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Chapter 9292treatment. These (financial) aspects could even impede research efforts aimed at investigating rare disorders, whereas the affected individuals might be in desperate need.Potential barriers for N-of-1 trials being subjected to WMO (drug research) may thus include:y Time and effort-consuming (for both clinicians, researchers, and METC);y Delay before trial commences;y Financial aspects (e.g., study medication including placebo, pharmacy costs (including staff costs, quality control, labelling, handling, storage, and dispensing), costs medical ethical review, and monitoring);y Ambiguity about ethical procedures (e.g., prospective research compared to retrospectively pooling data for treatment effect estimates when same procedure is replicated in multiple individuals).Toward a rare disorder trial frameworkIs it possible to work towards creating a situation in which multiple interventions for several RGNDs could be systematically investigated, using a master protocol?66,67 A standardized template of approved trial designs and outcome measures, with and without the use of placebo, could be developed in the context of good clinical practice and a trial service. Moreover, deviations of trial designs or (more invasive) outcome measures, and experimental therapies could be periodically presented to a delegation of a medical ethical committee to ensure we are behaving in an ethically responsible manner regarding the vulnerable affected individuals and novel therapies. ChallengesTrial development for rare disorders faces many challenges that should be addressed to efficiently realize interventional research for this patient population. For investigator-initiated studies (i.e., not initiated by a pharmaceutical company), financial issues may obstruct initiating a trial. In Annelieke Muller sHL.indd 292 14-11-2023 09:08