Advancing evidence generation in pediatric rheumatology beyond traditional randomized clinical trials: the potential of innovative designs

Over recent years, innovative trial methodologies have been increasingly developed to address important limitations of conventional randomized controlled trials, which may require large sample sizes, entail prolonged development timelines, and offer limited flexibility to incorporate emerging evidence as a study progresses. Master protocols, including basket, umbrella, and platform trials, are innovative trial designs enabling the evaluation of multiple interventions, populations, or research questions within a unifying protocol. By allowing different hypotheses to be tested within a common infrastructure, these trials offer a flexible and efficient framework for therapeutic development in rare and heterogeneous conditions sharing underlying immunopathogenic mechanisms, such as pediatric rheumatic diseases. Adaptive features can be incorporated into these designs, enabling emerging therapeutic targets, biomarkers, and treatment strategies to be integrated into ongoing studies. Although these approaches have been successfully applied to evaluate treatments for immune-mediated inflammatory diseases, with examples including biologic and CAR T-cell therapies, their use in pediatric studies has been limited so far. In this review, we discuss selected complex trial designs with particular relevance for pediatric rheumatology, focusing on Master Protocol and Sequential, Multiple Assignment Randomized Trials (SMART); we illustrate their potential application to pediatric rheumatic diseases and summarize recent methodological and regulatory guidance on key aspects required for their successful implementation.