Table 3 Major barriers to the conduct of randomized trials for rare diseases identified by use cases on RCT for drug repurposing
STUDY SET UP | Comments/rational | Identified as a hurdle (trial) (number of trials) |
|---|---|---|
Study design | Lack of natural history studies to inform about trial design Lack of registries validated surrogate outcomes and patient reported outcome measures to choose an appropriated study design Small and heterogeneous patients groups (risk of being underpowered to test efficacy) | HCQ4SurfDefect (1/6) |
Funding and funding mechanism | Non-commercial sponsors often face budgetary problems due to lack of public funding opportunities and/or poor flexibility of the external funding | ROP ROP, Redox, DevelopAKUre, ROCK-ALS, TAM DMD, HCQ4SurfDefect (6/6) |
Sponsorship | Lack of experience and/or insufficient knowledge of academic organizations about sponsor responsibilities in a multinational setting Lack of trial-specific legal support Co-sponsorship not yet possible in Europe | Redox, ROCK-ALS, HCQ4SurfDefect (3/6) |
Drug procurement | Tendering process to select drug supplier Custom restrictions Country-specify requirements for data on drug stability Lack of placebo suppliers | Redox, ROCK-ALS, HCQ4SurfDefect (3/6) |
Project management | Lack of experience in multinational trials in legal affairs department | ROP ROP (1/6) |
Data management | Lack of harmonization among countries Lack of experience on multinational trials from selected data centers | Not reported |
Vigilance (PV) | Lack of harmonization among countries Lack of experience on multinational trials from selected PV center | Redox (1/6) |
Monitoring | Lack of harmonization on monitoring plan requirements | Not reported |
COUNTRY SET UP | ||
Country selection | Scarcity of patients leads to large-scale studies, i.e., multicenter/multinational set-ups | Not reported |
NCA/EC approval/regulatory | Timing/unexpected delays Lack of harmonization | ROP ROP, ROCK-ALS, TAM DMD (3/6) |
Insurance | Lack of harmonization on requirements, minimum coverage varies among EU countries | ROCK-ALS (1/6) |
Good Clinical Practice (GCP) requirements | Lack of harmonization on GCP training content/extent | ROP ROP (1/6) |
SITE SET UP | ||
Site agreements | Lack of harmonization on site agreements templates even within the same country Country-specific terminology/interpretation (legal responsibilities, intellectual/industrial property, GDPR) included in site contracts, reference to the national, legal and regulatory framework (liability and insurance), templates tailored to industry sponsored trials, need to align with Consortium/Grant Agreements | ROP ROP, Redox, TAM DMD, HCQ4SurfDefect (4/6) |
Site compliance | Lack of personnel experienced in clinical research Lack of personnel involved in academic trials Personnel’s turnover due to trial’s extensions | Not reported |