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.

Tags: Artificial Intelligence (AI), digital health, FDA, Mobile Medical Apps, Mobile Technology
Print:
Email this postTweet this postLike this postShare this post on LinkedIn
Photo of Wade Ackerman Wade Ackerman

Wade Ackerman advises companies and trade associations on complex and novel FDA regulatory issues that require coordinated legal, regulatory, and public policy strategies.

Through more than 19 years of experience in private practice and positions within the FDA and on Capitol Hill, Wade…

Wade Ackerman advises companies and trade associations on complex and novel FDA regulatory issues that require coordinated legal, regulatory, and public policy strategies.

Through more than 19 years of experience in private practice and positions within the FDA and on Capitol Hill, Wade has acquired unique insights into the evolving legal and regulatory landscape facing companies marketing FDA-regulated products. He co-leads Covington’s multidisciplinary Digital Health Initiative, which brings together the firm’s considerable global resources to advise life sciences and health technology clients harnessing the power of information technology and data to create new and cutting-edge innovations to improve health and achieve better outcomes for patients.

Until June 2016, Wade served as Senior FDA Counsel to the U.S. Senate Health Education, Labor & Pensions (HELP) Committee Ranking Member Patty Murray (D-WA) and, prior to that, Chairman Tom Harkin (D-IA). While at the HELP Committee, Wade was involved in all major FDA legislative initiatives, oversight hearings, and other Senate HELP Committee activities concerning the FDA and the Federal Food, Drug, and Cosmetic Act. From January 2015 through June 2016, he helped negotiate many of the FDA-related provisions in the 21st Century Cures Act, which included reforms to FDA’s review and approval of new drugs, devices, combination products, and digital health software. He also worked closely with the FDA and other stakeholders as Congress examined legislative reforms in other key areas, including diagnostics and laboratory developed tests, cosmetics, and over-the-counter drugs.

Before taking his Senate role, Wade served for more than five years as Associate Chief Counsel within the FDA’s Office of Chief Counsel. He was responsible for providing legal advice to the FDA’s Center for Drug Evaluation and Research (CDER) and the Office of Commissioner (OC) on a wide range of issues. While at FDA, he also helped to develop and implement the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 and the Drug Quality and Security Act (DQSA) of 2013—both significant reforms to FDA’s regulatory authorities.

Read more about Wade AckermanEmail
Show more Show less
Photo of Krista Carver Krista Carver

Krista Carver co-chairs Covington’s Life Sciences – Pharmaceutical and Biotechnology Industry Group. Drawing on her nearly 17 years of experience at the firm, she provides strategic and practical advice to clients on an array of FDA regulatory issues, including those that intersect with…

Krista Carver co-chairs Covington’s Life Sciences – Pharmaceutical and Biotechnology Industry Group. Drawing on her nearly 17 years of experience at the firm, she provides strategic and practical advice to clients on an array of FDA regulatory issues, including those that intersect with other areas such as healthcare. Ms. Carver also assists clients with advocacy before FDA, including formal dispute resolution and citizen petitions, and maintains an active policy practice addressing legislative issues surrounding amendments to the Federal Food, Drug, and Cosmetic Act and related laws. Chambers USA reports that Krista “is a brilliant lawyer with deep technical expertise that she is able to boil down clearly and succinctly,” and that she “is incredibly impressive in biosimilars issues and biologics,” per Chambers sources. Krista co-chairs Covington’s IRA Task Force.

Krista’s areas of focus include:

  • Inflation Reduction Act;
  • Biosimilars;
  • Hatch-Waxman regulatory issues;
  • Orphan-drug designation and exclusivity matters;
  • Pediatric Research Equity Act and Best Pharmaceuticals for Children Act;
  • Digital health;
  • Gene therapies and human cellular, tissue, and cellular- and tissue-based products;
  • Risk evaluation and mitigation strategies (REMS), pharmacovigilance, postmarketing study requirements; and the CREATES Act; and
  • Clinical trial and submission issues including real-world evidence, decentralized clinical trials, and diversity in clinical trials.
Read more about Krista CarverEmail
Show more Show less
Photo of Nigel Howard Nigel Howard

For over 30 years Nigel Howard has specialized in technology transactions such as M&A, strategic alliances, licensing, distribution agreements and outsourcing. Clients range from start-ups and emerging companies to international corporations. He has led negotiations of billion dollar service agreements that were critical…

For over 30 years Nigel Howard has specialized in technology transactions such as M&A, strategic alliances, licensing, distribution agreements and outsourcing. Clients range from start-ups and emerging companies to international corporations. He has led negotiations of billion dollar service agreements that were critical to his client, and successfully handled the intellectual property and data issues on over 250 venture capital and M&A transactions.

