That was the beginning of Jofriet’s life with Crohn’s disease. It was also the beginning of a weird relationship with food. Over the next eight years, he would go through numerous surgeries and treatments, and those things, along with the actual symptoms of Crohn’s, would affect what he could eat and when. Sometimes he subsisted on nothing but Teddy Grahams and cans of Pediasure. Sometimes he didn’t eat at all, receiving all his nutrition through a tube that snaked from a pack on his back into his nose and down to his stomach. The only way Jofriet could go to homecoming during his sophomore year of high school was on a six-hour pass from the hospital where he was recovering from yet another abdominal surgery.
Today, at 18, he’s enjoying the best health he’s had since grade school. Nobody is exactly sure why his illness flared up in horrible ways throughout junior high and high school, but after some experimentation with his doctor, he’s finally found a medication that keeps his Crohn’s under control. And that has left Jofriet in an awkward position. Increasingly healthy, he doesn’t want to do anything that could jeopardize that health. It’s not unusual for Crohn’s patients in his situation to experiment informally, jumping mostly by instinct into fad diets, supplements, new foods and alternative therapies.
That kind of experimentation isn’t limited to Crohn’s patients. Everybody has tried one-person experiments at some point. You want to lose weight, so you try the low-carb diet you keep hearing about on the news. You have arthritis, and you think acupuncture might relieve your pain better than medication. Your kid has a cold, and taking a friend’s advice, you give him some zinc. In that way, N of 1 trials are nothing new.
The problem is that the results of all these little experiments are suspect. Few of us start by documenting a baseline, tracking symptoms before we try a new treatment. Nor do we usually document what happens after we start the new treatment or test different treatments separately, comparing them with each other and with what happens to our bodies without any treatment.
This distinguishes formal N of 1 experiments from basic, everyday decision-making about health. Some are more formalized than others, but the best have three important elements that don’t exist when patients, or patients and their doctors, are just trying things out, says Naihua Duan, a retired Columbia University biostatistician and part of a team of experts convened by the federal Agency for Healthcare Research and Quality that recently published a user’s guide to N of 1 experiments.
The first characteristic of a formal N of 1 experiment is randomized assignment of treatment conditions. That is, the patient should cycle either between periods using the active treatment and periods using some kind of placebo, or between periods of two different treatments. Second, neither the doctor nor the patient should know when the patient is taking the placebo or the treatment. That’s called blinding. Finally, the doctor and patient should track symptoms in detail throughout the experiment, just like Jofriet and Saeed did. If one of the symptoms is bloating, the amount of bloating should be recorded at various points in the day, every day, throughout the experiment.
Psychologists have been running one-person experiments, using some of these basic principles, since the mid-20th century. But the idea of single-subject research didn’t really make the leap to medicine of the body until the early 1980s when Gordon Guyatt, a Canadian physician now known as a founder of evidence-based medicine, began working in an interdisciplinary department at McMaster University in Ontario, with psychologists, biostatisticians, ethicists and clinical epidemiologists all working together.
At a weekly departmental seminar, one person would present his or her current research, and the others would lob around criticism and ideas. In these debates, Guyatt remembers, one of the psychologists kept bringing up the idea of N of 1 trials. Guyatt decided to learn more.
At the time, he was dealing with a lot of patients whose health experiences didn’t match up with the results of large randomized clinical trials. One of those was an asthmatic septuagenarian whose three prescribed medications didn’t seem to be helping. N of 1, Guyatt realized, could solve that problem.
Guyatt and his team meant to do three blind comparisons between a placebo and one of the three drugs: theophylline, a bronchodilator that eases breathing. But after switching between theophylline and placebo two times, they had to stop the experiment. It was already clear that changing the medication was making a big difference — and the patient was healthier on the placebo. The active drug was actually making the patient worse, not better. The results didn’t mean theophylline, which is still in use, was a bad drug. It was just a bad drug for this particular patient. With theophylline removed from his regimen, the patient flourished.
Guyatt published the results in The New England Journal of Medicine in 1986. “To definitively establish whether or not something works in an individual is kind of a thrill,” he says. “A trial of 1,000 people is a long-term process. Even just recruitment can take three years. There’s a lot of slogging. But N of 1 gets you answers quickly.”
While the improvements in N of 1 patients aren’t always as dramatic, research over the past 20-plus years has produced solid support for the idea that these studies really can help doctors and patients work together to make better decisions. That’s especially true when it comes to chronic illness.
Saeed, Jofriet’s doctor at Cincinnati Children’s Hospital Medical Center, relates another case: a girl with Crohn’s who believed that taking a probiotic eased her symptoms. Saeed’s subsequent N of 1 experiment showed that the probiotic wasn’t actually helping; the fluctuation in symptoms existed independently of whether she was taking it. So she stopped, and instead, she and her doctors focused on trying to figure out why the symptoms fluctuated.
In 1990, when Guyatt and his team published the first review of their work, these were the kind of results they were looking for — experiments that answered a question and changed a patient’s treatment plan. Of the 70 N of 1 experiments they’d done at that point, 50 led to a definitive answer, and 39 percent of those answers led to a change in treatment. Later studies found similar benefits of N of 1 trials.
And yet, from Guyatt’s perspective, N of 1 trials have been a disappointment. He and other scientists published a lot of research on the experiments in the early to mid-1990s, but then they mostly gave up. Although the experiments produced useful results, their logistical complexities made them expensive and difficult for individual patients and doctors to manage properly. At the same time, Guyatt and other scientists found themselves fighting internal bureaucracy for the right to do the experiments at all. “We hung on for five years or so,” Guyatt says. “And people still call me to ask about it periodically. I have a chat with them, and I say, ‘good luck.’ ”
Rise and Fall and Rise Again
Today, few people have even heard of N of 1 experiments. When Richard Kravitz, co-vice chair of research in the department of internal medicine at the University of California, Davis, does focus groups to see what doctors think about N of 1 trials, he usually has to start by explaining what an N of 1 trial is.
Kravitz studies how doctors’ behavior affects patients’ health, and he sees N of 1 experiments as a clever means of changing the way medicine is done — a chance to tailor care to patients’ individual needs without relying on ultra-high-tech, ultra-expensive genetic-sequencing technologies. “It allows you to implement personalized medicine without the ‘omics,’ ” he says. “You can be rigorous and scientific, but you don’t need a lab.”
Unfortunately, while N of 1 experiments may be more down to earth than personal genomics, they come with their own drawbacks — issues that led researchers like Guyatt to abandon them 20 years ago.