Frequently Asked Questions

Theory (2)

Treatments⁠—both pharmaceutical and nonpharmaceutical⁠—are classically evaluated in random control trials (RTCs). Large, carefully selected groups of participants and their doctors are blinded to which patients are getting which treatment or control.

In contrast, an n-of-1 trial looks only at the effects of different treatments on a single person. The trial periods and target outcomes are defined ahead of time. With the assistance of a compounding pharmacists, blinding and placebos are possible.

The two types of trials have radically different purposes⁠—the RTC is to determine broad efficacy and average treatment effects, and the n-of-1 determines the effect on a single individual.

“All RCTs do is show that what you’re dealing with is not snake oil,” according to William R. Shadish, PhD, a professor of psychological science at the University of California at Merced. “They don’t tell you the critical information you need, which is which patients are going to benefit from the treatment.”

According to Dr. Sunita Vohra and Salima Punja, BSc:

results from randomized controlled trials (RCTs), often considered the ‘gold standard’ of research evidence, are often not well suited to the realities of clinical practice given patient heterogeneity, comorbidities, and the use of multiple concurrent therapies. In fact, RCTs may exclude the majority of patients seen in routine clinical practice. In addition, evidence is lacking on the long-term effectiveness, comparative effectiveness, and additive effectiveness of many therapies for chronic conditions. This lack of relevant evidence can limit a clinician’s ability to make evidence-based decisions.

Category: Theory

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It’s easy to see why many people, even some doctors, believe n-of-1 studies are “not statistically valid.”

Many doctors weren’t exposed to the voluminous literature on N-of-1 studies in medical school or, if they were, quickly forgot the concept. Once they moved into clinical practice, they’ve been inundated, day after day, by drug reps justifying their drug’s superiority over others based on large parallel group random control trials (RCTs).

“This study of 3,500 patients shows that our drug X results in a 17% improvement in symptom Y,” says the drug rep, pointing to the study’s title. Parallel group RCTs are often perceived as the “gold standard” for proving a drug’s efficacy and safety.

In fact, statisticians have long argued that the results of RCTs are not generalizable for any given individual.

First, the RCT’s participants often have nothing in common with a given patient, whether because of age, sex, fitness levels or other variables. Historically, women and minority groups in particular have been underrepresented in studies.

Second, even if a study’s participants do appear to match the patient, research indicates that drug efficacy varies strongly from patient to patient, whether because of genetics, microbiome or behavior. Behind the headlines of all large studies reporting “average” benefits is compelling evidence that most drugs don’t work equally well for all people. This is called “heterogeneous treatment effects,” or HTC.

“All RCTs do is show that what you’re dealing with is not snake oil,” according to William R. Shadish, PhD, a professor of psychological science at the University of California at Merced. “They don’t tell you the critical information you need, which is which patients are going to benefit from the treatment.”

This means that, for an individual, a drug can’t be proven to be effective, much less optimal, unless it’s been systematically tested for that individual, ideally with crossovers, placebos and blinding. In short, an n-of-1 trial.

In fact, it’s the trial-and-error drug experiments (formally called “trials of therapy”) used by most doctors to find the best drug for an individual patient that lack scientific rigor. “These so-called trials are unblinded, have no control, and involve no formal assessment of effectiveness, making them vulnerable to invalid conclusions about treatment response,” observe Dr. Sunita Vohra and Salima Punja, BSc.

>> More on the difference between n-of-1 trials and large group RTCs.

Category: Theory

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