EVIDENCE-RND - Creating robust evidence for longitudinal progression changes and treatment effects in ultra- rare neurological diseases: the case of multisystemic autosomal-recessive ataxias

01.12.2021 bis 31.12.2021

There is a scarcity of robust trial design and analysis methods in ultra-rare neurological diseases (RND) affecting small cohorts (< 50) or even single cases. The urgency to find solutions is accelerated as disease- modifying compounds are now on the horizon for a growing number of RNDs, yet methods to generate robust evidence for treatment effects are missing. EVIDENCE-RND will develop a toolbox of innovative statistical methodologies designed to fill this gap. Our methods toolbox will deliver: (i) an optimized clinically meaningful composite endpoint for RNDs, including methods to evaluate applicability across ultra-rare RND subpopulations; (ii) robust progression models, including prediction of individual disease trajectories and quantification of their uncertainty; (iii) pharmacometrics models to analyse treatment efficacy and guide trial design and treatment decisions even in n-of-1 studies; (iv) randomization-based inference models for valid and efficient RCTs in ultra-small cohorts. As showcase, we will apply them to autosomal-recessive cerebellar ataxias, leveraging registry datasets from major transatlantic consortia (PREPARE, PROSPAX, EUROSCA, ESMI), close communication with patient organisations (Euro-Ataxia) and industry trial expertise (Novartis, AstraZeneca). Continuous interaction with EMA and C-Path will ensure that the overall goal will be readily achieved: to provide EMA with proposals for optimized outcomes, trial designs, and innovative analyses, optimized to be as informative as possible to allow robust evidence in the smallest possible populations.