N-of-1 Trials in Rare Genetic Neurodevelopmental Disorders

Clinicians need to have confidence in studies of the treatments they prescribe. Large double-blind randomized placebo-controlled clinical trials (DBRPCTs) are considered to be the standard for demonstrating efficacy and safety for common diseases. However, for millions of people worldwide with rare diseases, large DBRPCTs are not an option; not enough participants are available for the trial. As a result, alternative clinical trial designs are needed.¹ One promising tool is the N-of-1 design in which study participants are exposed sequentially to >1 treatments (including placebo or standard care; e.g., ABAB designs with A representing one treatment and B representing the other) with intervening washout periods.² (One potential source of confusion is that some refer to any type of study involving a single participant as N-of-1, but the definition used here is as outlined above.²) N-of-1 trials can be used for initial proof of treatment concept, to define experimental parameters/design of future studies, and for efficacy/effectiveness studies. Individual N-of-1 trials can be combined to pool results, which then are subject to statistical analyses that typically differ from those used in conventional DBRPCTs. Like other study designs, N-of-1 trials have their limitations, including potential selection bias, limited power, and carryover effects (due to inadequate washout periods between treatment phases), but in some respects, they may compare favorably to DBRPCTs.³