On December 7, FDA published the much-anticipated “Framework for FDA’s Real-World Evidence Program” for drugs and biological products (the “Framework”).  In a statement announcing the Framework, Commissioner Gottlieb recognized the opportunities and challenges of using real-world data (“RWD”) and real-world evidence (“RWE”) to enhance regulatory decision-making and noted that leveraging this information is “a top strategic priority for the FDA.”  FDA opened a docket for public comments on the Framework through February 5, 2019.

The Framework focuses in particular on the use of RWE to support regulatory decisions about effectiveness.  The agency outlines three considerations that will guide its overall RWE Program and inform the agency’s assessment of individual drug applications.  The Framework also offers background on the agency’s previous use and current initiatives with respect to RWE and related topics, such as innovative clinical trial designs.  This blog post provides an overview of FDA’s proposal and highlights a few initial takeaways noted by Covington’s Digital Health team.

The 21st Century Cures Act (“Cures Act”) required the agency to create a program for evaluating the use of real-world evidence (“RWE”) for two purposes: (1) to help support the approval of a new indication for an already-approved drug, and (2) to help support or satisfy postapproval study requirements.  The Cures Act also mandated that the agency publish a framework for implementing the RWE Program that describes the sources of RWE; the gaps in data collection activities; the standards and methodologies for collecting and analyzing RWE; and the priority areas, remaining challenges, and potential pilot opportunities that the RWE Program will address.  The new Framework covers drugs and biological products; FDA addressed the use of RWE in the context of medical devices separately in 2017.

As a threshold matter, FDA underscores the distinction between real-world data and real-world evidence.  The Cures Act defined “real world evidence” as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.”  In contrast, but similar to FDA’s approach for medical devices, the Framework differentiates between RWE and RWD as follows: RWD is defined as “data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources”; RWE, on the other hand, is “clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD” (emphasis in original). FDA explains that evaluating the use of RWE for regulatory decision-making involves assessing both the reliability and relevance of the underlying RWD and the methodologies used to generate RWE from the RWD.

Building on the definitions of RWD and RWE, FDA’s framework establishes a “three-part approach” for incorporating this information into regulatory decision-making for drugs and biological products:

  1. Whether the RWD are “fit for use” in regulatory decision-making;
  2. Whether the methodologies used to generate RWE can provide “adequate scientific evidence” to address the regulatory questions presented; and
  3. Whether the approach used in a particular case meets FDA’s regulatory requirements, such as established standards for data collection and study monitoring.

Here are a few initial takeaways from the Framework:

  • Guidance on RWE is Coming.  Within this Framework, FDA sets forth an overarching plan to develop guidance in a number of specific areas, including:
    • the reliability and relevance of RWD from medical claims and electronic health records used to generate RWE regarding drug product effectiveness;
    • potential gaps in sources of RWD and strategies for addressing them (one strategy identified in the Framework is exploring the use of mobile technologies, electronic patient reported outcome tools, wearables, and biosensors);
    • considerations for designing clinical trials that include pragmatic design elements and generate evidence of effectiveness for regulatory decisions;
    • observational study designs using RWD, including whether and how these studies might provide RWE to support product effectiveness in regulatory decision-making; and
    • as discussed in greater detail below, whether additional guidance is needed to address regulatory considerations when utilizing electronic source data. Of note, the agency says that it will not address HIPAA in future guidance, but it leaves open the possibility that it might provide additional guidance on other aspects of data privacy and cybersecurity of electronic source data.
  • Effectiveness Data. The RWE Program will focus on the potential use of RWE to support changes to labeling about drug product effectiveness, including adding or modifying an indication, adding a new population, or adding comparative effectiveness or safety information.  Although the Cures Act also calls for FDA to establish a program to evaluate the potential use of RWE for fulfillment of postapproval study requirements, the Framework contains little discussion of this potential use of RWE.
  • Concerns About Observational Studies and RWD. The Framework acknowledges “observational studies may provide credible evidence,” but finds a stronger scientific justification for using randomized controlled trials as evidence of drug effectiveness.  Indeed, the Framework indicates FDA will “consider reporting requirements for [observational studies] used to support effectiveness determinations.”  These statements in the Framework signal that FDA remains cautious about the potential uses of RWE for regulatory purposes; FDA appears focused on an incremental approach, such as RWE to support a supplemental indication of an approved oncology drug or RWE from a “hybrid” clinical trial with both traditional RCT and RWE elements used to generate data.  Bottom line, the burden will be on relevant stakeholders to demonstrate to FDA the ways that RWD and RWE can and should be used to support regulatory decisions.
  • Relation to Prescription Drug-Use-Related Software. FDA published the Framework shortly after issuing a proposal for regulating prescription drug-use-related software (see our earlier blog post here).  That said, these documents does not discuss whether and how they relate to each other, even though both implicate software disseminated by or on behalf of a drug sponsor.
  • Data Standards for Submissions. FDA recognizes the importance of developing data standards for submissions, to help ensure efficient review of RWD by the agency.  FDA indicates it has “already been active in developing data standards for regulatory use and will continue to expand its work in this area.”  This work will include identifying the relevant standards and methodologies to maximize the utility of RWD.
  • Use of Electronic Source Data for RWE. FDA touches on some of the regulatory considerations that arise from use of electronic source data, such as electronic health records and electronic data from clinical studies.  The agency points out that it already has published some relevant information on these topics, including regulations that focus on the quality, authenticity, and reliability of electronic records (21 CFR Part 11) and a related guidance published in 2017.  The agency highlights several key regulatory compliance issues, including informed consent, validation of electronic systems, audit trails for electronic records, and agency inspections.  FDA is considering whether additional guidance on the use of electronic source data is needed.

FDA stresses the importance of continued engagement with all stakeholders in building out its framework.  As FDA continues to develop policy in these areas, the agency will provide an opportunity for stakeholders to comment on specific regulatory issues and the agency’s proposed guidance documents.  The current docket gives stakeholders an opportunity to weigh in on FDA’s overarching strategic vision for implementing the RWE Program and the potential to offer important perspectives on how FDA can optimize the use of valuable real-world experiences in regulatory decision-making.