Abstract
Background/Aims:
There is growing interest in leveraging real-world data, such as electronic health records, administrative claims data, and patient registries, to generate real-world evidence studies that support the U.S. Food and Drug Administration’s premarket and postmarket regulatory determinations of effectiveness and/or safety for novel therapeutics. We examined the frequency and characteristics of real-world evidence studies used by the U.S. Food and Drug Administration to support premarket determinations of effectiveness and/or safety, as well as those required or requested by the U.S. Food and Drug Administration to be conducted postmarket after approval.
Methods:
We identified all novel therapeutics approved by the U.S. Food and Drug Administration between 2016-2024, using action packages from the Drugs@FDA database. Product labels, approval letters, and review documents were used to identify real-world evidence studies supporting premarket determinations of effectiveness and/or safety, as well as all postmarketing requirements or commitments outlined at the time of approval. Outcomes included the number of novel therapeutics approved with premarket and/or postmarket real-world evidence studies and characteristics of these studies, including study design, data source, and primary objectives.
Results:
From 2016-2024, the U.S. Food and Drug Administration approved 400 novel therapeutics for 543 indications, of which 43 (10.8%) had at least one real-world evidence study that supported premarket determinations of effectiveness and/or safety (64 unique studies), and 138 (34.5%) had at least one real-world evidence study required or request by the U.S. Food and Drug Administration to be conducted postmarket after approval (208 unique studies). Among the 64 unique premarket real-world evidence studies, the most common study designs were non-interventional (observational) studies (35, 54.7%) and externally controlled trials (17, 26.6%); 38 (59.4%) studies utilized electronic health or medical records, and 47 (73.4%) provided evidence on effectiveness. Among the 208 unique postmarket real-world evidence studies, the most common study design was non-interventional (observational) studies (159, 76.4%); 61 (29.3%) studies identified registries as the proposed data source, and 197 (94.7%) were designed to provide evidence on safety alone. The proportion of therapeutics approved with at least one postmarket real-world evidence study increased over time from 2 of 20 (10.0%) in 2016 to 23 of 47 (48.9%) in 2024; however, only 7 (3.4%) of these studies were classified by the U.S. Food and Drug Administration as fulfilled or submitted as of May 2025.
Conclusions:
Real-world evidence studies are infrequently used to support the U.S. Food and Drug Administration’s premarket determinations of effectiveness and/or safety but have been increasingly required or requested by FDA to be conducted postmarket after approval; however delays in completing postmarket real-world evidence studies may limit their regulatory impact.
Keywords: Real-world evidence, real-world data, pharmaceutical regulation
Introduction
The U.S. Food and Drug Administration (FDA) has historically required evidence from adequate and well-controlled trials to demonstrate the efficacy of new therapeutics, with early guidance suggesting at least two pivotal efficacy trials.1,2 In recent decades, however, a growing emphasis on accelerating market access, particularly for therapeutics treating serious conditions, has led FDA to adopt a more flexible interpretation of what constitutes sufficient evidence of efficacy. For example, the number of new approvals based on a single clinical trial,3,4 often supported by confirmatory evidence from non-interventional studies,5,6 has increased, as has the variability in the quality of pivotal trial evidence supporting approvals.3,7-10 In response, regulatory pathways designed to expedite approval of therapeutics for serious conditions have placed greater emphasis on continuing product evaluation efforts by conducting additional studies postmarket after approval.3,6,8,9
In this context, there has been growing interest in leveraging real-world data, such as electronic health records, administrative claims data, patient registries, and digital health data, to supplement traditional pivotal trials and generate real-world evidence on the usage, benefits, and risks of therapeutics.11-13 These data can capture broader, more diverse populations, reflect outcomes experienced through routine care, and can be integrated into a range of study designs, including hybrid, externally controlled, or pragmatic trials and observational studies.13,14 Such data are known to be used as part of premarket evaluations of high-risk medical devices, such as historical, non-concurrent control population cohorts (also known as externally controlled trials).15 FDA has also long relied on real-world evidence as part of its postmarketing safety surveillance efforts, through both passive systems, such as adverse event reporting, and active systems, such as registries and the Sentinel System.12,16 However, concerns remain regarding the relevance and reliability of real-world data, particularly in terms of data accrual and quality control and susceptibility to bias due to unmeasured confounding, for addressing more specific regulatory questions, including those related to determinations of therapeutic premarket effectiveness and safety and satisfying studies required or request to be conducted postmarket after approval.11,12
As real-world data sources have improved in availability and quality, and as methodological approaches have advanced, both Congress and FDA have committed to leveraging their potential to accelerate medical product development.13,17-24 Following the passage of the 21st Century Cures Act in 2016, FDA launched the Real-World Evidence Program, a framework for evaluating the use of real-world evidence to support regulatory decision-making.13 Furthermore, as part of the 2023 reauthorization of the Prescription Drug User Fee Act (PDUFA VII), FDA committed to publicly reporting aggregate information on submissions containing real-world data/real-world evidence.25 However, FDA's report lacks comprehensive data on all relevant submissions and omits specific details on study design and regulatory context.
