IN part due to improving computer technologies and the use of mobile phones and other biometric devices, Real World Evidence (“RWE”),3 or “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than traditional clinical trials,”4 is playing an increasingly significant role in how health care decisions are being made.5 In enacting the 21st Century Cures Act6 (“Cures Act”), Congress provided much needed foundation as to how the U.S. Food and Drug Administration (“FDA”) can and should integrate RWE into regulatory decision making. Among other things, the Cures Act added Section 30227 to the federal Food, Drug, and Cosmetic Act (“FDCA”). This provision requires that the Secretary of Health and Human Services (“HHS”) establish a program to “evaluate the potential use of real- world evidence…to help support the approval of a new indication for a drug approved under [the Act],” and to support post-approval study requirements.8

However, a number of issues linger as industry and FDA explore ways to utilize RWE in regulatory decision-making. For instance, the very “reality” of RWE has been criticized as certain data generally associated with RWE has proven to be unreliable for statistical purposes.9 Additionally, not all diseases that might benefit from RWE produce the kind of “big-data”10 that would generate sufficient evidence for product approvals, including, for instance, diseases having a relatively low prevalence in a given population. On top of these concerns, data privacy issues have become an additional stumbling block on the path to utilizing RWE for new product approvals, as the Health Insurance Portability and Accountability Act’s (“HIPAA”) Privacy Rule may require the prior authorization of thousands of research participants whose data is being utilized, in order for a Sponsor to make claims about safety and efficacy.

Despite these important considerations, the future of RWE appears bright, and it brings with it the potential to revolutionize the way drugs are approved. Jonathan Jastrow, the chair of the medical policy council at FDA’s Center for Drug Evaluation and Research (“CDER”), described utilizing RWE to “take an existing database, punch a button, and compare one drug to another therapy or device … show evidence of efficacy and get labeling of a marketable product in the US” as the “Holy Grail.”11 In this article, we explore the challenges and opportunities presented by RWE as industry and FDA evaluate and react to the ever-developing panacea of big-data solutions to regulatory constraints. We begin our anal-ysis by exploring the general regulatory paradigm that determines how drugs are currently approved for use in the United States. Our discussion will then turn to RWE itself, along with a description of FDA’s framework.

Statutory and Regulatory Background

The FDA is responsible for “protecting the public health by ensuring the safety, efficacy, and security of [medical products, such as pharmaceuticals].” Consequently, the FDA regulates all aspects of drug manufacturing and distribution.

A drug is defined by the FDCA as an article “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.”12 In order to market a drug in the United States, manufacturers must provide FDA with “substantial evidence of effectiveness,” which is defined as:

[E]vidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.13

The current regulations governing adequate and well-controlled investigations state that the “purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation.”14 Reports of such adequate and well-controlled investigations “provide the primary basis for determining whether there is ‘substantial evidence’ to support the claims of effectiveness for new drugs.”15

The High Cost of Product Development and the 21st Century Cures Act

However, the costs associated with conducting clinical trials have grown to be prohibitively large. According to one study published in the Journal of the American Medical Association, “the estimated median capitalized research and development cost per [drug] product was $985 million, counting expenditures on failed trials.”16 Thus, drug development costs, in conjunction “with the development of sophisticated, new analytical capabilities,”17 caused both industry and FDA to seek new ways to satisfy FDA’s evidentiary requirements. In response, Congress’ role in framing out the Cures Act significantly changed the outlook for RWE, which had been relegated to FDA’s Sentinel Initiative. The Sentinel System is a database containing information on over 100 million individuals in a network of 18 collaborating institutions, which FDA extensively utilized for post-market surveillance of approved drugs prior to 2016. FDA’s Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research frequently perform safety monitoring studies by utilizing information contained in the Sentinel System. In the event that a particular safety concern is identified, FDA has also used the Sentinel System to plan studies before a drug is approved. Historically, utilizing RWE derived from the Sentinel system “to support effectiveness determinations [was] much more limited.”18 However, with the passage of the Cures Act, the use of RWE expanded beyond the Sentinel System. The Cures Act contains two major requirements, namely:

(1) that FDA establish a regulatory program framework and (2) that FDA issue a guidance document that describes the circumstances under which sponsors of drugs may rely on RWE in order to support the approval of a new indication for an already approved drug or to support post-approval requirements. Pursuant to these requirements, in December of 2018, FDA issued the “Framework for FDA’s Real-World Evidence Program” (“Framework”).19

