Использование реальных доказательств в США. Управление по контролю за продуктами питания и лекарственными препаратами и Европейское агентство по лекарственным препаратам утверждают онкологические продукты, поддерживаемые односторонними испытаниями (Advisory and Drug Argency and the European Medicals Agency (European Medicals Agency)2022-2025).

Real-world evidence (RWE) is increasingly utilized in oncology regulatory submissions that are supported by single-arm trials (SATs). In this review of recent FDA and EMA approvals, 18 applications with SATs (15 unique products) included RWE. Regulatory review documents suggested that RWE or observational approaches were mostly viewed as contextual/supportive evidence in most cases, with only 2 providing substantial evidence in regulatory decision-making. RWE has shown strong potential to provide supportive and complementary clinical evidence across a broad range of use cases with SATs and provides opportunities to accelerate clinical development.

Introduction

Single-arm trials (SATs) are increasingly used to evaluate the efficacy and safety of anticancer drugs to support oncology drug approvals, particularly in contexts where randomized controlled trials (RCTs) are infeasible or unethical, such as for rare cancers with small patient populations or aggressive diseases where withholding an experimental treatment is not acceptable. 1 , 2 While SATs can accelerate access to novel therapies, the absence of a randomized control arm often leaves residual uncertainties.

Real-world evidence (RWE), derived from real-world data (RWD), is increasingly recognized as a valuable complement to traditional RCTs 3 and as a critical component in emerging hybrid trial designs. 4 , 5 External controls derived from RWD are also recognized as a possible type of control arm 6 and can help mitigate uncertainties by providing contextual/supportive or even substantial evidence to support regulatory decision-making, especially when SATs serve as pivotal trials in indications with high unmet need. 7–9

There is increasing global regulatory interest in leveraging high-quality RWE for regulatory decision-making. 10 , 11 The 2023 U.S. Food and Drug Administration (FDA) guidance on the use of external controls for SATs provides considerations for use of RWD sources to derive control arm data for SATs. 12 The European Medicines Agency (EMA) has also published a reflection paper on establishing efficacy based on SATs 13 and is currently developing a reflection paper on the use of external controls based on both trial data and RWD for regulatory decision-making. 14

A comprehensive oncology-specific evaluation of recent regulatory application review documents by FDA and EMA is needed to shed light on regulatory evaluations/feedback, trial characteristics, RWE approaches, methodological challenges, and lessons learned regarding regulatory utilization of RWE in oncology approvals. We therefore reviewed oncology drug approvals from Jan 2022 through August 2025 in which SATs were supplemented by RWE. Our analysis focused on FDA New Drug Applications (NDAs) and Biologics License Applications (BLAs), as well as EMA Marketing Authorizations approvals (MAAs), to understand how RWE has been applied and evaluated in regulatory decision-making.

Methods

We systematically reviewed FDA NDA/BLA approvals and EMA MAAs between January 2022 and August 2025 to identify original oncology submissions. US approvals were identified from FDA.gov sources including the Center for Biologics Evaluation and Research (CBER) “Biological Approvals by Year,” the Center for Drug Evaluation and Research (CDER) “Calendar Year Approvals” and “CDER Drug Approvals by Month.” European oncology MAAs were obtained from the EMA “Download table of medicines” resource. Data sources and linkages are listed in Table S1 .

For each oncology approval with active document links, we retrieved regulatory reviews. EMA approvals information was obtained using European Public Assessment Report, while FDA approvals were assessed using multidisciplinary review (summary, clinical, non-clinical, statistical, and pharmacology review) documents, supplemented by approval letters, product labels, risk assessment and risk mitigation reviews, and administrative correspondence.

Documents were screened using predefined RWE- and SAT-related keywords ( Table S2 ). Approvals flagged for potential RWE content underwent full‑text review. Data were extracted by one reviewer, with uncertainties resolved by a second reviewer and adjudication by a third if necessary. Extracted variables were compiled into prespecified summary tables capturing product details, SAT characteristics, RWE/RWD elements, and regulatory comments.

Results

Between January 1, 2022 and August 31, 2025, FDA (CDER and CBER) issued 553 original approvals, of which 134 involved oncology products. EMA granted 330 original approvals during this period, including 66 in oncology ( Figure S1, see online supplementary material for a color version of this figure). Among these, 18 applications (7 FDA, 11 EMA) incorporated SATs supplemented by RWD/RWE, corresponding to 15 unique oncology products (with 3 approved by both agencies; Table S3 ).

