Informing Dose for Pediatric Rare Diseases—A Survey of Recent Orphan Drugs Approvals

Collectively, pediatric rare diseases affect millions of children worldwide. Yet, treatment options are limited. Dose selection presents unique challenges in pediatric rare disease drug development. Traditional dose-finding approaches are impractical for these populations, and conventional pediatric dosing methods like exposure matching face limitations when insufficient adult data exists. Herein, we analyzed dosing strategies and study design characteristics used for new molecular entities (NMEs) for orphan indications approved between 2013 and 2022 that included a pediatric indication at initial approval. Among 63 evaluable products included in this analysis, initial pediatric dose selection was supported by adult data in the same indication (37%), adult healthy volunteer data (33%), nonclinical data only (14%), adult data from different indications (10%), and pediatric data from different indications (5%). The use of modeling and simulation to support initial dose selection was explicitly mentioned for 21% of products. Nearly half (48%) utilized multiple data sources for dose selection. Study design characteristics included multiple dose level evaluation (49%), intra-patient dose escalation (33%), interim pharmacokinetic evaluation (10%), pharmacokinetic/biomarker-driven dosing (5%), and age group staggering (5%). Multiple design features were incorporated in 17% of drugs. This analysis reveals diverse approaches to pediatric dose selection in rare diseases and the use of adaptive study design elements suggests recognition of the need for flexible approaches in these challenging populations. Utility of modeling and simulation, ability to leverage all available data sources, and increased implementation of adaptive trial designs could improve dose selection and optimization in pediatric rare disease drug development.