State-of-the-Art on Model-Informed Drug Development Approaches for Pediatric Rare Diseases

Pediatric rare diseases present unique challenges for drug development due to small patient populations, ethical constraints on clinical trial design, and limited prospectively defined natural history data. Model-Informed Drug Development (MIDD) has emerged as a powerful paradigm to address these challenges by leveraging quantitative methods to enhance decision-making across all stages of drug development. This paper reviews the state-of-the-art MIDD approaches being applied to pediatric rare disease therapeutics, including the traditional pharmacometrics methodologies of population pharmacokinetic/pharmacodynamic (PK/PD) modeling, physiologically based pharmacokinetic (PBPK) modeling, disease progression modeling, and more future-facing Bayesian trial designs, and real-world data integration. We highlight how these methods facilitate dose optimization, support extrapolation from adult or other pediatric data, and enable more efficient and ethical clinical trial strategies. Case studies from recent regulatory submissions illustrate the growing acceptance of MIDD in pediatric rare disease contexts. Finally, we discuss the technological and regulatory advances driving this field forward, as well as current limitations and future opportunities for expanding the impact of MIDD on accelerating safe and effective treatments for children with rare diseases.