The possibility of generating and storing clinical data electronically is making significant progress in the study of orphan drugs (ODs). Nevertheless, to help advance progress, regulatory agencies should consider implementing innovative trial designs, developing flexible policies, and incorporating real-world data (RWD) to evaluate clinical outcomes [1]. The US Food and Drug Administration (FDA) definition of RWD is data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources such as electronic health records or disease registries [2]. Real-world evidence (RWE) is clinical evidence on the use and potential benefits or risks of a medical product derived from the RWD analysis. It can inform therapeutic development, research on health care systems, quality improvement, safety surveillance, and well-controlled effectiveness studies 3, 4, 5. Caution should be exercised when relying on the analysis of existing data and the evidence presented in the reports, as it can lead to erroneous conclusions. This concern is particularly relevant in precision molecular medicine for rare diseases 6, 7∗∗. For these reasons, an important aspect to consider is how RWE should be used and reported. A group of Canadian researchers published a guide with recommendations for reporting RWE in May 2023 [8].

There are different types of RWE, such as those obtained by collecting and using patient-reported outcomes (PROs), which can provide valuable information on the effectiveness, safety, and tolerability of health interventions from patient perspective. The EMA currently uses RWE for safety monitoring and recently announced that the use of RWE will be established across its spectrum of regulatory use cases by 2025 9∗, 10, 11. The 21st Century Cures Act, signed into law in December 2016, was designed to help accelerate medical product development and bring innovations to patients who need them in the US. The regulation builds on the FDA's work to incorporate patient perspectives into the development of drugs, biologics, and devices. It enhances the ability to improve clinical trial designs, including the use of RWE and clinical outcome assessments (COA), which is expected to accelerate the development and review of new medical products [12]. COA describes feelings or functions and can be reported by a health care provider, patient or caregivers. There are four types: patient-reported outcomes (PROs), clinician-reported outcomes (ClinROs), observer-reported outcomes (ObsROs) and performance outcomes (PerfOs). The difference between them is the perspective on a patient's health status. PROs are direct patient feedback through questionnaires or numerical rating scales. ClinROs are information coming from a trained health-care professional regarding their interpretation of signs or behaviors that can be observed related to a patient's disease. ObsROs are assessments of observable signs related to a patient's health condition as reported by caregivers. PerfOS are measurements collected when a patient is asked to complete a well-defined, repeatable, and standardized task, such as the word recovery test 13, 14.

Both agencies release comprehensive assessment dossiers for every marketing-authorization application—whether approved or refused: the European Medicines Agency issues a European Public Assessment Report (EPAR), while the U.S. Food and Drug Administration provides a Drug Approval Package (DAP) 15, 16.

The aim of this study was to analyze how the EMA and the FDA have incorporated RWD and RWE into orphan drug approvals for neuromuscular diseases between January 2015 and January 2025.