BACKGROUND: Academic-sponsored trials for rare diseases face many challenges; the present paper identifies hurdles in the set-up of six multinational clinical trials for drug repurposing, as use cases. METHODS: Six academic-sponsored multinational trials aiming to generate knowledge on rare diseases drug repurposing were used as examples to identify problems in their set-up. Coordinating investigators leading these trials provided feedback on hurdles linked to study, country, and site set up, on the basis of pre-identified categories established through the analysis of previous peer-reviewed publications. RESULTS: Administrative burden and lack of harmonization for trial-site agreements were deemed as a major hurdle. Other main identified obstacles included the following: (1) complexity and restriction on the use of public funding, especially in a multinational set up, (2) drug supply, including procurement tendering rules and country-specific requirements for drug stability, and (3) lack of harmonization on regulatory requirements to get trial approvals. CONCLUSION: A better knowledge of the non-commercial clinical research landscape and its challenges and requirements is needed to make drugs-especially those with less commercial gain-accessible to rare diseases patients. Better information about existing resources like research infrastructures, clinical research programs, and counseling mechanisms is needed to support and guide clinicians through the many challenges associated to the set-up of academic-sponsored multinational trials.

AKU Society Cambridge UK

Amyloidosis Research and Treatment Center Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and Department of Molecular Medicine University of Pavia Pavia Italy

ANR French National Research Agency Paris France

Department of Medical Genetics and Skeletal Rare Diseases IRCCS Rizzoli Orthopaedic Institute Bologna Italy

Department of Neonatology Charité Universitätsmedizin Berlin Germany

Department of Neurology Klinikum rechts der Isar Technical University of Munich Munich Germany

Department of Pediatrics Dr von Hauner Children's Hospital University Hospital LMU Munich German Center for Lung Research Lindwurmstraße 4 80337 Munich Germany

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

Division of Developmental and Neuropaediatrics University Children's Hospital Basel University of Basel Spitalstrasse 33 Postfach 4031 Basel Switzerland

ECRIN European Clinical Research Network Infrastructure Paris France

EURORDIS Rare Diseases Europe Paris France

Inserm Transfert Paris France

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