The use of real-world evidence (RWE) in FDA drug approvals has surged dramatically over the past three years, with nearly all new molecular entities and biologics now incorporating some form of real-world data in their regulatory submissions, according to a comprehensive systematic review published in Clinical Pharmacology & Therapeutics.
The study analyzed 136 FDA-approved new drug applications (NDAs) and biologics license applications (BLAs) from January 2019 through June 2021, revealing that 116 approvals (85%) incorporated RWE in any form. The proportion of approvals including RWE studies increased substantially over the study period, rising from 38 of 51 (75%) approvals in 2019 to 53 of 59 (90%) in 2020, and reaching 25 of 26 (96%) in the first half of 2021.
Growing Regulatory Impact
Among the 88 approvals that included RWE studies specifically intended to support product safety or effectiveness, the majority demonstrated meaningful regulatory impact. FDA appeared to use 65 of these 88 RWE studies (74%) in its benefit-risk assessments, with 8 studies (9%) classified as providing substantial or primary evidence and 57 studies (65%) serving as supportive evidence.
The therapeutic areas with the highest utilization of RWE were oncology (30 of 43 approvals in that area), infectious disease (16 of 17), neuroscience (13 of 25), and endocrinology and metabolism (8 of 14). These areas share common characteristics that may favor RWE use, including substantial drug development activity, frequent eligibility for expedited programs, and challenges with traditional randomized controlled trials due to small patient populations or ethical considerations regarding placebo controls.
Quality Standards and Common Pitfalls
Despite the growing acceptance of RWE, the study revealed that not all submitted evidence met FDA's standards. Among the 88 approvals with RWE intended to support safety or effectiveness, 13 studies (15%) were deemed inadequate for FDA decision-making, while 10 studies (11%) were not directly addressed in FDA's published reviews.
FDA's documented feedback on RWE studies identified several recurring issues across 37 approvals. Methodological problems were the most common concern, cited in 23 cases, including issues such as immortal time bias, confounding factors, selection bias, and lack of comparability between trial data and real-world data. Sample size concerns affected 8 studies, while omission of patient-level data was noted in 3 cases, limiting FDA's ability to independently verify results.
In one example of inadequate evidence, FDA stated: "Due to major methodological issues (including immortal time bias, selection bias, misclassification, confounding, and missing data), the FDA does not consider these [RWE] results adequate to support regulatory decision making."
Conversely, successful RWE submissions demonstrated rigorous methodology. In approving lonafarnib for Hutchinson-Gilford progeria syndrome, FDA noted: "The Agency agreed to the use of the external contemporaneous control in the matched analysis because the trial investigators and Applicant took adequate measures to minimize potential sources of bias."
Product Labeling Integration
The study found that 38 of the 88 approvals (43%) with RWE intended to support safety or effectiveness included references to the RWE studies or their findings in the final product labels. This integration into prescribing information represents a direct pathway for RWE to influence clinical decision-making by healthcare providers.
The therapeutic areas most commonly incorporating RWE into product labels differed somewhat from overall usage patterns, with infectious disease leading at 11 of 17 approvals (65%), followed by neuroscience at 9 of 25 (36%), and endocrinology and metabolism at 4 of 14 (29%).
Regulatory Framework Evolution
The findings reflect FDA's broader commitment to advancing RWE use following the 21st Century Cures Act of 2016, which required the agency to develop a program for evaluating RWE to support new indications and fulfill post-approval study requirements. FDA published its RWE framework in 2018 and continues developing guidance on regulatory expectations for RWE in medical product approvals.
The study authors noted that successful RWE submissions consistently demonstrated several key characteristics: use of fit-for-purpose real-world data sources, rigorous study design that often emulated target trials, transparent methodology allowing for independent verification, and early communication with FDA during the planning and design phases.
Future Implications
As RWE methodology continues evolving, the research suggests that future regulatory guidance will likely emphasize fit-for-purpose real-world data selection and careful attention to study design and analysis. The authors anticipate that demonstration projects, workshops, and shared learning from successful use cases will continue advancing development of regulatory guidelines and best practices in analytical methodology.
The study's limitations include coverage of only the first half of 2021, focus solely on approved applications (excluding complete response letters), and insufficient sample sizes to identify specific design or analytic factors most likely to result in substantial evidence classification.
The research provides empirical evidence that RWE is becoming integral to FDA's regulatory decision-making process, while highlighting the critical importance of methodological rigor in generating evidence that meets regulatory standards for supporting drug approvals.
