Determining minimal clinically important differences for neurodevelopmental outcome measures in Angelman syndrome

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Project Summary/Abstract Angelman syndrome (AS) is a rare neurogenetic condition that results in a host of clinical traits, including severe developmental delays and extremely limited functional abilities. Therapeutic development efforts have increased substantially in the last several years, with seven pharmaceutical companies currently conducting or preparing Phase 1 trials. As a result, there is a critical need to improve the utility of core clinical outcome measures so that they can be deployed effectively in future clinical trials in AS. The overall goal of this study is to use existing data on over 800 administrations of two core instruments, the Bayley Scales of Infant Development and the Vineland Adaptive Behavior Scales, to establish meaningful change thresholds for these two measures for individuals with AS. To achieve this goal, we will calculate for each measure (a) distribution-based minimal clinically important difference (MCID), and (b) anchor-based MCID. The anchor-based MCID aligns well with the U.S. Food and Drug Administration’s (FDA’s) guidance on establishing “meaningful within-patient change” (see https://www.fda.gov/media/132505/download), yet even the FDA recognizes that empirical data are necessary to contextualize changes on Clinical Outcome Assessments. The distribution- based MCID approach will provide this “reality check” on the anchor-based approach, ensuring that thresholds for change are both statistically significant and clinically meaningful.