Therefore, to establish a baseline understanding of real-world evidence use in regulatory decision-making, we aimed to evaluate the frequency and characteristics of real-world evidence studies used by FDA to support premarket and postmarket determinations of effectiveness and safety for all novel therapeutics approved between 2016 and 2024. We specifically focused on real-world evidence studies submitted in premarket applications that supported determinations of effectiveness and/or safety, and real-world evidence studies required or requested by FDA to be conducted postmarket after approval.
Methods
This study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.26 Institutional review board approval and patient informed consent were not required because the study used public, non-identifiable data and did not involve human participant research.
Data sources and study sample
We used publicly available action packages from the Drugs@FDA database to identify all new drugs (i.e., small molecular therapeutics) and biologics approved by FDA between January 1st, 2016, and December 31st, 2024.27 We excluded new formulations, generics, biosimilars, and non-therapeutics agents (e.g., diagnostic agents and contrast agents).3
Therapeutic and regulatory characteristics
For each therapeutic, clinical indications for use were abstracted from product labels and approval letters and classified into previously described therapeutic areas (eMethods in Appendix 1).8 Next, we identified orphan designation and regulatory pathways through which FDA can expedite clinical trial testing or regulatory review (priority review, accelerated approval, breakthrough therapy, and fast track) by reviewing approval packages, end-of-year summaries, and the orphan product designation database.9,28
Identification of real-world data/real-world evidence within drug approval packages
We relied on FDA’s definitions of real-world data and real-world evidence studies.12 Specifically, FDA defines real-world data as data relating to patient health status and/or the delivery of health care that are routinely collected outside of clinical trial settings, including electronic health or medical records, registry, and administrative claims data, which can be analyzed to generate real-world evidence regarding the usage and potential benefits or risks of a medical product. real-world evidence study designs include non-interventional (observational) studies, externally controlled trials (e.g., historical or concurrently collected control arms), self-controlled trials, randomized controlled trials incorporating real-world evidence elements (e.g., platform trials, pragmatic trials), and other (e.g., meta-analyses, pooled analyses).24,29,30
Real-world evidence studies supporting premarket determinations of effectiveness and/or safety
To identify real-world evidence studies supporting premarket determinations of effectiveness and/or safety, we manually reviewed publicly available approval package documents in the Drugs@FDA database, including product labels, approval letters, and review documents (Multi-Discipline, Integrated, Summary, Clinical, Medical, Statistical, Other, Administrative and Correspondence Documents). Each document was read with particular focus on sections detailing clinical evidence, study designs, and regulatory review discussions. We supplemented our review by searching keywords related to real-world data/real-world evidence developed and informed by FDA guidance documents (eTable 1 in Appendix 1).13,17-24
For each premarket real-world evidence study, we assessed whether FDA designated it as substantial or supportive evidence. Substantial evidence was identified based on the explicit use of the term “substantial evidence” within the approval documents. These studies were further characterized as either pivotal trials incorporating real-world data elements (e.g., external comparator arm) or as confirmatory evidence for approvals based on a single pivotal trial. Supportive evidence was defined as studies that did not meet the level of substantial evidence but provided evidence for approval as explicitly stated by FDA. Real-world evidence studies submitted by the sponsor and deemed insufficient by FDA (neither substantial nor supportive) were excluded from the sample, as they were not considered in the regulatory decision-making process due to inadequate support for approval. Lastly, we determined how often real-world evidence studies were listed in product labels.
Real-world evidence studies required or requested by FDA to be conducted postmarket after approval
To identify real-world evidence studies required or requested by FDA to be conducted postmarket after approval, we reviewed all postmarketing requirements or commitments outlined at the time of approval (eMethods in Appendix 1).31 Additional clinical evidence that may not be generated through specific postmarketing requirements, including those related to long-term drug effectiveness or efficacy in subgroup data, can be generated through postmarketing commitments, which are studies or clinical trials that a sponsor has agreed to conduct but are not required by statute or regulation.31 We manually reviewed FDA approval letters and review documents to identify all postmarketing requirements and commitments outlined by FDA to be conducted after approval. We documented each postmarket study where real-world evidence was intended to satisfy a postmarketing requirement or commitment.