In substance, the Framework contains three discrete sections that describe (1) the Current Use of Real-World Data (“RWD”) for Evidence Generation, (2) the Framework for Evaluating RWD/RWE for Use in Regulatory Decision-making, and (3) Stakeholder Engagement.20 With respect to the first section, Current Uses of RWE for Evidence Generation, the Framework describes the history of RWE, relevant databases routinely utilized by FDA and also describes trial designs using RWD to generate evidence. The Framework also describes the way in which FDA has historically used RWE to support product approvals in certain, albeit rare, instances, such as when it would not be ethical or feasible to use a parallel assignment control arm.21 Finally, FDA describes two trial designs that utilize RWD to generate evidence, namely: (1) randomized controlled trials integrated into health care systems and (2) observational studies using RWD to generate RWE.22 Notably, FDA committed itself to evaluating the role that observational studies may play in providing evidence of a drug’s effectiveness. Subsequently, FDA has published seven additional guidance documents23 related to RWE, which explore the following topics: (1) assessing electronic health records and medical claims data, (2) assessing registries to support regulatory decision making, (3) considerations for the use of RWD and RWE to support regulatory decision making, (4) data standards for submissions containing RWE, (5) submitting documents utilizing RWE, (6) using EHR in clinical investigations, and (7) using RWE to support regulatory decision making.24 Commentators have noted a number of themes that characterize FDA’s draft guidance documents, namely, that (1) data should be fit for a specific purpose and be accurate, complete, and traceable, (2) sponsors should be transparent, and studies should be reproduceable, and (3) sponsors should actively engage with FDA prior to conducting a study utilizing RWE.25

Challenges Posed by the Use of RWE in Drug Development

Although FDA has responded to its statutory mandate to generate a framework for RWE, issuing a myriad of guidance documents to assist industry, a variety of problems remain unresolved in utilizing RWE in regulatory decision making. Some have even argued that the term “real-world evidence” like “reality television” presents a skewed interpretation as to how “real” the evidence relied upon actually is.26 For instance, data relating to billing records are “known to be woefully inaccurate when it comes to shedding light on the actual clinical care are provided.”27 Data collection issues have also been identified. For example, commentators have noted that data drawn from clinical treatment is not “initially collected with a view to generating secondary evidence for later retrospective or observational analysis.”28 In keeping with the example, when providers collect medical billing information, they do not do so with an eye towards that information later being used to support a marketing application for a pharmaceutical product. In addition, as alluded to earlier, less common diseases that do not produce large amounts of data may not provide sufficient data to assist in real-world evidence regulatory decisions. For example, “slow-severity diseases (e.g., arthritis) and low-prevalence diseases not treated in specialty centers may routinely generate less data, while the data actually collected is likely to be less comprehensive.”29 Commentators also see data collection issues as a potential cause for concern due to bias. “Selection bias” makes it particularly difficult for sponsors to “know whether effectiveness outcomes resulted from differences in the types of intervention or differences in the patients chosen,”30 and a connected issue exists with encroachment of “performance bias,” which, especially in the case of observational studies, causes patients in distinct groupings to “adhere to treatment plans differently, including varying degrees of success in taking medications at the right time and the right dosage.”31 Additionally, the current regulatory regime for protecting patient data, HIPAA, requires that sponsors of clinical studies acquire authorization prior to using their personally identifiable health information.

The recent growth in the usage of RWE in marketing authorizations applications has been tremendous. According to one independent study, “78% of FDA’s decisions in 2020 included [an RWE] study to support safety and/or effectiveness—up from 53% in 2019.”32 However, before RWE can be the “Holy Grail” capable of delivering all of its promises in a drug development project, the aforementioned issues must be solved. FDA must, for instance, provide industry with additional and more specific guidance as to data standards and data analysis expectations.

Opportunities with RWE and its Future

Despite the issues elaborated upon above, the future of RWE is bright. Among the most notable benefits of utilizing RWE to approve new indications for drugs that already have marketing authorization approvals is that this information can potentially enable more products to be covered by government reimbursement programs like Medicare. This is the case because, unless there has been a national or local “coverage decision” made by CMS, generally, drugs are not reimbursed for off-label33 promotions. Moreover, doctors routinely prescribe off-label drugs. In some cases, off-label prescriptions are the standard of care and result in as much as 93.5% of prescriptions for certain pediatric conditions.34 Under the current regime, if a beneficiary wants to be reimbursed for an off-label indication, they must engage in a burdensome and serpentine approval process with CMS. CMS will then only approve coverage for the drug if the evidence submitted by a beneficiary shows that the drug’s “use is medically accepted, taking into consideration the major drug compendia, authoritative medical literatures, and/or accepted standards of medical practice.” 35If, on the other hand, FDA’s RWE program helps manufacturers to significantly reduce the cost of premarket submissions, then many of those most in need will have coverage for much needed pharmaceutical interventions.


