Serious interest in the use of real-world data (RWD) and real-world evidence (RWE) to support drug development first arose when Congress passed the 21st Century Cures Act of 2016.1 The intent was to accelerate drug development and supplement traditional clinical trial data with data from a more diverse array of patients with wide-ranging comorbidities that receive treatment in a broader variety of treatment settings. The Cures Act required the U.S. Food and Drug Administration (FDA) to publish a framework for a program to evaluate the use of RWE in regulatory decision making, which the agency published in December 2018.2
During the COVID-19 pandemic, RWD and RWE were essential sources of information for the FDA to expedite approvals of COVID-19 vaccines and therapeutics and to allow other clinical studies to progress under the changing circumstances. Faced with limited access to traditional clinical trial data due to lockdowns, the agency rapidly pivoted from reluctance to willingness to rely on RWE for policy and regulatory decision making.3
Another driver of interest in RWD and RWE is the increasing use of FDA programs designed to accelerate the approval process, such as Breakthrough Therapy, Fast Track, and Accelerated Approval designations. In many cases, drug candidates with these designations are approved on the basis of limited clinical trial data and with the requirement that post-approval studies are performed, some of which may use RWE and RWD.4 However, there have been questions raised about the feasibility of using RWD/RWE for such post-approval studies.
The challenge for the FDA is ensuring that the right RWD used to generate RWE is selected and that they are of high quality, afford sufficient coverage,5 and — for post-approval studies in particular — are suitable for emulating the data obtained in actual clinical trials.4 There is greater variability in RWD and arguably a greater risk of data gaps.5 Some data, such as those collected by wearables and health apps, for instance, are not actually intended to serve as RWE but are being used for this application.
Some of these issues are being addressed by the rapidly growing array of RWE sources. An analysis of 90 examples of RWE used to support regulatory decisions on medical devices was published by the FDA in March 2021.6 The vast majority included registries or medical records, with just two relying on patient-generated data and three on digital health devices. Regardless of the source, the key to successful use of RWD and RWE is validating the data. Understanding and characterizing individual data sets and then organizing and integrating the data from multiple sources is a real challenge.5
To flesh out its RWE/RWD framework, the FDA published three draft guidance documents in September, October, and November 2021. Further guidances are anticipated.
The first, Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products Draft Guidance for Industry September 2021,8 assesses three primary factors when considering the use of electronic health records (EHRs) or medical claims data in clinical studies to support regulatory decisions on effectiveness or safety.
The second, Data Standards for Drug and Biological Product Submissions Containing Real-World Data,9 addresses the requirements that various types of RWD be presented in a standard electronic format that the FDA can process as part of a normal drug application evaluation.
The third, Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products,10 outlines the FDA’s proposed approach to assessing the use of patient registries to support regulatory decisions.
In the draft guidance on using EHR and medical claims data, the FDA does not specify particular data sources but focuses on providing general principles for the use of RWD.11 The agency provides recommendations on how to select and validate data sources that appropriately address the study question in terms of study populations, exposure, outcomes of interest, and other factors; develop and validate definitions for study design elements; and maintain the provenance and quality of data during “accrual, curation, and transformation into the final study-specific dataset.”
Importantly, the guidance makes clear that the FDA does not expect RWD/RWE to ever replace clinical trials, but that it has the potential to significantly supplement and augment clinical trial results.12 The agency also strongly encourages drug developers to consider the use of RWD well in advance and to initiate dialogue and collaboration with regulators as early as possible. Furthermore, when electing to use EHR and medical claims data, the relevant method of data capture, potential missing data, and data validation must all be considered.
Notably, the agency views this draft guidance as a preliminary document and expects to provide updates as its experience with RWD and RWE increases.11
The second RWD/RWE draft guidance issued by the FDA in October 2021 focuses on what drug developers should do when submitting product study data in drug applications that are derived from real-world sources. Standardization of such data is a real challenge, because it comes from so many different sources that capture data in different formats.13 Data covered in this guidance include data from EHRs, medical claims data, data from product and disease registries; patient-generated data, including data from in-home-use settings; and data gathered from other sources that can inform on health status, such as mobile devices.14
The guidance provides examples of how to map RWD to the Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model (SDTM). It also specifies that RWD must use the data standards set forth in the FDA’s Data Standards Catalog.15 Sponsors are again encouraged to contact the agency early on in the process to discuss the data and data transformation approaches that have been proposed, including the processes that will be in place to increase confidence in the RWD and the means by which those processes will be electronically documented.13
In the latest draft guidance issued in November 2021, the FDA focuses on patient registries as RWD/RWE sources, homing in on the factors that should be considered when determining if such data are fit for use in regulatory decision-making processes.16 Such factors include how the data will be used, the enrolled patient population, the type of data collected, how data sets are generated and maintained, how the data is curated and analyzed, and whether the data can be supplemented by data from other sources.
As in the other two draft guidances, the FDA stresses here the importance of early interaction with agency representatives before any study that will rely on RWD/RWE from patient registries is initiated. Ideally, sponsors will present proposed protocols and analysis strategies with clear explanations of how the reliability, relevance, and comprehensiveness of the data sources and methodologies used to validate key design elements and maintain quality during data accrual, curation, and transformation will be assured.16
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