This review focuses on the pitfalls of traditional randomized clinical trials, and suggest more modern approaches with new endpoints. Co-authored by members of the FDA, they also discuss newer treatments under development which may be better suited for these strategies.
This paper discusses the various possible clinical trial designs that are well suited for a disease like PAH. The authors point out that orphan diseases make the typical parallel design of randomized blinded trials difficult and often risky. Novel trial designs can result in smaller trials which are less costly, while at the same enriched to allow for larger treatment effects.