However intangible the concept may be to those unaware of this significant regulatory development, RWE exists at the intersection of rapidly improving information technology capabilities and the sometimes sclerotic regulatory landscape. Nonetheless, FDA has enthusiastically responded to its Congressional mandate to create a framework for implementing RWE in regulatory decision making. As with any new and promising regulatory paradigm, RWE faces challenges known and as yet unknown in the coming years, but the promise of its potential to expand the portfolio of drug products or their indications for use warrants that industry accept and overcome them in partnership with FDA.

1 Joshua Ari Van De Riet, JD, RAC-Devices, is an Associate Attorney with Benjamin L. England and Associates, a boutique firm specializing in FDA and Customs/Import related matters located in Glen Burnie, Maryland.

2 Andrew Harrison, J.D., M.S. Regulatory Science, is a Senior Attorney, FDA & Life Sciences, with Benjamin L. England and Associates.

3 RWE should be distinguished from Rea World Data which is defined as “[d]ata relating to patient health status and/or the delivery of health care routinely collected from electronic health records (EHRs), claims, registries, PROs and devices, etc.” See, Real-world evidence. U.S. Food and Drug Administration. Retrieved March 22, 2022, from

4 21 U.S. Code §355g(b).

5 See, Footnote 2.

6 Public Law 114-255.

7 Codified at 21 U.S. Code §355g

8 21 U.S. Code §355g(a)(1).

9 44 Am. J. L. and Med. 161.

10 “Big Data” is defined as “an accumulation of data that is too large and complex for processing by traditional database management tools.” See, Merriam-Webster.

Big Data Definition & meaning. Merriam-Webster. Retrieved April 24, 2022, from

11 Real World Evidence: Can it support new indications, label expansions? Regulatory Affairs Professionals Society (RAPS). (n.d.). Retrieved April 25, 2022, from,-label-expansions.

12 21 U.S. Code §201(a), et seq.

13 21 U.S. Code §355(d).

14 21 C.F.R. §314.126(a).

15 Id.

16 Wouters OJ, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA. 2020;323(9):844–853. doi:10.1001/jama.2020.1166.

17 See, Footnote 2.

18 Framework for FDA’s Real-World Evidence Program (2018). US Food and Drug Administration. Retrieved from

19 The Framework did not apply to medical devices. FDA issued a separate guidance document titled Use of Real-World Evidence to Support Regulatory Deci sion-Making for Medical Devices on August 31, 2017, to assist manufacturers of medical devices in understanding how to use RWE.

20 See, Footnote 17.

21 Id.

22 Id.

23 Guidance documents non-binding and represent FDA’s current thinking on a given topic. Guidance documents do not “create or confer” any rights. Industry is free to utilize alternative approaches not referenced in a guidance document as long as the approach “satisfies the requirements of the applicable statutes and regulations.” See, Guidances. Office of Regulatory Affairs. U.S. Food andDrug Administration. Retrieved April 27, 2022, from’s%20current,the%20applicable%20statutes%20and%20regulations.

24 To access FDA’s complete list of guidance documents related to RWE, see Footnote 2.

25 Making Sense of FDAs 2021 Real-World Evidence Guidance (On-Demand Webcast). Regulatory Affairs Professionals Society. Retrieved April 25, 2022, from


26 See, Footnote 8.

27 Id. at 164.

28 Id. at 165.

29 Id.

30 Id. at 167.

31 Id.

32 See, Footnote 24.

33 Off-label use is defined as “use for a non-FDA approved indication, that is, one that is not listed on the drug’s official label/prescribing information.” See, Off-label use is defined as “use for a non-FDA approved indication, that is, one that is not listed on the drug’s official label/prescribing information.”

34 Andrade SRA, Santos PANM, Andrade PHS, da Silva WB. Unlicensed and off-label prescription of drugs to children in primary health care: A systematic review. J

Evid Based Med. 2020 Nov;13(4):292-300. doi: 10.1111/jebm.12402. Epub 2020 Oct 13. PMID: 33047516.

35 Id.