For each real-world evidence study required or requested by FDA to be conducted postmarket after approval, we determined its FDA-assigned status using the Postmarketing Study and Clinical Trial Requirements and Commitments Database (i.e. pending, delayed, ongoing, released, submitted, fulfilled; last updated by FDA on August 9, 2024).32 Because fulfilled and released requirements are displayed on the online database for only one year after the date of fulfillment or release, we used previously developed methods to search archived FDA.gov files.33,34 When final-status archives were unavailable, we recorded the most recent status and date for each postmarketing requirement or commitment.
Characteristics of real-world evidence studies
For real-world evidence studies with adequate descriptions, we classified each by its design (non-interventional [observational] study [e.g., prospective or retrospective cohort study], externally controlled trial [e.g., clinical trial with historical or concurrently collected control arm], self-controlled trial, randomized controlled trial incorporating real-world data elements [e.g., platform trial, pragmatic trial], and other [e.g., meta-analysis, pooled analysis]), real-world data source (i.e., electronic health or medical records [including data derived from expanded access/compassionate use programs], registry, administrative claims data), and primary focus (i.e., to generate evidence for effectiveness and/or safety).
Statistical analysis
Descriptive statistics were used to characterize the study sample. Chi-square tests were used to compare therapeutic and regulatory characteristics between therapeutics with versus without at least one real-world evidence study supporting premarket determinations of effectiveness and/or safety at approval, as well as between those with versus without at least one real-world evidence study required or requested by FDA to be conducted postmarket after approval. Characteristics compared included drug type, year of approval, therapeutic area, orphan product designation, and use of a special regulatory pathway. Due to small cell counts, the assumptions underlying Chi-square approximations were not fully met. Therefore, we estimated p-values using Monte Carlo simulation with 10,000 replicates and a 2-sided P<.001 for statistically significance. Analyses were performed using R Statistical Software v4.2.0.
Results
Between 2016 and 2024, FDA approved 400 novel therapeutics for 543 indications (eTable 3 in Appendix 1). There were 43 (10.8%) approvals with at least one real-world evidence study that supported premarket determinations of effectiveness and/or safety (Table 1; eTable 4), totaling 64 unique studies. Of these, 31 (72.1%) had no additional real-world evidence studies required or requested by FDA to be conducted postmarket after approval. There were 138 (34.5%) approvals with at least one real-world evidence study required or requested by FDA to be conducted postmarket after approval, totaling 208 unique studies. Of these, 126 (91.3%) had no real-world evidence studies that supported premarket determinations of effectiveness and/or safety. Overall, 12 (3.0%) approvals had at least one real-world evidence study that supported premarket determinations of effectiveness and/or safety and at least one real-world evidence study required or requested by FDA to be conducted postmarket after approval.
Table 1.
Characteristics of Therapeutics Approved by the U.S. Food and Drug Administration With vs. Without Real-World Evidence Studies, 2016-2024 (N=400)
| Therapeutics with Real-World Evidence Studies Supporting Premarket Determinations of Effectiveness and/or Safety |
Therapeutics with Real-World Evidence Studies Required or Requested by FDA to be Conducted Postmarket after Approval |
|||||
|---|---|---|---|---|---|---|
| Yes (n=43) | No (n=357) | P-value | Yes (n=138) | No (n=262) | P-value | |
| Submission Type | No. (%) | No. (%) | 0.29 | No. (%) | No. (%) | 1.00 |
| BLA | 16 (37.2) | 104 (29.1) | 41 (29.7) | 79 (30.2) | ||
| NDA | 27 (62.8) | 253 (70.9) | 97 (70.3) | 183 (69.8) | ||
| Year | ||||||
| 2016 | 1 (2.3) | 19 (5.3) | 0.12 | 2 (1.4) | 18 (6.9) | 0.02 |
| 2017 | 6 (14.0) | 40 (11.2) | 14 (10.1) | 32 (12.2) | ||
| 2018 | 4 (9.3) | 55 (15.4) | 23 (16.7) | 36 (13.7) | ||
| 2019 | 2 (4.7) | 42 (11.8) | 15 (10.9) | 29 (11.1) | ||
| 2020 | 11 (25.6) | 37 (10.4) | 9 (6.5) | 39 (14.9) | ||