Of the 15 products, 8 (53.3%) were for hematologic malignancies, 5 (33.3%) for solid tumors, and 2 (13.3%) for oncology-related conditions ( Table S3 , Table 1 ). Ten (66.7%) were approved for adults-only, 4 (26.7%) for adults and pediatric patients, and 1 (6.7%) for pediatric patients only. All SATs were registrational studies. Among 11 EMA approvals, 6 (54.5%) had Orphan Drug designation, 6 (54.5%) received PRIME (PRIority MEdicines) status, 7 (63.6%) were granted Conditional Marketing Authorization, and 1 (9.1%) was approved under Exceptional Circumstances. All 7 FDA approvals had Orphan Drug designation, with 2 (28.6%) receiving accelerated approval, 5 (71.4%) priority review, 3 (42.9%) breakthrough therapy, and 3 (42.9%) fast track designations.

RWE approaches and regulatory comments

All 15 products included at least 1 RWE approach, and 8 used multiple approaches including historical clinical trial data and literature (25 distinct approaches in total) ( Table 2 ). The most common design was a retrospective cohort study design ( n = 16 out of 25, 64.0%), often using patient-level data ( n = 19, 76%) from electronic medical records ( n = 6, 24.0%), registries (5 disease registries [20.0%], 1 product registry [4.0%]), or site-based chart collections ( n = 7, 28.0%). Propensity score (PS) matching ( n = 6, 24.0%) or weighting ( n = 8, 32.0%) was frequently applied to facilitate comparative effectiveness ( n = 21, 84%; Table S4 ).

We classified regulatory comments on evidence from RWD or observational approaches into 3 categories, based on recurring regulatory language: (1) substantial evidence, when considered adequate and well-controlled to support efficacy and safety; (2) contextual/supportive, when judged useful for contextualization or when provided supportive information; and (3) not supportive, when described as exploratory or inconclusive. Regulatory assessment of the 25 RWD/observational approaches found that 15 were supportive, 6 were not supportive, and only 2 provided substantial evidence (regulatory reviewer comments and quatations are included in Table S5 ). Notably, in use case that supported substantial evidence: eflornithine (trade name IWILFIN) leveraged a prior clinical trial (ANBL0032) to construct an external control arm, 15 and; alpelisib (trade name VIJOICE) relied on a retrospective chart review (EPIK-P1) as pivotal evidence. 16 Methodological critiques were identified in 11 cases (6 not supportive and 5 contextual/supportive evidence) with recurring themes (regulatory reviewer comment and quotations are included in Table S6 ), including small sample sizes, population heterogeneity, missing or unmeasured covariates, nonaligned outcome assessments, post-hoc design, and non-contemporaneous treatments ( Tables S7 and S8 ).

Discussion

Our review of oncology approvals from 2022 through 2025 highlights both opportunities and limitations of using RWE to support SATs. Across 15 products reviewed, RWE usually served as supportive or contextual evidence rather than as substantial evidence. While regulators acknowledged the value of RWE in providing benchmarks—they identified methodologic challenges that limited its weight in decision-making.

Regulatory implications

Only 2 submissions (eflornithine, alpelisib) were judged to provide data of sufficient quality for substantial evidence . These examples show that although RWD or observational approaches can address critical gaps when RCTs are lacking, regulators require rigorous study design, robust data provenance, and methodological transparency. For regulatory decision-making, particularly when RWE is intended to contribute to substantial evidence, the evidentiary threshold is appropriately high and requires fit-for-purpose data source (relevant, reliable and high-quality data), a clearly defined population, reliable outcome ascertainment, prespecified analytic plans, and adequate approaches to address confounding, selection bias, and other threats to validity. 12 , 17 FDA and EMA are broadly aligned in principles, and reviewers consistently flag confounding, heterogeneity, and incomplete outcome assessments.

While only 2 use cases utilized RWD and related observational approaches to produce substantial evidence, this should not imply that RWD/E lacks value. In most use cases as reported in the study findings, RWE served a supportive role, delivering important contextual and clinical insights that complemented other evidence, even when it was not relied on as the primary source of substantial evidence. Therefore, limited acceptance of RWE as substantial evidence should not be equated with limited overall utility of RWE. For example, RWE can characterize treatment patterns and outcomes in broader clinical populations, evaluate patients underrepresented in trials, 18 describe evolving standards of care, assess long-term effectiveness and safety, 19 and capture clinical and population heterogeneity. In this way, RWE can provide a complementary evidentiary dimension rather than serving solely as an imperfect substitute for randomized evidence.

Methodological trends

Retrospective cohort studies, drawn from electronic health records (EHRs), chart reviews, or disease registries, were the dominant RWE design, with PS matching or weighting frequently employed to mitigate imbalances between SAT and real-world populations. However, regulators consistently highlighted important limitations, including small sample sizes, selection and clinical heterogeneity, missing or unmeasured critical information, non-synchronized outcome assessment, post-hoc analyses, and non-contemporaneous treatments. Small cohorts often undermined statistical robustness, while heterogeneity arose from differences in patient eligibility, baseline characteristics, disease biology, and treatment practices. Missing information such as the Eastern Cooperative Oncology Group (ECOG) performance status, tumor burden, or concomitant medications introduced residual confounding, and non-standardized or delayed outcome assessments (eg, deviations from Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) reduced comparability. Post-hoc cohort assignment introduced the potential for immortal-time bias, and changes in the standard of care, along with disruptions such as the COVID-19 pandemic, further complicated interpretation. While PS adjustment methods are widely employed, regulators emphasized that they rarely resolve these issues fully, underscoring the potential need for prospective study designs in certain circumstances, harmonized endpoint definitions, and higher-quality data collection.

