Exploring human biology with N-of-1 clinical trials

Abstract

Studies on humans that exploit contemporary data-intensive, high-throughput 'omic' assay technologies, such as genomics, transcriptomics, proteomics, and metabolomics, have unequivocally revealed that humans differ greatly at the molecular level. These differences, which are compounded by each individual's distinct behavioral and environmental exposures, impact individual responses to health interventions such as diet and drugs. Questions about the best way to tailor health interventions to individuals based on their nuanced genomic, physiologic, behavioral, etc. profiles have motivated the current emphasis on 'precision' medicine. This review's purpose is to describe how the design and execution of N-of-1 (or personalized) multivariate clinical trials can advance the field. Such trials focus on individual responses to health interventions from a whole person perspective, leverage emerging health monitoring technologies, and can be used to address the most relevant questions in the precision medicine era. This includes how to validate biomarkers that may indicate appropriate activity of an intervention as well as how to identify likely beneficial interventions for an individual. We also argue that multivariate N-of-1 and aggregated N-of-1 trials are ideal vehicles for advancing biomedical and translational science in the precision medicine era since the insights gained from them can not only shed light on how to treat or prevent diseases generally, but also provide insight into how to provide real time care to the very individuals who are seeking attention for their health concerns in the first place.

The Potential of Integrative Cancer Treatment Using Melatonin and the Challenge of Heterogeneity in Population-Based Studies: A Case Report of Colon Cancer and a Literature Review

“…An alternative approach to a parallel group of RCTs may be N-of-1 study designs, with the potential to minimize costs and resources [264]. Multivariate and aggregated N-of-1 study designs are suitable for advancing biomedical and translational studies in precision medicine and can also provide participants with real-time care [260]. N-of-1 studies deserve attention to optimize the integrative treatment of complications caused by cancer and anticancer therapy and could be included in future medical research programs focused on collaboration with patient partners [265].…”

“…In terms of complementary treatment, N-of-1 studies are more suitable for treating symptoms of chronic and stable diseases [259]. N-of-1 trial designs can optimize treatment for patients, including those who cannot be included in RCTs due to uncertainty about the appropriate treatment pathway or for other reasons beyond the study criteria [259,260]. In N-of-1 studies, each participant serves as his or her own control.…”

“…In N-of-1 studies, each participant serves as his or her own control. The duration of the N-of-1 study depends on the withdrawal period, i.e., washout to avoid carryover effects from the previous intervention and to properly assess the effect of the next intervention [260].…”

Brain Wave Oscillations as an Objective Neurophysiological Biomarker of Homeopathic Subjective Well-Being

“…Seeking to achieve a higher level of evidence, these initial results could then be tested in a series of single-subject (N-of-1) trials, 67 68 for example.…”

Emerging therapeutic drug monitoring technologies: considerations and opportunities in precision medicine

“…These studies would also help to identify which individual would benefit from which drugs, and aggregated analyses of N-of-1 studies could identify markers of drug response. Such analyses may also help with, e.g., the identification of molecular PD biomarkers, or drug-specific biomarkers, that reflect biochemical and functional changes in the body that occur in response to a drug ( Shipkova and Christians, 2019 ); the characterization of ADME processes associated with drug-drug and drug-supplement interactions; improving our understanding of human biology ( Schork et al, 2023 ); and validating drug repurposing opportunities and drug-patient matching ( Cremers et al, 2016 ).…”