Joyce P. Samuel , Susan H. Wootton, Travis Holder, Donald Molony
The single patient (n-of-1) trial can be used to resolve therapeutic uncertainty for the individual patient. Treatment alternatives are systematically tested against each other, generating patient-specific data used to inform an individualized treatment plan. We hypothesize that clinical decisions informed by n-of-1 trials improve patient outcomes compared to usual care. Our objective was to provide an overview of the clinical trial evidence on the effect of n-of-1 trials on clinical outcomes.
N-of-1 trials are single patient randomized trials that can provide direct and objective assessments of treatment effects in the individual patient and can be particularly helpful when treatment benefits differ significantly between patients . They can be used in chronic conditions which may require long-term treatment but with insufficient evidence to support the routine use of one treatment option over another. They are best suited for treatments with a relatively rapid onset and offset of action and when objective assessments of treatment effect are possible. Given the current emphasis on patient-centered and personalized care, n-of-1 trials could be an important decision-support tool when applied in clinical practice by informing treatment decisions based on patient-derived data. Advocates of this underutilized treatment approach suggest that important outcomes may be improved when treatment decisions are individualized using n-of-1 trials, as ineffective therapies can be discontinued altogether or replaced with superior alternatives.
A comprehensive literature search was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines . The protocol was previously published and registered on PROSPERO (CRD42020166490) .
The database searches yielded 3122 unique records that were reviewed for eligibility criteria. After excluding 3086 records based on title and abstract, another 25 articles were excluded following full-text review (complete list of excluded full-text articles included in the Supporting Information, S2 File). One additional article  was identified after a review of reference lists of included articles, resulting in 12 studies selected for inclusion in this scoping review. See Fig 1 for the study selection process with reasons for exclusion. Among the 12 studies, eight were completed with published results, three were either ongoing or completed with results not published yet, and one was terminated after six patients were enrolled without results published.
We comprehensively reviewed the body of literature describing randomized trials testing the n-of-1 approach. The studies encompassed only six broad disease categories: atrial fibrillation, chronic pain, chronic airflow limitation, attention-deficit hyperactivity disorder, pediatric hypertension, and perceived statin intolerance. N-of-1 trials could potentially be helpful in various diseases, as long as the baseline condition is stable and chronic, the treatments have a relatively rapid onset and offset of action, and objective measurements of treatment success or failure are possible. Additional disease states amenable to n-of-1 trials include diabetes, irritable bowel syndrome, depression, asthma, and insomnia.
Insufficient sample sizes likely precluded these studies from identifying statistically significant results using frequentist analyses. The question of whether the n-of-1 trial approach will improve clinically meaningful outcomes if applied to a large swath of patients remains unanswered. N-of-1 trials could also be preferred if they result in equivalent clinical outcomes but greater patient satisfaction and fewer office visits. Adequately powered trials are needed to understand their potential role in improving patient satisfaction, adherence, and clinical outcomes. We may find that just as patients show differences in their responses to treatment options, they may also vary in whether n-of-1 trials can improve their outcomes.
Citation: Samuel JP, Wootton SH, Holder T, Molony D (2022) A scoping review of randomized trials assessing the impact of n-of-1 trials on clinical outcomes. PLoS ONE 17(6): e0269387. https://doi.org/10.1371/journal.pone.0269387
Editor: Richard Evans, Thomas Jefferson University, UNITED STATES
Received: January 28, 2022; Accepted: May 19, 2022; Published: June 2, 2022
Copyright: © 2022 Samuel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: JPS is supported in part by a grant awarded to the University of Texas Health Science Center at Houston, the Clinical and Translational Sciences Award (1UL1TR003167-01) from the NIH National Center for Advancing Translational Sciences. https://ncats.nih.gov/ctsa The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.