FDA publishes new landscape analysis of real-world evidence in regulatory decision-making

The US Food and Drug Administration (FDA) has published a new webpage cataloguing examples of how real-world evidence (RWE) has been applied in regulatory decision-making since 2011. Its release coincided with an FDA convening event, where Agency staff and industry shared lessons from these case studies and outlined next steps for RWE submissions.

The initiative, led by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER), aims to provide greater transparency into when and how RWE contributes to approvals, safety decisions, and labeling updates.

The webpage consolidates more than a decade of case studies, dating back to 2011, where RWE played a role in determinations ranging from product approvals to regulatory assessments that concluded no action was necessary. Through these examples, the FDA is signaling both the growing relevance of RWE in regulatory science and its commitment to making decision-making processes more visible to stakeholders, including industry, healthcare providers, and patients.

Approvals supported by RWE

Several approvals highlighted in the analysis demonstrate how RWE can complement or substitute for traditional trial data. For instance, UCB’s antiepileptic drug Vimpat® (lacosamide) received approval for expanded use in pediatric populations after the FDA reviewed retrospective cohort data drawn from PEDSnet, a pediatric clinical research network. The study analyzed electronic health records from over 680 patients and 28 neonates, providing the additional safety evidence needed to support a new loading dose regimen.

Similarly, Novartis’ Vijoice® (alpelisib) was granted accelerated approval in 2022 for patients with PIK3CA-related overgrowth spectrum (PROS). In this approval, efficacy was established through a single-arm non-interventional study using medical charts of patients enrolled in an expanded access program across seven sites in five countries. Given the rarity and severity of the condition, traditional randomized controlled trials (RCTs) were not feasible; instead, RWD were judged to provide “substantial evidence of effectiveness.”

Another notable case involved BioMarin’s Voxzogo® (vosoritide), where RWE from the Achondroplasia Natural History registry in the US served as an external control arm. This registry data, combined with single-arm trials, provided confirmatory evidence alongside an RCT, strengthening the approval package.

In the biologics space, Bluebird Bio’s gene therapy Skysona® (elivaldogene autotemcel) received accelerated approval for boys aged 4–17 with early, active cerebral adrenoleukodystrophy (CALD). The decision was based on an externally controlled trial that compared treated patients with a natural history cohort, supplemented by data from a non-interventional study. The FDA determined that this RWE provided substantial evidence that Skysona slows disease progression.

Safety communications and labeling changes

Beyond product approvals, RWE has underpinned important safety communications and label updates. For example, retrospective analyses conducted through the FDA’s Sentinel System revealed clinically significant uterine bleeding risks associated with oral anticoagulants, leading to a class-wide labeling change in 2021. Another Sentinel study linked hydrochlorothiazide to increased risks of non-melanoma skin cancer, prompting label revisions in 2020.

More recently, retrospective cohort studies using claims data from the CBER BEST initiative informed updated warnings for mRNA COVID-19 vaccines (Comirnaty® and Spikevax®) regarding the risk of myocarditis and pericarditis. These post-market findings led to revised prescribing information in June 2025.

FDA–Duke-Margolis convening highlights next steps for RWE

The publication of the report coincided with the "FDA Convening: Regulatory Submissions with Real-World Evidence: Successes, Challenges, and Lessons Learned", held with the Duke-Margolis Institute for Health Policy on September 23, 2025. The event fulfilled commitments under the Prescription Drug User Fee Act (PDUFA VII, covering 2023–2027) and the Medical Device User Fee Act (MDUFA V, covering 2023–2027) and drew nearly 4000 online participants alongside hundreds in Washington, DC, underscoring broad interest in the topic.

Speakers from the FDA and industry sponsors reflected on case studies featured on the new webpage, sharing successes, challenges, and lessons learned. Discussions emphasized the need for early engagement with the agency, clearer guidance, and consistent approaches to RWE submissions.

Key strategies highlighted included developing and updating guidance, forming a cross-center RWE subcommittee, creating an RWE analytics team, expanding reviewer training, and increasing transparency with external stakeholders. The FDA’s Advancing RWE Program was also spotlighted as a mechanism to promote consistency and shared learning. The program offers selected sponsors the opportunity to meet with FDA staff early to discuss how RWE can be incorporated into medical product development.

The new webpage and convening underscore the FDA’s progress in using RWE, while also highlighting the need for continued clarity and consistency. As data sources and methods evolve, transparency and collaboration will remain central to ensuring RWE supports robust regulatory decisions. The Evidence Base will share further insights from the event in the weeks ahead.