Navigating regulatory scenarios for accelerating drug repurposing in rare diseases: a multi-stakeholder perspective on the challenges and opportunities

Background: The lack of treatments for patients with a rare disease calls for innovative approaches in drug development. A potential solution to accelerate therapy development is to find new therapeutic uses for existing drugs, i.e. drug repurposing. One way of advancing drug repurposing is to focus on similarities in the molecular and clinical manifestations across multiple rare diseases, by studying drug repurposing candidates in induced pluripotent stem cell (iPSC) models and subsequently grouping diseases in basket trials composed of multiple sub-studies. However, the absence of a single route to navigate the regulatory process, in combination with limited regulatory experience in academia poses a challenge for this approach. To provide more insight into the perceived regulatory challenges and opportunities for basket trials in drug repurposing for rare diseases, a multi-stakeholder dialogue was organised in March 2025. The aim of this dialogue was to contribute to a better alignment of stakeholder perspectives to accelerate therapy development for rare diseases, by identifying and mapping challenges and opportunities in three regulatory scenarios for basket trials in drug repurposing for rare diseases. Results: In total, 28 experts (regulatory, preclinical, clinical, patient, industry, HTA, and other) from eight European countries participated in an interactive online meeting. Thematic analysis of the meeting content showed the most important challenges and opportunities in navigating the regulatory scenarios, covering themes such as preclinical evidence in iPSC models, design of basket trials, involvement of patient organisations, regulatory roles and responsibilities, pharmaceutical product development, HTA and reimbursement, and societal views on repurposed drugs. Conclusions: This multi-stakeholder dialogue highlights the continued need for 1) early regulatory guidance for academic innovators, 2) a (re)calibration of regulatory roles and responsibilities, and 3) early creation of collaborative spaces involving patient organisations, HTA bodies and marketing authorisation holders in the development process to optimize the potential of innovative methods. This multi-stakeholder alignment is essential for the compliant adoption of iPSC models and clinical basket trial designs as promising accelerators for drug repurposing in rare diseases.