OBJECTIVES: Half of rare diseases affect children, and many are progressive multi-system conditions for which novel disease modifying treatment options are under development. Demonstrating value is particularly challenging in this context but essential to maximize treatment access. This study reviews common barriers to constructing and informing health economic models for rare progressive pediatric diseases and explores current and potential solutions.

METHODS: Economic models developed for a series of rare progressive diseases, including metachromatic leukodystrophy, Alport Syndrome, lysosomal storage diseases and cystic fibrosis were reviewed and systematically evaluated against ISPOR criteria and AdVISHE guidelines. The review highlighted and itemized challenges that had been encountered in conducting health economic assessments associated with novel interventions for these conditions and summarized the approaches that were applied to align with best practice.

RESULTS: Pediatric clinical trials for rare diseases frequently have heterogenous populations, small sample sizes, single arm design and relatively brief follow up. In addition, model conceptualization is frequently challenged by a paucity of published literature. To overcome data gaps, economic analyses exploited natural history studies and data from regional/global registries; in addition, clinicians and key stakeholders were commonly consulted to define/confirm populations of interest, characterize the standard of care, and develop a better understanding of the condition. Where only single arm trial data were available, generating control data introduced additional uncertainty due to databases including outcomes of interest and important prognostic and treatment effect modifiers. Identifying a well-studied proxy disease was broadly necessary for conceptualization, informing model inputs and supporting cross-validation. Thorough sensitivity analyses were essential to assess the implications of potential parameter biases and structural uncertainty.

CONCLUSIONS: Anticipating evidence generation and economic modeling challenges early in orphan drug development for pediatric conditions can help guide development of health economic analyses that align with current best practice and accelerate access to novel therapeutics.