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N-of-1 Trials: A Scientific Approach to Personalised Medicine for Patients with Rare Retinal Disease

Updated: Jul 3

Authors: Zarbin & Novack (2021)


This article focuses on Retinitis Pigmentosa (RP), a group of inherited retinal degenerative diseases with a prevalence of ∼1 in 4,000, affecting 2 million persons globally. There are >50 ongoing retinal gene therapy clinical trials, most of them for relatively rare diseases such as RP. There are two fundamental problems associated with assessing treatments for RP; small target patient populations and patient heterogeneity, which mean the traditional parallel randomised controlled trial (RCT) design may not be feasible. Alternative methodologies include cross-over designs, adaptive designs (including response-adaptive randomisation, ranking and selection, internal pilot, sequential designs), and N-of-1 trials. N-of-1 trials are randomised, prospective, controlled, multiple crossover trials in a single patient. According to the Oxford Centre for Evidence-Based Practice, aggregated N-of-1 trials constitute level 1 evidence (as do systematic reviews of randomised trials). Advantages of N-of-1 trials summarised in the article include that each patient is assured exposure to the experimental treatment, which may facilitate recruitment. In addition, each patient serves as his/her own control, which reduces variance, minimises confounding and enables recruitment of patients with comorbidities, which is generally discouraged in parallel group RCTs. As a result, it may be easier to identify treatment effects, or lack thereof, in specific subpopulations of patients. Limitations of N-of-1 trials are also discussed, such as the potential for drop out (although this is also a concern in group-based RCTs) and carryover effects. Despite the limitations identified, the authors explain how N-of-1 trials can provide a useful means by which to assess treatments for rare diseases with rigor equal to or greater than that afforded by parallel group RCTs. N-of-1 trials can be considered as alternatives to parallel group RCTs when the number of potential participants is small because of the rarity of the underlying condition.


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Full reference: Zarbin, M. A., & Novack, G. (2021). N-of-1 Clinical Trials: A Scientific Approach to Personalized Medicine for Patients with Rare Retinal Diseases Such as Retinitis Pigmentosa. Journal of Ocular Pharmacology and Therapeutics, 37(9), 495-501.

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