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

Area of Science:

• Medical research methodology
• Rare disease clinical trials
• Vascular anomalies therapeutics

Background:

• Randomized controlled trials (RCTs) are standard for therapeutic evaluation but struggle with rare diseases due to small, heterogeneous patient populations.
• Vascular anomalies (VAs) present a unique model for exploring alternative clinical trial designs.
• Challenges in rare disease research necessitate adapted methodologies for effective treatment assessment.

Purpose of the Study:

• To achieve international expert consensus on the most suitable clinical trial designs for evaluating medical treatments for VAs.
• To assess the feasibility, acceptability, and suitability of various trial designs through expert opinion.
• To provide guidance for the development of VAs clinical trial protocols.

Main Methods:

• A two-round Delphi method was employed, collecting international expert opinions (physicians, patients/caregivers) via e-questionnaires.
• Four clinical scenarios with ten therapeutic situations were presented, comparing different treatment modalities and comparators.
• Consensus was defined as ≥60% agreement among participating experts.

Main Results:

• Twenty-nine experts participated in round one, and 26 in round two.
• Consensus was reached for 2 out of 10 situations, supporting cross-over and within-person designs.
• Consensus was not achieved for 8 situations, highlighting the heterogeneity of VAs and the lack of a single optimal design.

Conclusions:

• Cross-over and within-person designs offer advantages for VAs trials, including reduced sample size and masked assessment.
• The heterogeneity of vascular anomalies indicates that a universally optimal trial design may not exist.
• Further empirical studies are needed to validate these preliminary findings and refine VAs trial protocols.