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A\u00a0systematic approach is needed for comparing various design and analysis strategies to identify \u201coptimal\u201d approaches for a clinical trial in a chosen RND with the given resource constraints. For this purpose, we propose a pharmacometrics\u2010informed clinical scenario evaluation framework (CSE\u2010PMx), which includes some important research hallmarks relevant to RND clinical trials: a disease progression model for simulating individual longitudinal outcomes, the choice of a suitable randomization method for trial design, and an option to perform subsequent statistical analysis with randomization tests. We illustrate the utility of CSE\u2010PMx for an exemplary randomized trial to compare the disease\u2010modifying effect of an experimental treatment versus control in patients with Autosomal\u2010Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS). In the considered example, our simulation evidence suggests that a nonlinear mixed\u2010effects model (NLMEM) with a population\u2010based likelihood ratio test analysis is valid, robust, and more powerful than some conventional methods such as two\u2010sample <jats:italic>t<\/jats:italic>\u2010test, analysis of covariance (ANCOVA), or a mixed model with repeated measurements (MMRM). Our proposed framework is very flexible and generalizable to clinical research in other rare disease indications.<\/jats:p>","DOI":"10.1002\/psp4.70082","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T19:39:39Z","timestamp":1754422779000},"page":"1705-1714","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Pharmacometrics\u2010Informed Trial Simulation Framework for Optimizing Study Designs for Disease\u2010Modifying Treatments in Rare Neurological Disorders"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2997-8566","authenticated-orcid":false,"given":"Yevgen","family":"Ryeznik","sequence":"first","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala 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