N-of-1 trials in clinical research: Methodological foundations, statistical approaches and implementation challenges

N-of-1 trials offer a unique and rigorous methodology for evaluating individualized treatment responses, particularly within the context of personalized medicine. This article provides a comprehensive explanation of the conceptual and methodological underpinnings of N-of-1 trials, with particular emphasis on statistical techniques and considerations critical for their design and analysis. Existing guidelines for planning and conducting these studies are summarized, along with a discussion of the practical and theoretical challenges to their implementation in clinical practice. We provide an overview for clinicians and researchers who may be unfamiliar with the design. As most of the existing guidance has focused on design and implementation considerations, we expand on the statistical analysis. We aim to support researchers and methodologists in understanding and advancing the methodological toolkit necessary for high-quality N-of-1 research.