Rare disease clinical trials in Italy (2022–May 2026): current trends, future challenges, and the evolving role as reporting member state

Introduction Rare diseases represent a major public health challenge characterised by high unmet medical need, limited patient populations, and increasing methodological complexity in clinical research. Since the implementation of Regulation (EU) No. 536/2014 and the launch of the Clinical Trials Information System (CTIS) on 31 January 2022, the European clinical trial landscape has undergone profound regulatory transformation. This study analysed the evolution of rare disease clinical trials in Italy from 2022 to 2026 within the framework of the implementation of the Clinical Trials Regulation (CTR). Methods Clinical trial applications submitted to the Italian Medicines Agency (AIFA) between 1 January 2022 and 31 May 2026 were analysed, using data from the Osservatorio sulla Sperimentazione Clinica dei medicinali (OsSC) and the CTIS. Trials were categorised by year, therapeutic area, and Investigational Medicinal Product (IMP) characteristics. They were further analysed by phase, sponsor profile, study population, and Italy’s role as Reporting Member State (RMS). Results Of 3,299 total submissions, 969 (29.37%) involved rare diseases. While the absolute number of rare disease trials fluctuated between 201 and 258, their proportional share declined due to faster growth in non-rare disease research. Phase III studies predominated, followed by Phase II trials, consistent with a late-stage development focus. Commercial sponsors accounted for the vast majority of rare disease trials. Conversely, non-commercial research represented a minor share and underwent a progressive structural contraction. Research activity was concentrated in oncology, nervous system diseases, immune disorders, and congenital diseases. Chemical compounds remained the predominant IMP, whereas Advanced Therapy Medicinal Products accounted for a limited fraction. In trials where Italy acted as RMS, the landscape was dominated by multinational commercial Phase III studies, whereas non-commercial activity remained largely mononational and Phase II-oriented.