generated data, device-generated data, public health surveillance data, clinically annotated biobanks, and medical device data repositories. The FDA does not endorse one type of RWD over another, leaving the choice of source to sponsors based on the appropriateness for the study.
RWD Suitability: The suitability of RWD depends on its relevance to specific study questions. The guidance provides flexibility for sponsors to choose RWD sources based on their appropriateness for the study, with no endorsement of one type over another.
Potential Applications of RWE in Regulatory Submissions: The draft guidance outlines diverse purposes for which RWE may be applicable in regulatory eCTD submissions. These include generating hypotheses, serving as a historical or concurrent control group, supporting marketing authorization, re-training AI/ML-enabled medical devices, and providing evidence for various regulatory decisions.
Application of Investigational Device Exemption (IDE) Requirements: The FDA discusses the application of IDE requirements to the collection of RWD, emphasizing the need for an approved IDE for certain investigations involving devices. However, it clarifies situations where an IDE might not be required, such as when a device is used in the normal course of medical practice.
Use of RWD from Devices Authorized for Emergency Use: The guidance addresses the use of RWD from devices authorized for emergency use under section 564 of the FD&C Act. Clinical data routinely collected from devices authorized under Emergency Use Authorization (EUA) may be considered RWD and may be used to support regulatory decision-making.
FDA Collaboration: In cases of uncertainty regarding the applicability of IDE regulations to a particular RWD collection activity, sponsors or Institutional Review Boards (IRBs) are encouraged to contact the FDA. The FDA expresses its intent to work with sponsors to develop the least burdensome approach for generating RWE efficiently.
Study Design and Planning: The document emphasizes the importance of careful assessment of study design when using RWD. Similar to traditional clinical studies, careful planning and documentation are crucial, including decisions on randomization, controls, error control, data gathering, and precision of outcome measures.
Methods for Study Designs Using RWD: The FDA does not endorse a specific study design, leaving the choice to sponsors based on the study question, device, and objectives. Possible study designs include single-arm studies with external controls, non-interventional studies, and randomized controlled trials using RWD.
Documentation for FDA Review: Regulatory submissions should include the purpose of using RWE, study design, RWD sources, and version information. Fit-for-purpose assessment should evaluate data relevance, reliability, and completeness. Protocols and reports should provide detailed information on study aims, design, data source details, and operational definitions.
The FDA’s draft guidance on the use of real-world evidence for regulatory decision-making for medical devices provides comprehensive insights into considerations, sources, applications, and regulatory requirements. Sponsors are encouraged to engage with the FDA, and the document emphasizes transparency, documentation, and careful study design considerations when using RWD to generate RWE for regulatory purposes.
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