Developing Meaningful Score Differences for the Bayley-4 and Vineland-3 in Angelman Syndrome using a Delphi Panel

ObjectivesTo develop within-patient meaningful score differences (MSDs) on the Bayley Scales of Infant Development, Fourth Edition (Bayley-4), and the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3), for individuals with Angelman syndrome (AS). MethodsA Delphi method, involving a panel of 19 caregivers of individuals with AS, was used to establish MSDs for Bayley-4 and Vineland-3 Growth Scale Values. MSD was defined as the smallest change that would noticeably impact the daily functioning of an individual with AS or family quality of life in a way that was important to the individual with AS or their family. For each subscale of the Bayley-4 and Vineland-3, the panel was presented with 2 to 4 vignettes describing varying levels of baseline functioning and asked to select a MSD from a range of potential values. An iterative process involving three rounds of ratings and two rounds of discussion was used to build consensus. The median caregiver rating from round 3 was retained as the final recommended MSD value for each vignette. ResultsFinal MSD ratings for the five subscales of Bayley-4 and 10 subscales of the Vineland-3 had an agreement rate of 70% or higher. MSD thresholds for each subscale were not single cut-offs, but rather reflected a range of MSD values dependent on level of baseline functioning. ConclusionsThe Delphi Panel method incorporates the caregiver perspective to provide preliminary estimates of what constitutes meaningful within person change on the Bayley-4 and Vineland-3 in individuals with AS with various levels of baseline functioning. Highlights To acquire regulatory approval in drug development, sponsors must demonstrate both statistical significance and clinical meaningfulness of a treatment effect.While several clinical trials are underway in AS, within person meaningful score difference thresholds are not yet established for the most commonly used outcome measures, namely the Bayley and Vineland. Aligning with FDA guidance, we have developed an innovative qualitative approach using a Delphi panel to incorporate caregiver perspectives in defining meaningful change and generated preliminary patient-informed meaningful score differences (MSDs) for individuals with Angelman Syndrome. What caregivers of individuals with AS consider to be a MSD on the measures depends primarily on the baseline severity of their childs presentation.