Towards coordinated adult–paediatric development in pulmonary arterial hypertension: lessons from EU paediatric investigation plans

Background Pulmonary arterial hypertension (PAH) in children is a rare, severe and progressive condition for which treatment strategies largely rely on adult evidence and clinical experience1. Under the EU Paediatric Regulation, a Paediatric Investigation Plan (PIP) is a mandatory requirement for all new medicines agreed with the European Medicines Agency (EMA) through its Paediatric Committee (PDCO), defining the studies needed to generate robust efficacy and safety evidence to support a paedtric indication2. However, paediatric drug development in PAH remains particularly challenging due to small patient numbers and widespread off-label use, making fully powered randomised controlled trials (RCTs) often unfeasible1. Extrapolation from adult data is increasingly accepted but remains difficult in PAH because conditions beyond disease similarity must be met3. We reviewed agreed PIPs to identify the main challenges in this area and opportunities for improvement. Methods Retrospective analysis of PIPs for PAH treatments agreed by the EMA between 2007 and 2023, focusing on study design, sample size, endpoints, modifications, and use of extrapolation and pharmacokinetic/pharmacodynamic (PK/PD) data. Results Thirteen PIPs were agreed, most requiring multiple modifications (mean six per PIP), reflecting feasibility and recruitment constraints. Five included double-blind placebo-controlled trials and eight open-label designs using non-controlled, standard-of-care–controlled or extrapolation-based approaches. Primary endpoints in double-blind studies were heterogeneous, with four different measures used, and secondary endpoints varied widely across programmes, including haemodynamics, exercise capacity, clinical worsening, WHO functional class, biomarkers and imaging.Extrapolation to younger children was implemented in few PIPs. Planned sample sizes were frequently reduced, with recruitment particularly challenging in children <2 years of age. To date, six medicines have obtained an EU paediatric indication for PAH. Conclusions Paediatric PAH drug development remains constrained by recruitment challenges and the lack of validated surrogate efficacy endpoints. Extrapolation from adult data is a promising strategy; however, differences in disease expression, developmental physiology and treatment response mean that exposure matching alone is insufficient without demonstrating a comparable exposure–response relationship. Robust implementation requires harmonised clinically meaningful pharmacodynamic endpoints across age groups and prospective alignment of adult and paediatric study designs. Consensus on surrogate endpoints, early regulatory engagement and international collaboration are key to coordinated development and accelerated access to evidence-based therapies for children with PAH. These findings support a shift from standalone paediatric trials towards prospectively coordinated adult–paediatric programs.