Clinical development of novel therapies for pulmonary artery hypertension (PAH) requires trials of larger patient cohorts, who are studied for longer periods and with more robust and meaningful efficacy endpoints, using event-driven studies. When employing an event-driven methodology in orphan conditions such as PAH, it is important to consider study endpoints, the use of placebo, and the approach used for treatment. The most relevant clinical endpoints in rare conditions, such as death, can be a rare event in the trial duration. The use of composite or surrogate endpoints based on biomarkers can provide a wealth of information regarding benefits observed in randomised controlled trials (RCTs). Biomarkers that predict morbidity and mortality at an early stage are required. The use of placebo in event-driven studies of PAH is a growing issue, as the development of novel treatments over past years means that future therapies possibly cannot be compared against placebo. Crossover study designs, randomised discontinuation trials, registry trials, and re-randomisation may instead be utilised in RCTs of PAH. Owing to the heterogeneity of responses to PAH treatment, differing strategic approaches should be assessed in RCTs including combination therapy and sequential therapy.
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