The ethical and regulatory oversight of any clinical activity related to human subjects is commonly determined based on its categorization as either clinical practice or research. Prominent bioethicists have criticized the traditional distinctions used to delineate these categories, calling them counterproductive and outmoded, and arguing that learning and clinical practice should be deliberately and appropriately integrated. Personalized trials represent a clinical activity with characteristics that overlap both categories, making ethical and regulatory oversight requirements less straightforward. When the primary intent of the personalized trial is to assist in the conduct of individualized patient care with an emphasis on protecting the clinical decision from the biases inherent in usual clinical practice, how should this activity be regulated? In this article, we will explore the ethical underpinnings of personalized trials and propose various approaches to meeting regulatory requirements. Instead of imposing standard research regulations on the conduct of all personalized trials, we recommend that personalized trialists and IRB panels should consider whether participation in a personalized trial results in any foreseeable incremental increase in risk to the participant compared with usual care. This approach may reduce regulatory barriers, which could promote more widespread uptake of personalized trials.

The n-of-1 trial can utilized in clinical practice as a decision support tool, which may improve patient outcomes by providing both the patient and the clinician with objective evidence to inform personalized treatment decisions. As its use broadens, it will be important to study whether the added time and effort of an n-of-1 trial results in measurable improvements in important patient outcomes compared to usual clinical practice. Parallel-group randomized clinical trials testing the n-of-1 approach versus usual care have been undertaken in a number of medical settings. A systematic review will be performed according to PRISMA guidelines, using MEDLINE, Embase, Cochrane, CINAHL, PsycINFO, Scopus, and Web of Science to search for randomized clinical trials in humans, without date or language restriction. Reports from the gray literature and ongoing studies in trial registries will be included. Articles will be screened by two independent reviewers with a third reviewer consulted to adjudicate disagreement. The quality of included studies will be assessed using the Cochrane Collaboration\'s tool for assessing risk of bias. A narrative synthesis will explore the differing methodological approaches of the included studies. The protocol will be registered in the PROSPERO registry, and the results of the review will be published in a peer-reviewed journal. To our knowledge, this systematic review will be the first to comprehensively assess the existing research on randomized trials testing the n-of-1 trial approach in clinical practice.