Public-private partnerships and the interest of industry in smaller niche markets have resulted in an increase of treatments for patients with rare diseases.¹ Small populations and substantial heterogeneity pose considerable challenges to the production of robust evidence of the safety and efficacy of these new treatments in clinical trials.² This challenge has prompted innovative trial designs.³ One of the designs that has been proposed for studying efficacy of drugs for patients with rare diseases is the single-patient, or N-of-1, trial.⁴ Although aggregation of multiple N-of-1 trials holds the potential of efficiently producing evidence of efficacy of treatments,⁵ this approach has not been explicitly compared with a randomized clinical trial (RCT).

N-of-1 trials can provide high-class evidence on drug treatment effectiveness at the individual patient level and have been given renewed interest over the past decade due to improvements of the initial single patient design. Despite these recent developments, there is still no consensus under what circumstances N-of-1 trials should be considered as part of evidence-based clinical care and when they represent medical research with need for institutional review board (IRB) approval. This lack of consensus forms an obstacle for a more widespread implementation of N-of-1 trials. Based upon the existing literature, we as a group of researchers involved in N-of-1 trials and members of the IRB of a tertiary academic referral center, designed a practical flowchart based on an ethical framework to help make this distinction. The ethical framework together with a practical flowchart are presented in this communication.

Objective To perform a systematic review of published N-of-1 trials (e.g. single patient cross-over trials) in neurological disorders, including an assessment of methodological quality and reporting. Methods We searched PubMed, MEDLINE and Embase, from inception date - the first of December 2019, for reports on N-of-1 trials in neurological disorders. Basic trial information on design, disease, intervention, analysis and treatment success was extracted. Strengths and weaknesses of the N-of-1 trials were assessed using the CONSORT extension for N-of-1 trials (CENT) 2015 criteria checklist and the Jadad score as measures of quality and reporting. Results We retrieved 40 reports of N-of-1 trials in neurological disorders (19 individual N-of-1 trials, 21 series of N-of-1 trials). Most N-of-1 trials were performed in neuromuscular and neurodegenerative / movement disorders. Unlike the majority of trials that studied the main symptom(s) of a chronic stable condition, nine N-of-1 trials studied a stable chronic symptom of a progressive or acute neurological disorder. Besides pharmacological interventions, electrical stimulation protocols and nutritional products were studied. A mean total CENT score of 20.88 (SD, 9.10; range 0-43) and mean total Jadad score of 2.90 (SD, 2.15; range 0-5) were found as methodological measures of quality and reporting across all N-of-1 trials Conclusions N-of-1 trials have been reported in numerous neurological disorders, not only in chronic stable disorders, but also in progressive or acute disorders with a stable symptom. This indicates the emerging therapeutic area of N-of-1 trials in Neurology. Methodological quality and reporting of N-of-1 trials were found suboptimal and can easily be improved in future trials by appropriately describing the methods of blinding and randomization and follow CENT guidelines. As most N-of-1 trials remain unreported in medical literature, this systematic review probably only represent the tip of the iceberg of conducted N-of-1 trials in neurological disorders. In addition to conventional trial designs, N-of-1 trials can help to bridge the gap between research and clinical care by providing an alternative, personalized level 1 evidence-base for suitable treatments.

To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously. We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT. The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases. ClinicalTrials.gov Identifier: NCT02045667