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Cannabidiol for severe behavioral manifestations in TSC, MPS III, and FXS994this challenge, we included three disease groups in our study. Combining the results of the N-of-1 trials in different patient groups potentially yields information that may be extrapolated to the RGNDs population level.42CBD is expensive, costing about 500 US dollars per month for rare epilepsies, although highly depending on dosages. If this study shows efficacy of CBD for severe behavioral manifestations, our major goal is to get CBD accessible to those patients who are expected to benefit, which could be facilitated by licensing and reimbursement by healthcare authorities and insurances. Before the start of the trial, we consulted ZIN (The National Health Care Institute in the Netherlands, “Zorginstituut Nederland”) and CBG (the Dutch Medicines Evaluation Board, “College ter Beoordeling van Geneesmiddelen”) on the study design, inclusion and exclusion criteria and outcome measures. Advises on outcome measures included justification for choice of the ABC-I subscale, particularly as this study aims for a broad indication of behavioral problems not associated with a specific syndrome, and defining and justifying a testing hierarchy for the endpoints with the CGI high in the testing hierarchy. An extensive list of secondary endpoints is generally accepted for an exploratory study, while limiting the number of endpoints to those relevant to support the claimed indication is recommended for a confirmatory study. Furthermore, several approaches were suggested for supporting extrapolation, such as substantiation through mechanism of action with similar effects of CBD on behavioral manifestations regardless of the neurodevelopmental disorder, subgroup analysis per disorder indicating the absence of effect modification, and inclusion of additional neurodevelopmental disorders.The burden for the patient of the study is mostly caused by the use of blinded cross-over periods, the use of placebo, the prolonged dose titration phase, and the filling in of questionnaires by caregivers. The benefits of the study include the fact that patient-centered N-of-1 studies may help individuals to better self-manage their behavioral symptoms. The patients involved in the N-of-1 trials may draw immediate benefit from the trial as every patient is exposed to the treatment with CBD, and the N-of-1 design will enable an individual treatment decision in terms of evidence-based medicine. This is unlike many population-based trials where, depending on the protocol Annelieke Muller sHL.indd 99 14-11-2023 09:07