| 2021 | 6 (14.0) | 41 (11.5) | 17 (12.3) | 30 (11.5) | ||
| 2022 | 2 (4.7) | 33 (9.2) | 12 (8.7) | 23 (8.8) | ||
| 2023 | 7 (16.3) | 47 (13.2) | 23 (16.7) | 31 (11.8) | ||
| 2024 | 4 (9.3) | 43 (12.0) | 23 (16.7) | 24 (9.2) | ||
| Therapeutic Class | ||||||
| Cancer and hematology | 14 (32.6) | 122 (34.2) | 0.09 | 16 (11.6) | 120 (45.8) | <0.001 |
| Neurology and psychology | 5 (11.6) | 48 (13.4) | 33 (23.9) | 20 (7.6) | ||
| Infectious disease | 3 (7.0) | 48 (13.4) | 24 (17.4) | 27 (10.3) | ||
| Autoimmune, musculoskeletal, and dermatology | 4 (9.3) | 44 (12.3) | 25 (18.1) | 23 (8.8) | ||
| Cardiovascular, diabetes, and hyperlipidemia | 0 (0) | 19 (5.3) | 13 (9.4) | 6 (2.3) | ||
| Other | 17 (39.5) | 76 (21.3) | 27 (19.6) | 66 (25.2) | ||
| Orphan Designation | ||||||
| Yes | 34 (79.1) | 172 (48.2) | <0.001 | 58 (42.0) | 148 (56.5) | <0.001 |
| No | 9 (20.9) | 185 (51.8) | 80 (58.0) | 114 (43.5) | ||
| Priority Review | ||||||
| Yes | 32 (74.4) | 227 (63.6) | 0.18 | 82 (59.4) | 177 (67.6) | 0.13 |
| No | 11 (25.6) | 130 (36.4) | 56 (40.6) | 85 (32.4) | ||
| Accelerated Approval | ||||||
| Yes | 22 (51.2) | 49 (13.7) | <0.001 | 11 (8.0) | 60 (22.9) | <0.001 |
| No | 21 (48.8) | 308 (86.3) | 127 (92.0) | 202 (77.1) | ||
| Breakthrough Therapy | ||||||
| Yes | 18 (41.9) | 108 (30.3) | 0.17 | 31 (22.5) | 95 (36.3) | <0.001 |
| No | 25 (58.1) | 249 (69.7) | 107 (77.5) | 167 (63.7) | ||
| Fast Track | ||||||
| Yes | 21 (48.8) | 135 (37.8) | 0.18 | 54 (39.1) | 72 (27.5) | 0.02 |
| No | 22 (51.2) | 222 (62.2) | 84 (60.9) | 190 (72.5) | ||
Real-world evidence studies supporting premarket determinations of effectiveness and/or safety
Characteristics of therapeutic approval.
Among the 43 therapeutics approved with at least one real-world evidence study that supported premarket determinations of effectiveness and/or safety (Table 1), 16 (37.2%) were biologics and 27 (62.8%) small molecule drugs. Therapeutics indicated for the treatment of cancer and hematology (14, 32.6%) and neurology and psychology (5, 11.6%) were most common. Overall, 34 (79.1%) of these therapeutics received orphan designation, 32 (74.4%) priority review, 22 (51.2%) accelerated approval, 18 (41.9%) breakthrough therapy, and 21 (48.8%) fast track. The proportion of therapeutics approved with at least one premarket real-world evidence study varied over time, peaking in 2020 (11/48, 22.9%; Figure 1). There were 12 (27.9%) therapeutics where the real-world evidence studies were referenced in the product label. There were no approvals that relied solely on real-world evidence studies for premarket determinations of effectiveness and/or safety.
Figure 1.
Proportion of therapeutics approved between 2016 and 2024 with real-world evidence studies supporting premarket determinations of effectiveness and/or safety, and those with real-world evidence studies required or requested by FDA to be conducted postmarket after approval
Compared to therapeutics without any real-world evidence studies supporting premarket determinations of effectiveness and/or safety, those approved with at least one such study were more likely to have orphan designation (34/43 [79.1%] vs. 172/357 [48.2%]; P<0.001) and accelerated approval (22/43 [51.2%] vs. 49/357 [13.7%]; P<0.001), but there were no statistically significant differences in the likelihood of priority review, breakthrough therapy, or fast track (P>0.001; Table 1).
Characteristics of unique real-world evidence studies.
Among the 64 unique real-world evidence studies that supported premarket determinations of effectiveness and/or safety, 35 (54.7%) were non-interventional (observational) studies, 20 (31.3%) were clinical trials (externally controlled trials, self-controlled trials, or randomized controlled trials incorporating real-world evidence), 5 (7.8%) were meta-analyses or pooled analyses, and 4 (6.3%) did not have clearly defined designs (Table 2). The most common non-interventional study designs included unspecified observational studies (11, 17.2%) and retrospective observational studies (6, 9.4%). Most studies relied on electronic health or medical records (38, 59.4%), of which 15 (39.5%) were derived from expanded access, or registries (10, 15.6%). In terms of the primary focus, 17 (26.6%) provided evidence on both effectiveness and safety, 30 (46.9%) on effectiveness alone, and 17 (26.6%) on safety alone.
