Consensus for the most suitable trial design to assess therapy for rare vascular malformations: a Delphi study

Randomized controlled trials are the gold standard for assessing therapeutic interventions but face challenges in rare diseases due to small sample sizes and heterogeneous conditions. Vascular anomalies (VAs) constitute an interesting model for investigating adapted trial designs. We aimed to assess consensus among international experts in determining the most appropriate trial design for studying the therapeutic effect of a medical treatment for VAs. By using a two-round Delphi method, this study collected opinions from international experts (physicians and patients/caregivers) on the feasibility, acceptability, and suitability of various trial designs for VAs. Experts completed an e-questionnaire based on four clinical scenarios including ten therapeutic situations comparing different treatment modalities and comparators. We considered consensus as ≥ 60% agreement. More than 200 experts were solicited; 29 participated in the first round and 26 in the second. Consensus was achieved for 2 of the 10 situations, favoring cross-over and within-person designs. The designs allow intra-patient comparisons, reduce required sample size; ensure patient access to the experimental treatment; and masked assessment. However, consensus was not reached for 8 of the 10 situations, reflecting heterogeneity and the absence of a universally optimal design. These findings provide preliminary guidance for early protocol planning and require confirmation through empirical studies.