Nigel is a “tremendous attorney” singled out for his detail-oriented approach, according to clients interviewed by Chambers and Partners. Peer commentators note his admirable commercial awareness, which achieves business-focused results, often in the most challenging of circumstances. He uses his extensive experience with IP and technology to advise on the commercial imperatives underlying these agreements.

Nigel has been ranked by Chambers Global, Chambers USA, Legal 500, Best Lawyers in America, and Who’s Who in American Law. He is frequent speaker on AI, data, distribution, and technology legal issues. His past and current clients include American Airlines, the American Bankers Association, American Express, AstraZeneca, British Airways, Brown Brothers Harriman, Cathay Pacific, Cisco, CoBank, DoubleClick, Etihad, HPE, Farelogix, Iberia, Mars, Merck, Merrill Lynch, Microsoft, NCR, the NFL, Novartis, P&G, Philippine Airlines, Promontory Financial, Singapore Airlines, Teva, TouchTunes, UBS, and Wyeth.

Read more about Nigel HowardEmail
Show more Show less
Photo of Denise Esposito Denise Esposito

Denise Esposito co-chairs Covington & Burling’s global Food, Drug, and Device Practice Group. Denise has more than 30 years of experience in the life sciences industry, including in senior leadership roles within the U.S. Food and Drug Administration (FDA), as the General Counsel…

Denise Esposito co-chairs Covington & Burling’s global Food, Drug, and Device Practice Group. Denise has more than 30 years of experience in the life sciences industry, including in senior leadership roles within the U.S. Food and Drug Administration (FDA), as the General Counsel of a publicly traded biopharmaceutical company, and as a Partner in private practice. She provides strategic, policy, and regulatory advice to biopharmaceutical, medical device, and other FDA-regulated clients, with a focus on matters that involve navigation of FDA and the complex political and policy challenges faced by regulated industry. Denise’s practice includes advising clients on product development, marketing authorization strategies, incentive programs, expedited approval programs, life cycle management, and the advertising and promotion of medical products. She works with clients on FDA engagement strategies, formal and informal FDA dispute resolution, FDA administrative hearings and public meetings, and crisis management around FDA actions.

Denise’s work runs the gamut of therapeutic areas and product types, including infectious disease, oncology, regenerative medicine, combination products, diagnostics, and digital health.  She also has specialized expertise in the development and approval of medical countermeasures (MCMs) against pathogens that can cause global pandemics or be used in acts of bioterrorism or bio-warfare and was part of the FDA’s Medical Countermeasures Initiative MCMi team while at the Agency.  She has worked with FDA, the Biomedical Advanced Research and Development Authority (BARDA), and other agencies involved in the U.S. government’s response to national public health emergencies and was heavily involved in the industry’s response to the COVID-19 pandemic.

Denise joined Covington in 2015 from FDA, where she served most recently as Chief of Staff to the Commissioner.  In that role, Denise provided strategic advice to the Commissioner and other senior FDA officials on significant FDA policies and initiatives, and coordinated and managed the Commissioner’s priority issues and agency operational issues.  Prior to becoming Chief of Staff, Denise served as the Deputy Chief Counsel for Drugs and Biological Products in FDA’s Office of the Chief Counsel, and as Deputy Director and Acting Director of the Office of Regulatory Policy in FDA’s Center for Drug Evaluation and Research (CDER).

Denise is Chambers-ranked in the U.S. and globally for Life Sciences Regulatory and Compliance and has been named a Life Sciences “Power Player” by Insider.

Read more about Denise EspositoEmail
Show more Show less