Table 2.
Characteristics of Unique Real-World Evidence Studies, 2016-2024
| Supporting Premarket Determinations (n=64) | Required or Requested by FDA to be Conducted after Approval (n=208) | ||
|---|---|---|---|
| Study Design | No. (%) | Study Design | No. (%) |
| Non-interventional (observational) study | 35 (54.7) | Non-interventional (observational) study | 159 (76.4) |
| Retrospective cohort study | 5 (7.8) | Retrospective cohort study | 10 (4.8) |
| Prospective cohort study | 2 (3.1) | Prospective cohort study | 42 (20.2) |
| Retrospective observational study | 6 (9.4) | Unspecified cohort study | 2 (1.0) |
| Prospective observational study | 1 (1.6) | Prospective observational study | 31 (14.9) |
| Unspecified observational study | 11 (17.2) | Unspecified observational study | 46 (22.1) |
| Case report or series | 3 (4.7) | Nested case-control | 1 (0.5) |
| Retrospective cross-sectional study | 1 (1.6) | Case series | 2 (1.0) |
| Natural history study | 5 (7.8) | Surveillance, field, or pharmacovigilance study | 25 (12.0) |
| Surveillance study | 1 (1.6) | Clinical trial | 3 (1.4) |
| Clinical trial | 20 (31.3) | Externally controlled trial | 3 (1.4) |
| Externally controlled trial | 17 (26.6) | Self-controlled trial | 0 (0.0) |
| Self-controlled trial | 3 (4.7) | Randomized controlled trial incorporating real-world evidence | 0 (0.0) |
| Randomized controlled trial incorporating real-world evidence | 0 (0.0) | Flexible | 33 (15.9) |
| Other | 5 (7.8) | Other | 8 (3.8) |
| Meta-analysis | 4 (6.3) | Integrated data analysis | 8 (3.8) |
| Pooled data analysis | 1 (1.6) | Not specified | 5 (2.4) |
| Not specified | 4 (6.3) | ||
| Data Source | Data Source | ||
| Electronic health or medical records | 38 (59.4) | Electronic health or medical records | 2 (1.0) |
| Records derived from expanded access/compassionate use | 15 (23.4) | Registry | 61 (29.3) |
| Registry | 10 (15.6) | Administrative claims data | 5 (2.4) |
| Administrative claims data | 2 (3.1) | Multiple | 8 (3.8) |
| Prior clinical trial | 3 (4.7) | Flexible | 39 (18.8) |
| Multiple | 2 (3.1) | Not specified | 93 (44.7) |
| Not specified | 9 (14.1) | ||
| Primary Focus | Primary Focus | ||
| Effectiveness only | 30 (46.9) | Effectiveness only | 2 (1.0) |
| Effectiveness and safety | 17 (26.6) | Effectiveness and safety | 9 (4.3) |
| Safety only | 17 (26.6) | Safety only | 197 (94.7) |
Overall, 23 (35.9%) studies were classified by FDA as substantial evidence: all 20 externally controlled or self-controlled trials identified were pivotal trials incorporating real-world data elements, and 3 non-interventional studies were identified as confirmatory evidence. Supportive evidence included 41 (64.1%) non-interventional studies (examples in Table 3).
Table 3.
