In Clinical Trials, Small is Beautiful

By Ann Neuer 
June 26, 2014 | As clinical trials are ballooning in size and becoming more global, there is a parallel trend toward smaller and smaller. How about a clinical trial with just one subject? 

Known as “N-of-1”, this kind of trial is gaining traction for its usefulness in very specific circumstances. Most notably, orphan indications and cancer treatments that are prescribed following genetic testing seem to be the best candidates for N-of-1 trials. That’s because studies for orphan indications are notoriously difficult to enroll due to the limited numbers of subjects; and cancer treatments are often linked to the genetic variability of tumors, meaning a treatment effective for one individual might be totally ineffective for another. Reflecting this interest in genetic variability, approximately 10% of labels for treatments approved by the Food and Drug Administration now have pharmacogenomics information, which describes how genes affect an individual’s response to drugs. . 

“These factors indicate that the N-of-1 concept is consistent with the personalized medicine mantra. There is the belief that each person is unique biochemically, which could impact which interventions are chosen and how they work,” says Nicholas Schork, Ph.D., Professor and Director of Human Biology at the J. Craig Venter Institute in La Jolla, California.  

Schork In single person trials, the subject is also his or her own control, and they generally use a crossover design allowing the subject to receive one or more treatments or placebo in a randomized manner. These studies provide a pragmatic approach to individualized patient care, whereby a greater understanding of genetic mutations can shed light on the biology that creates unique conditions. “Why not sequence genomes of individuals with conditions whose determinants aren’t clear? If we understand the nature of their molecular defect, we can begin to think about developing treatments and monitoring devices in those individuals,” Dr. Schork comments.   

Much of his work is focused on creating tools that identify cancer-causing gene mutations, and then working toward treatments. As part of this effort, his team at JCVI is trying to establish an N-of-1 protocol so they can collect data objectively that might be useful in monitoring cancer. This approach will enable researchers to explore the characteristics of individuals, determining who responds to Drug A or Drug B, and then developing a marker that can distinguish responses. “This kind of trial accounts for all of the nuances of the individual as opposed to starting with the average response in the population, which for anti-cancer drugs, can be quite low,” says Dr. Schork.  

Laurie Smith, Ph.D. M.D., a clinical and biochemical geneticist, at the Center for Pediatric Genomic Medicine (CPGM) at Children's Mercy in Kansas City, and her colleague Carol Saunders, Ph.D., Deputy Director, are looking to N-of-1 trials to improve understanding and treatment of unusual disorders. They have an ongoing N-of-1 trial in a patient with D-, L-2D hydroxyglutaric aciduria, a rare mitochondrial disorder that may exist in only a dozen people worldwide. Babies with this disorder, which can cause seizures, developmental delay, and poor muscle tone, generally die before their first birthday. According to Dr. Smith, “The patient for whom we assisted in generating an N-of-1 trial is about one year old and is doing well.” 
This CPGM patient was diagnosed early through rapid genome sequencing, affording Dr. Smith the opportunity to confer with a German research group who had discovered that patients with this disorder have altered levels of certain metabolites, including citrate. This finding was the foundation for understanding the pathophysiology of this condition and indicated the potential role of citrate supplementation in its improvement. The German group had recently tried a similar treatment on several patients, the results of which were shared with the CPGM group prior to publication. “These kinds of studies are mostly considered anecdotal, but there is the potential to actually discover new treatments,” says Dr. Smith.  

As evidence, she and Dr. Saunders explain that another rare condition known as LEOPARD syndrome may be amenable to an N-of-1 study. The disease is caused by mutations in the PTPN11 gene, and is sometimes associated with a progressive cardiomyopathy. In mouse studies, treatment with rapamycin, an antibiotic, has reversed the cardiomyopathy in mice with this condition.  
“If we can identify babies with LEOPARD syndrome, perhaps their cardiomyopathy could be treated with rapamycin,” says Dr. Saunders. 
She explains further that a key challenge of N-of-1 trials is buy-in from providers because this approach is far from the norm. In the case of LEOPARD syndrome, Dr. Saunders notes, “A patient would have to be very severe before an experimental therapy would be considered.” 

This observation coincides with comments from Robert Temple, MD., Deputy Director for Clinical Science and Deputy Director (acting), Office of Drug Evaluation I, Center for Drug Evaluation and Research (CDER) in FDA. Dr. Temple explains that the agency sees few of these studies. On, which lists 169,000 studies, a mere 20 are for N-of-1 trials, and of that group, only eight are actively recruiting or will begin recruiting subjects.  
“There are no regulatory guidances or regulations specific to N-of-1 studies. Rather, investigators must conform to all of the existing guidelines for Good Clinical Practice that oversee the conduct of clinical trials,” Dr. Temple remarks. It is worth noting that if there is no intent to change the labeling of an existing drug, an investigational new drug application is not needed for an N-of-1 trial.

Although use of this approach is just beginning, its promise is to provide researchers with a meaningful way to explore therapies for rare diseases and for understanding the relationship between tumor variability and cancer treatment. 








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