Big Evidence with Small Samples: A Methodological Perspective on N-of-1 (Single Case Experimental Designs) Based on Medical Studies

Epistemological Foundations: The Crisis of the "Average Patient" and the Need for Personalized EvidenceThe gold standard of modern medicine, evidence-based medicine (EBM), primarily relies on randomized controlled trials (RCTs) that utilize a nomothetic approach, aiming to discover general laws applicable to populations.1,2 However, this "average patient" paradigm creates an epistemological gap when applied to the individual in clinical practice.3 While RCTs provide high external validity for populations, they often mask inter-individual variability, leading to the "tyranny of the average".4,5 In medical research, the tension between the nomothetic (population-based) and idiographic (individualbased) approaches has sparked significant criticism regarding the clinical utility of aggregate data.6,7 Traditional EBM often struggles to address heterogeneous treatment effects, in which a medication that benefits the majority may be ineffective or even harmful to an individual.[8][9][10] This limitation necessitates a shift toward a more nuanced understanding of evidence, one that prioritizes the unique