Examples of Real-World Evidence Studies Identified from Novel Therapeutic Approval Packages
| Supporting Premarket Determinations of Effectiveness and/or Safety | |||||||
|---|---|---|---|---|---|---|---|
| Therapeutic (Brand) |
Approval Date |
Approved Indication | Language | Evidence Level |
Primary Focus |
Real- World Data Source |
Real-World Evidence Study Design |
| Pretomanid (Pretomanid) | 8/14/2019 | Pulmonary extensively drug resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB) | “The Applicant has provided substantial evidence of the effectiveness of the pretomanid, bedaquiline, and linezolid (BPaL) regimen and sufficient safety information to support approval in a limited and specific patient population, adults with XDR-TB or TI/NR MDR-TB. In a single phase 3 clinical trial in patients with XDR-TB or TI/NR MDR-TB, superiority of the BPaL regimen on clinical outcomes was demonstrated compared to XDR-TB historical controls.” | Substantial evidence: component of pivotal trial | Effectiveness | Medical records | Externally controlled trial |
| Arimoclomol citrate (Miplyffa) | 9/20/2024 | Neurological manifestations of Niemann-Pick disease type C (NPC) | “The confirmatory evidence of the effectiveness of arimoclomol was derived from 1) clinical data from open-label extension (OLE) of NPC002; 2) clinical data from the non-interventional study NPC-001…” | Substantial evidence: confirmatory evidence | Effectiveness | Medical records | Prospective observational study |
| Vosoritide (Voxzogo) | 11/19/2021 | Increase linear growth in pediatric patients with achondroplasia with open epiphyses | “Studies 111-205 and 111-302 were submitted to demonstrate long-term efficacy of vosoritide. Because both were uncontrolled, the Applicant proposed to use external control data as a comparator. The Applicant used data from the AchNH study as the primary source for their comparative analyses and used pooled data from 3 other NH sources for supportive analyses.” | Supportive evidence | Effectiveness | Registry | Externally controlled trial |
| Required or Requested by FDA to be Conducted Postmarket after Approval | |||||||
| Therapeutic (Brand) |
Approval Date |
Approved Indication | Language | Regulatory Authority |
Primary Focus |
Real- World Data Source |
Real-World Evidence Study Design |
| Semaglutide (Ozempic) | 12/5/2017 | improve glycemic control in adults with type 2 diabetes mellitus | “Conduct a medullary thyroid carcinoma registry-based case series of at least 15 years duration to systematically monitor the annual incidence of medullary thyroid carcinoma in the United States and to identify any increase related to the introduction of Ozempic (semaglutide) into the marketplace. This study will also establish a registry of incident cases of medullary thyroid carcinoma and characterize their medical histories related to diabetes and use of Ozempic (semaglutide).” | 505(o) | Safety | Registry | Case series |
| Ensartinib hydrochloride (Ensacove) | 12/18/2024 | anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) without history of ALK-inhibitor | “Conduct an integrated analysis of data from clinical trials and observational studies (e.g., real world evidence), post-marketing reports, and other sources to further characterize the safety and efficacy/effectiveness of ensartinib in older adults ages 65 years and older, and in patients of underrepresented racial and ethnic minority groups, with locally advanced or metastatic ALK positive non-small cell lung cancer.” | 506b | Effectiveness and safety | Multiple | Integrated data analysis |
Real-world evidence studies required or requested by FDA to be conducted postmarket after approval
Characteristics of therapeutic approvals.
There were 138 therapeutics approved with at least one real-world evidence study required or requested by FDA to be conducted postmarket after approval: 126 (91.3%) had at least one postmarketing requirement, 10 (7.2%) had at least one postmarketing commitment, and 3 (2.2%) had at least one of each. Of these, 41 (29.7%) were biologics and 97 (70.3%) small molecule drugs. Therapeutics indicated for the treatment of neurology and psychology (33, 23.9%), autoimmune, musculoskeletal, and dermatology (25, 18.1%), and infectious disease (24, 17.4%) were most common. Overall, 58 (42.0%) of these therapeutics received orphan designation, 82 (59.4%) priority review, 11 (8.0%) accelerated approval, 31 (22.5%) breakthrough therapy, and 84 (60.9%) fast track. The proportion of therapeutics approved with at least one real-world evidence study required or requested by FDA to be conducted postmarket after approval increased from 2 of 20 (10.0%) in 2016 to 23 of 47 (48.9%) in 2024 (Figure 1).
There were statistically significant differences in therapeutic area between therapeutics approved with versus without at least one real-world evidence study required or requested by FDA to be conducted postmarket after approval (Table 1). Compared to therapeutics approved by FDA without any required or requested postmarket studies with real-world evidence to be conducted after approval, those approved with at least one such study were less likely to have orphan designation (58/138 [42.0%] vs. 148/262 [56.5%]; P<0.001), accelerated approval (11/138 [8.0%] vs 60/262 [22.9%]; P<0.001), and breakthrough therapy (31/138 [22.5%] vs 95/262 [36.3%]; P<0.001).
Characteristics of unique real-world evidence studies.
Among the 208 unique real-world evidence studies required or requested by FDA to be conducted postmarket after approval, 194 (93.2%) were as part of a postmarketing requirement and 14 (6.7%) were as part of a postmarketing commitment. Of the 194 postmarketing requirements, 189 (97.4%) were issued under FDAAA authority, 3 (1.5%) under accelerated approval, 1 (0.5%) under the animal efficacy rule, and 1 (0.5%) under PREA. The most common study design was non-interventional (observational) studies (159, 76.4%), of which 73 (45.9%) had prospective designs. There were 33 (15.9%) studies classified as having flexible designs because the postmarketing requirement or commitment descriptions outlined that study sponsors could determine the appropriate study designs. While 61 (29.3%) studies relied on real-world data from registries, 39 (18.8%) were classified as having flexible real-world data sources, and 93 (44.7%) study descriptions did not specify real-world data sources. Only 2 (1.0%) studies were intended to provide evidence on effectiveness only, whereas 197 (94.7%) were intended to provide evidence on safety only, and 9 (4.3%) on both effectiveness and safety.
