In Nature’s article “Time for one-person trials” Nicolas J. Schork commented that clinical trials and research studies ought to focus on the individual rather than an average response to a therapy.
Nicholas Schork is currently director of human biology at the J. Craig Venter Institute in La Jolla, California, professor at the UCLA (San Diego) and at the Translational Genomics Research Institute (TGen) in Phoenix, AZ. He was formerly director of Complete Genomics, a genomic testing company before it was purchased by BGI, a Chinese conglomerate. Several years ago I attended a day-long training program in San Diego. At that time I had the opportunity to meet with Schork and his team to discuss my research in nutrigenomics, and using the results from an N of 1 case history to determine whether a nutritional intervention is efficacious based on a person’s genotype.
N refers to the number of participants or subjects that are part of a research study or clinical trial, which is then used to determine whether a treatment effect is statistically significant and not a chance occurrence. Typically there is a control group and a treatment group. “N of 1” is the term coined to describe studies where each person serves as his or own control. Clinicans have been using this approach for centuries, under the term “case history”.
Clinicians employing a personalized health model use this “case history” approach much of the time because no two individuals will respond the same way to a drug, nutritional intervention, or therapy. In effect, the person is his/her own control. Typically, an objective biomarker is evaluated before a personalized intervention is implemented, and then reevaluated an appropriate period time after the intervention. The results are compared and then a determination is made whether the intervention or therapy was successful based on a quantifiable change in the biomarker. An analysis can be done, usually Chi Square, to determine if the change was statistically significant using an N of 1. Aggregated results of many N of 1 studies will provide essential information about how best to treat subsets within the population or even the population at large.
Genoma International is conducting an ongoing 10-year study of more than 150 women predisposed to breast cancer based on their estrogen metabolism genomic test results. Some of these women have SNPs (single nucleotide polymorphisms) in single genes in phase I detoxification, others have SNPs in more than one of these genes. Some women have one or more SNPs only in phase II detoxification genes. Still others have SNPs on genes involved in both phase I and phase II detoxification.
To add more complexity to this scenario, some women have phase II genes that are deleted or missing. Each of the genes mentioned above in phase I and phase II detoxification is critically important in removing potentially carcinogenic molecules from a woman’s body. To conduct a clinical trial to test whether a nutrigenomic intervention successfully prevents breast cancer in each one of these subpopulations would be tremendously expensive and time consuming. Given that there is so much genetic variation between and within the subpopulations, very large studies would be needed to show statistical significance. Rather than using the standard model of medical research, where everyone is assumed to be genetically and biochemically identical, at Genoma International each woman in this longitudinal study is her own control, through monitoring whether a nutrigenomic intervention changes biomarkers and also prevents breast cancer. Over time, the results of many N of 1 studies provide valuable information to stratify treatment options to better personalize intervention strategies.
A second population of 75 women diagnosed with ER+ breast cancer are part of an N-of-1 study evaluating the effectiveness of personalized nutrigenomic interventions based on genomic test results to prevent the cancer’s recurrence. Some of these women are using or have used conventional cancer therapies. To date, not one woman diagnosed with ER+ breast cancer and using nutrigenomics to mitigate the effects of poor estrogen metabolism because of her genes has had a recurrence of the disease. Nor have any of the 150 women using nutrigenomic interventions to prevent breast cancer developed the disease.
As Nicholas Schork points out there are significant obstacles to making N of 1 trials commonplace, including regulatory agencies, researchers, clinicians and pharmaceutical trials that operate on the belief that there is a single common, universal mechanism of action for a disease.
Healthcare professionals can now look at the unique genotype, circumstance and situations of each patient. Clinical trials are slowly starting to focus on the individual, or N of 1. Genoma International webinars and courses highlight case histories from our clinical archives, illustrating where we have used genomic testing to personalize prevention or treatment strategies, before and after biomarkers, and a summary of our findings to help promote this concept.
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