Looking for an N-of-1 service for a single patient trial?

Most drugs aren't effective for most people.
“Number Needed to Treat” for one patient to benefit, illustrated for the top ten drugs in the US. Source.

Recognizing that most top selling drugs in the US benefit only a fraction of treated patients, some researchers have advocated single patient drug trials for nearly 30 years.

An n-of-1 trial applies standard scientific methodology — including placebos, blinding, random block rotation, crossovers, washouts and statistical analysis — to determine a drug’s efficacy for an individual patient. The rigor and specificity mean that n-of-1 trials “facilitate finely graded individualized care, enhance therapeutic precision, improve patient outcomes, and reduce costs,” according to a 2013 review of 2,154 single patient trials.

N-of-1 trials also avoid cognitive biases—confirmation bias, a desire to please the doctor, the placebo effect, the natural progression of an illness, to name a few—that can commonly skew the unstructured drug sampling, aka trial and error method, that most clinicians rely on.

To date, though, we’ve seen a failure of all attempts to provide off-the-shelf n-of-1 services that the average doctor might use for a patient.

“We spend so much effort on precision in diagnosis, yet we have very little precision about treatment,” says Eric Larson, Executive Director and Senior Investigator, Kaiser Permanente Washington Health Research Institute.

Why?

Here’s a shortlist of explanations offered in the excellent 2008 paper, What Ever Happened to N-of-1 Trials? Insiders’ Perspectives and a Look to the Future.

1) The average physician’s toolbox doesn’t include the necessary statistical hammers and saws to do a meaningful analysis. “In clinical practice, physicians use evidence and experience to generate a list of treatment options. Patients and physicians move down the list based on trial and error.”

2) N-of-1 trials require physicians to squeeze another process and script into their already-packed days. “Clinicians must explain the idea to their patients, see them regularly throughout the trial, and evaluate the results jointly at the trial’s end. … Taking the time to sell an unfamiliar concept—let alone follow through on the logistics—might be untenable.”

(A 2017 history of n-of-1 trials offers a more prosaic take: “‘did the treatment help’ is too easy, and has too much face validity, compared to the more onerous substitution of a formal N of 1 trial.”)

3) Beyond the pragmatic challenges, N-of-1 trials force physicians out of their “cure-dispenser” role. “While clinicians understand that the practice of medicine involves uncertainty, they are not necessarily comfortable with it. Recommending that a patient enroll in an n-of-1 trial acknowledges this uncertainty, suggesting that the physician does not really know what is best. It is much easier—and arouses far less cognitive dissonance—to simply write a prescription.”

As Gordon Guyatt, who pioneered research at McMaster University indicating the empirical superiority of N-of-1 trails, summed up: “[Physicians] tend to have ways that they’ve learned to operate where they’re comfortable, and it’s hard to move outside these ways. It’s hard to do something extra that’s going to take time, and energy, and initiative.”

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