As of May 2025, according to FDA reporting, 4 (1.9%) of the real-world evidence studies were classified as fulfilled, 3 (1.4%) as submitted, and 9 (4.3%) as released. The majority were classified as pending (82, 39.4%), delayed (54, 26.0%), or ongoing (49, 23.6%), with no publicly available status information for 7 (3.4%) studies.
Discussion
In this study of all 400 novel therapeutics approved by FDA between 2016 and 2024, approximately 11% had at least one real-world evidence study submitted in premarket applications that supported determinations of effectiveness and/or safety, and 35% had at least one real-world evidence study required or requested by FDA to be conducted postmarket after approval. While the proportion of approvals with real-world evidence studies supporting premarket determinations of effectiveness and/or safety varied over time, those with real-world evidence studies required or requested by FDA to be conducted postmarket after approval increased. However, the vast majority of postmarket real-world evidence studies were classified by FDA as pending, delayed, or ongoing. These findings highlight that, despite growing interest in using real-world evidence to inform regulatory decision-making, such studies are infrequently used to support premarket determinations of effectiveness and/or safety, and delays in completing postmarket real-world evidence studies may limit their regulatory impact.
Our study found that approximately 11% of novel therapeutic approvals had at least one real-world evidence study that supported premarket determinations of effectiveness and/or safety, and the real-world evidence studies were referenced in the product label for fewer than one-third of these. FDA has indicated that the use of real-world evidence studies to support novel therapeutic approvals has been limited, occurring most often in the context of oncology and rare diseases.13,35,36 Consistent with this, our evaluation found that one-third of therapeutics with premarket real-world evidence studies were for cancer and hematology, and that approvals supported by real-world evidence were significantly more likely to have orphan designation and accelerated approval than those without real-world evidence. These pathways often involve therapeutics targeting an unmet need and where patient populations may be smaller and more difficult to recruit and retain in traditional randomized controlled trials. This may explain why externally controlled trials and non-interventional studies incorporating real-world data elements, such as medical records derived from expanded access, were commonly identified in our analysis. In fact, nearly all the studies classified by FDA as providing substantial evidence were externally controlled pivotal trials. These findings likely reflect the challenge of leveraging real-world evidence to support most premarket applications, since many therapies lack clinical practice evidence at this stage. As such, real-world evidence studies may be more suitable and may be more commonly seen in supplemental new indication approvals.
There was an increase in the proportion of novel therapeutic approvals that had at least one real-world evidence study that supported premarket determinations of effectiveness and/or safety in 2020. Although this trend may appear related to the COVD-19 pandemic (e.g., disruptions to clinical trial recruitment, site closures, or staffing shortages leading to greater reliance on real-world evidence), such interpretation is likely overly speculative. Therapeutics approved in 2020 would generally have had applications submitted approximately 6 months earlier for priority review or 10 months earlier for standard review, meaning that the pivotal trial supporting these applications were likely completed in 2019, prior to the onset of the pandemic. Therefore, it is more plausible that the observed variation reflects random fluctuation rather than a pandemic-related effect.
We found that over one-third of all novel therapeutics were approved with at least one real-world evidence study required or requested by FDA to be conducted postmarket after approval, with the proportion of such approvals increasing over time. However, the vast majority of these postmarket real-world evidence studies were classified by FDA as pending, delayed, or ongoing. While FDA has long relied on required or voluntary postmarket studies to generate new evidence on the safety and effectiveness of approved therapeutics, our findings align with prior evaluations demonstrating low completion rates for these studies.33,34,37 This may reflect that most postmarket real-world evidence study descriptions are brief and often either lack specific data source details or rely on registries.33,34 Furthermore, prospective cohort studies and registries typically require lengthy patient recruitment and follow-up periods, which may delay the ascertainment of safety outcomes and contribute to slower or lower completion rates.
There was also a decrease in the proportion of novel therapeutics that were approved with at least one real-world evidence study required or requested by FDA to be conducted postmarket after approval in 2020. It is possible that disruptions in healthcare utilization patterns during the COVID-19 pandemic reduced the reliability of claims and electronic health record data sources, which may have caused FDA to deprioritize real-world evidence in postmarketing requirements and commitments.
