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Acosta, M.T.* ; Aibar, J.Á.* ; Arango, C.* ; Cirauqui, E.A.* ; Baeza, C.* ; Berry-Kravis, E.* ; Bishop, K.I.* ; Busner, J.* ; Chapman, C.* ; Chaumette, B.* ; del Cerro, I.* ; Diaz, J.C.* ; Dorffner, G.* ; Edgar, C.J.* ; Giorgi, S.* ; Hölter, S.M. ; Kittel-Schneider, S.* ; Latzman, R.D.* ; Moreno, C.* ; Pallanti, S.* ; Colzi, C.* ; Plasencia, C.* ; Radtke, F.* ; Rockwood, K.* ; Santuccione Chadha, A.* ; Sevinc, G.* ; Singh, M.K.* ; Smith, S.H.* ; Tandon, P.K.* ; Tinoco, D.* ; Broggi, E.* ; Morgan, S.F.* ; Magaraggia, I.* ; Zaragoza Domingo, S.*

Outcome strategies for clinical trials in Neuropaediatric rare diseases.

Neurosci. App. 5:107021 (2026)
Publ. Version/Full Text DOI PMC
Free journal
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Neuropaediatric Rare Diseases (NRDs) impose a profound and multidimensional burden on patients, families, and healthcare systems. Persistently low clinical trial success rates reflect an unmet methodological need as much as a therapeutic one. A fundamental bottleneck is the absence of fit-for-purpose clinical outcome assessments. In fact, instruments validated for non-rare or adult populations fail to capture clinically meaningful change in heterogeneous, small, and developmentally complex NRD populations. Building directly on a systematic catalogue of methodological challenges in NRD outcome research published by our group (Acosta et al., 2025), this paper presents a structured set of actionable outcome strategies proposed by a large multidisciplinary expert group convened under the auspices of the European College of Neuropsychopharmacology (ECNP) and the International Society for CNS Clinical Trials and Methodology (ISCTM). Using a structured, iterative expert-opinion approach, each identified challenge served as a prompt for developing one or more candidate strategies, each mapped one-to-one to its corresponding barrier. Strategies are presented across four thematic domains: (1) innovative methodologies to enhance ecological validity and reduce rater context effects; (2) novel or adapted outcomes and endpoints that preserve clinical meaningfulness under conditions of high heterogeneity and limited sample sizes; (3) the purposeful use of natural history resources; and (4) approaches to support comparability and synthesis across programmes. Additional considerations address caregiver expectancy bias and recruitment, stakeholder alignment, maturational confounding, and preclinical-clinical connectivity. Collectively, these strategies constitute a practical, challenge-mapped “living” toolbox for clinical scientists designing NRD trials. Each strategy is already in use or validated in analogous rare-disease contexts. Realising their potential at scale requires institutional programmes, pre-competitive co-validation platforms, systematic stakeholder co-design, and early engagement with regulatory agencies as scientific partners in endpoint development.
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Publication type Article: Journal article
Document type Review
Keywords Clinical Outcome Assessments ; Clinical Trials ; Digital Health Technologies ; Natural History Data ; Neuropaediatric Rare Diseases ; Outcome Measures
ISSN (print) / ISBN 2772-4085
e-ISSN 2772-4085
Journal Neuroscience Applied
Quellenangaben Volume: 5, Issue: , Pages: , Article Number: 107021 Supplement: ,
Publisher Elsevier
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)