In a new article published in Nature, prominent researcher Nicholas J. Schork, director of human biology at the J. Craig Venter Institute in La Jolla, California, writes that with the continued focus on precision medicine should come a different type of clinical trial—involving one person instead of many participants per study.
Doctors have long done informal single-participant studies, known as N-of-1 trials, on their own. “For instance, a doctor may prescribe one drug for hypertension and monitor its effect on a person’s blood pressure before trying a different one. But few clinicians or researchers have formalized this approach into well-designed trials—usually just a handful of measurements are taken, and only during treatment,” Schork writes. “If enough data are collected over a sufficiently long time, and appropriate control interventions are used, the trial participant can be confidently identified as a responder or non-responder to a treatment. Aggregated results of many N-of-1 trials (all carried out in the same way) will offer information about how to better treat subsets of the population or even the population at large.”
In order to formalize the N-of-1 approach, researchers must first solve some practical problems. “These include exploiting the diversity of health-monitoring devices, developing new ones and identifying appropriate disease biomarkers, such as tumour DNA circulating in the bloodstream,” Schork explains. “It will also require a cultural shift on many levels—in regulatory agencies, in pharmaceutical companies and, most of all, in the clinic.”
Schork also describes the problems with the design of today’s clinical trials. For example, in conventional phase III trials involving thousands of participants, very little data are collected on genetics, lifestyles, and diets, so additional study is needed later in order to better determine effectiveness and to establish any underlying mechanisms. Other study designs take different approaches in order to get more specific information. For example, basket trials test the effectiveness of a particular therapy based on mode of action, regardless of the disease the therapy is intended to treat, and umbrella trials look at the effectiveness of multiple drugs for a single disease.
The current Stand Up to Cancer and Melanoma Research Alliance Dream Team (which Schork is part of) clinical trials take the umbrella approach. “We are giving genomically guided treatment to around 70 people out of 100 with late-stage melanoma—choosing from an array of 40 or so drugs (the rest of the participants are receiving the standard treatment usually given to such patients),” he explains. “Here, the effectiveness of matches between drugs and genetics will be compared with standard care.”
Still, even these very specific study designs may not be personalized enough, according to Schork. Even among people who share a mutation known to be targeted by a specific drug, many other factors can affect how or if that person responds to therapy—something that is “particularly true for those with cancer,” he says.
For N-of-1 trials, data will need to be collected every day or periodically over months or years for the person involved in the study. Using crossover designs would allow researchers to look at the effects of different interventions in a single person. Still, “sometimes N-of-1 trials will be neither appropriate nor feasible,” Schork concedes. “For instance, the costs are probably too high for public-health studies that investigate the effect of a population-wide intervention, such as adding fluoride to drinking water.”
But there are notable advantages to this approach. The effectiveness of various therapies for participants in this study are being vetted for the person taking part in the research, rather than just offering potentially beneficial information for future generations. “Indeed, members of hundreds of patient-advocacy groups, for instance for rare genetic diseases, are eager to be involved in studies to test candidate drugs,” Schork concluded.