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General discussion2919starting a trial with uncertain possibilities for reimbursement to avoid undesirable and unethical situations. N-of-1 in clinic or research?A practical flowchart based on an ethical framework was designed to help distinguish an N-of-1 trial to be considered as part of evidence-based clinical care or representing medical research with need for approval from the institutional review board (IRB).65 If there is a treatment option and the effectiveness will be examined for the affected individual with the highest level of evidence, one wants to start an N-of-1 trial. Such a trial in one individual is not subject to the Dutch Medical Research Involving Human Subjects Act (WMO), because a ‘case study’ (N=1) has not been considered as research with generalizable results applicable to the population other than the direct population of interest. It is thus considered experimental care. It enables rapid care for a particular affected individual, which is essential to this patient population. If there is the idea to follow the study protocol in more than one individual, possibly and eventually attempting to provide treatment effect estimates at a group level, it is subject to the WMO and often concerns drug research.From two sides this might be odd and sometimes even undesirable. On the one hand, even for one individual, a medical ethical view may be valuable. Interventions for this population may often be experimental, expensive and burdensome. As such, it might be desirable to have the ethical considerations co-assessed by a recognized and knowledgeable ethical committee, such as a medical ethical committee (METC) or the Dutch Central Committee on Research Involving Human Subjects (CCMO). However, submitting a study protocol including all documentation required for clinical trials with medicinal products (EU Clinical Trial Regulation) is time and effort-consuming. Especially if the METC would assess all single N-of-1 trials, the amount of work for both METC and clinicians may be prohibitive. On the other hand, for N-of-1 trials in a few individuals, starting a clinical trial is comparable with large clinical trials in terms of financial and time effort. For a particular affected individual participating in such a (prospective) clinical trial, it may take at least one year before the trial will start, while health conditions are often devastating with an urgent need for Annelieke Muller sHL.indd 291 14-11-2023 09:08