FDA has committed to publicly reporting information on submissions that include premarket and/or postmarket real-world evidence studies, as well as to formally evaluating the use of real-world evidence studies to satisfy studies required or requested by FDA to be conducted postmarket after approval. As of September 2025, FDA’s website25,38 documents eight drug approvals by the Center for Drug Evaluation and Research in which real-world evidence was used to support regulatory decision-making since 2011: Actemra, Aurlumyn, Nulibry, Orencia, Prograf, Vijoice, Vimpat, and Voxzogo. Of these, our evaluation identified and included two of these cases—Nulibry and Voxzogo. The remaining six original approvals did not meet our eligibility criteria: Actemra, Orencia, Prograf, and Vimpat were originally approved before 2016, while Aurlumyn and Vijoice involved a new dosage form and new indication submitted as a distinct NDA, respectively, and were therefore excluded from our sample of novel therapeutic approvals. Our analysis identified an additional 41 novel therapeutics, not listed on FDA’s website, where real-world evidence informed regulatory decision-making, which aligns with other evaluations of real-world evidence in regulatory decision-making.35,36,38 These findings highlight the need for greater transparency in FDA’s reporting, including in what circumstances the real-world evidence studies qualify as confirmatory evidence, as well as causes for delays in the conduct of postmarket real-world evidence studies.40 Additionally, clearer guidance is needed on the most suitable therapeutic areas, study designs, and reasons for deeming real-world evidence studies insufficient to better inform their use in both premarket and postmarket settings.
Our study has several limitations. First, we relied on publicly available information. Therefore, we had to identify real-world evidence study characteristics from descriptions provided in FDA approval letters and review documents. Furthermore, we did not have access to confidential communications between FDA and sponsors regarding the use of real-world data/real-world evidence, including the full sample of real-world evidence studies submitted but not considered. Second, we did not evaluate real-world evidence studies used to support labeling changes for an approved product (i.e. supplemental indication approvals) or approvals made through the Center for Biologics evaluation and Research.25,38 Third, given that the majority of postmarketing requirements and commitments were classified as pending, delayed, or ongoing, we were unable to determine how often these studies will eventually be used to inform regulatory decision-making, if completed. Additionally, fulfilled and released postmarketing requirements and commitments are displayed on the online database for only one year. While we relied on various source to capture their status, including searching archived versions of the database, reliance on archives introduces the potential for underestimation of the true proportion of completed studies.
Conclusion
Across all 400 novel therapeutics approved by FDA between 2016 and 2024 found that real-world evidence studies are infrequently used to support FDA’s premarket determinations of effectiveness and/or safety. Although the proportion of approvals with real-world evidence studies required or requested by FDA to be conducted postmarket increased over time, delays in completing these studies may limit their regulatory impact. These findings highlight the need for further evaluation to identify the most suitable therapeutic areas, study designs, and real-world evidence data sources to better inform their appropriate use in both premarket and postmarket settings.
Supplementary Material
Acknowledgements
Funding/support and role of the sponsor:
This work was supported by grants from Arnold Ventures. However, the funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Mr. Li is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Grant support:
This work was supported by grants from Arnold Ventures to the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency. However, the funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Potential Competing Interests:
Dr. Ramachandran reported receiving research support from the Stavros Niarchos Foundation through Yale Law School for a project entitled Re-envisioning Publicly Funded Biomedical Research and Development and the US Food and Drug Administration for a project entitled Best Practices for Adequately Representing Women, Older Adults and Patients Identifying as Racial and Ethnic Minorities in Oncology Research: A Positive Deviance Approach; consultant fees for the ReAct-Action on Antibiotic Resistance Strategic Policy Program at Johns Hopkins Bloomberg School of Public Health in 2022, which was funded by the Swedish International Development and Cooperation Agency; and grant support from Arnold Ventures and the Greenwall Foundation outside the submitted work. Dr Ross reported receiving grants from the US Food and Drug Administration; Johnson and Johnson; Medical Device Innovation Consortium; Agency for Healthcare Research and Quality; National Heart, Lung, and Blood Institute; and Arnold Ventures outside the submitted work. Dr. Ross also is an expert witness at the request of relator attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. that was settled in September 2022. Dr. Ross is a deputy editor at JAMA. Dr. Wallach is supported by the FDA, Arnold Ventures, Johnson & Johnson through the Yale Open Data Access project, and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under awards 1K01AA028258 and 1R01AA032254. Dr. Wallach previosly served as a consultant to Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC.
Footnotes
Data access and responsibility: Mr. Li and Dr. Wallach had full access to all the data in the study. Dr. Wallach takes responsibility for the integrity of the data and the accuracy of the data analysis.
Data Sharing Statement:
Data are available upon request (joshua.wallach@emory.edu) with publication.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are available upon request (joshua.wallach@emory.edu) with publication.