The design of an RWE study should be aligned with the evidentiary role it is expected to play, as well as with the clinical research question. When RWE is used as an external control for a SAT, the comparability of eligibility criteria, treatment context, follow-up, and endpoint definitions is essential. When RWE is used to complement trial evidence, depending on the clinical research question, its value may also derive from capturing real-world heterogeneity, treatment sequencing, long-term outcomes, and patient populations that are not well represented in clinical trials.

Furthermore, it is important to note that in certain rare disease or unmet need settings, where randomized controlled trials are not feasible, RWE may represent the best available evidence; in such contexts, RWE can provide critical insights that would otherwise remain uncaptured, offering irreplaceable value in informing regulatory and clinical decisions. 7

Future directions

The integration of RWE in oncology SATs is likely to expand. For substantial evidence generation purposes, the role of RWE would depend on overcoming methodological and operational challenges. 20 Key avenues for improvement may include prospective RWE collection through companion studies that align endpoints and data quality with SATs, along with pre-specification and registration of RWD protocols to reduce bias and concerns associated with post hoc analyses. Standardization of data capture and outcome definitions, along with the development of regulatory-grade cohorts for rare cancers, would further strengthen the reliability of external controls. Early partnership with regulators is critical to ensure RWE strategies are “fit for purpose” depending on clinical and regulatory context, and additional precedent-setting approvals will also play an important role in establishing utilization of RWE in regulatory decision-making. Additionally, further cross-sector multi-disciplinary stakeholder collaborations and demonstration projects are needed to assess and highlight unique value RWE can bring in providing supportive and complementary evidence in clinical and regulatory decision making across various clinical circumstances. It is important to note that RWE studies should also follow transparent, comprehensive, and standard recommendations for reporting and dissemination of findings. For instance, ESMO Guidance for Reporting Oncology real-World evidence (GROW) report provides key recommendations for reporting real-world evidence studies in oncology. 21

Limitations

Our dataset was restricted to publicly accessible regulatory documents from regulators, possibly omitting confidential discussions and additional analyses submitted by sponsors. Nonetheless, this review captures the most recent original oncology medicinal product approvals and offers cross-agency coverage. Additionally, our categorization scheme simplified complex regulator critiques, potentially overlooking nuances of case-specific assessments. However, we provided verbatim regulator quotations in our tables.

Conclusion

RWE has emerged as a valuable complement to SATs in oncology drug development, helping to contextualize outcomes and in rare cases, providing substantial evidence to support approvals. In recent FDA and EMA oncology approvals supported by SATs, RWE was used primarily as supportive or contextual evidence, reflecting the high evidentiary threshold for regulatory decision-making rather than limited overall value of RWE. Advancing RWE as a credible evidentiary tool will continue to require robust study design, transparency, and data quality, supported by greater standardization and regulatory collaboration.

Supplementary Material

Acknowledgments

The views and opinions expressed in this paper are those of the authors and may not necessarily reflect the views or opinions of any other public or private entity.

Author contributions

Le Su (Formal analysis, Methodology, Writing—original draft, Writing—review & editing), Lei Chen (Conceptualization, Methodology, Writing—review & editing), Ronac Mamtani (Writing—original draft, Writing—review & editing), Seema Betigeri (Conceptualization, Writing—review & editing), Rebecca Hubbard (Writing—review & editing), and Mehmet Burcu (Conceptualization, Supervision, Writing—original draft, Writing—review & editing)

Supplementary material

Supplementary material is available at The Oncologist online.

Funding

None declared.

Conflicts of interest

L.S., L.C., S.B., and M.B. are salaried employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, United States. L.C. and M.B. own stocks in Merck & Co., Inc., Rahway, NJ, United States. S.B. owns stocks in Merck & Co., Inc., Rahway, NJ, United States and in Bristol-Myers Squibb Company. R.M. reports having received research funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Astellas, and reports having received personal fees from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Astellas, Bristol-Myers Squibb Company, Roche, Pfizer, Seagen outside of this submitted work. R.H. reports no conflict of interest. The views and opinions expressed in this paper are those of the authors and may not necessarily reflect the views or opinions of any organization, employer, or affiliated group.

Data availability

All data analyzed are publicly available from the sources referenced in the manuscript.

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