Presentation (CTI)

OBJECTIVES: External data are increasingly valued in confirmatory trials, either to design External Control Trial (ECT) or to contextualize Randomized Controlled Trials (RCT) or Single-Arm Trials (SAT), often using Real-World Data (RWD). Their use is relevant in oncology and rare diseases. In Europe, the EMA has issued two reflection papers supporting their role, one dedicated to SAT and another to RWD, with further guidance on ECT expected soon. This work aimed to quantify and assess the role of external data through a scoping review of oncology and rare diseases submissions over the past decade.
METHODS: This work follows the PRISMA-ScR guidelines. Oncology and rare disease drug submissions (2015-2025) were extracted from the EMA database. Oncology products were identified using ATC codes, while orphan designation served as a proxy for rare diseases. EPARs were screened using predefined keywords, followed by manual curation to identify records supporting efficacy. Data was extracted using a standardized charting grid developed to ensure alignment with regulatory expectations. For ECTs, key methodological elements contributing to pivotal acceptance were collected.
RESULTS: Out of 501 submissions, 51 used external data. Overall, 63 pivotal trials were identified across oncology, rare diseases, and both indications (16, 27, and 20, respectively), including 36 SATs, 19 RCTs, and 8 ECTs. Among ECTs, 6 used primary data retrospectively collected and 2 used data from previous clinical studies. Key methodological considerations strengthening elements of submission were also noted and quantified (e.g. early scientific advice, use of estimand framework, study design alignment).
CONCLUSIONS: While external data are increasingly valued, their role remains mainly supportive, as no pivotal applications have yet been accepted based on external arms derived from large RWD sources. Most rely on primary data retrospectively collected or previous clinical development programs. Efforts are needed to generate fit-for-purpose data, alongside robust methodologies to expand their role toward pivotal acceptance.