Clinical Research: Phase 1 - Phase 4

Premier Voices #3: The Placebo Problem Part 1 With Scott Millard

The placebo effect’s impact on drug development is widely known, but you may be surprised to learn that the word “placebo” has had multiple meanings — all of them pejorative — going back hundreds of years. Scott Millard, Premier Research’s Executive Director for Strategic Development and Analgesia, explores the role of placebos in the latest episode of our Premier Voices podcast.

Way back in the 14th century, “placebo” was used to describe people who attended funerals of people they didn’t know, feigning a connection to the deceased to partake of the food and drink served to the mourners. In the 19th century, it was applied to sycophants and others eager to please. From there, the term evolved to describe drugs that give patients psychological relief of their illnesses without providing therapeutic benefit.

The placebo effect is a genuine psychological and physiological phenomenon whose impact on drug development has grown considerably since 1948, when the first placebo-controlled trial was undertaken to evaluate streptomycin as a treatment for pulmonary tuberculosis. While they don’t treat any condition per se, these inert compounds can relieve physiological functions like heart rate, blood pressure, lung function, and gastric motility.

But high placebo response can severely undermine efforts to demonstrate the effectiveness of new treatments. Even large studies that have shown prior clinical efficacy have failed because of high placebo response, a factor blamed in part for the failure of nine in 10 neuropathic and cancer pain trials over the past decade.

Subjective trial data

The placebo effect is especially evident in analgesic trials because patient response is almost entirely subjective. In the absence of objective measures like tumor size, researchers rely on patient-reported outcomes that can be influenced heavily by subjects’ expectations — and those expectation have changed as trials have become larger in scope and longer in duration.

Two major factors are at play here:

  • People suffering chronic pain tend to crave the attention of the physicians and other personnel they encounter during drug trials. With these trials now lasting 12 weeks on average versus four weeks in the ‘90s, patients interact more with these professionals and spend more time in therapeutic environments, and that exposure by itself can drive up placebo response.
  • Trials are much larger now than they were in the past, engaging more sites and encompassing more treatment arms. Notwithstanding the valid clinical reasons for this expanded scope, larger trials mean less procedural control and greater outcome variability.

While there is strong scientific basis behind the trend toward longer and more complex trials, the increase in placebo response has been dramatic, as illustrated by an analysis of 84 neuropathic pain studies over nearly two decades. In 1996, patients in pain trials judged study drugs to be 30 percent more effective than placebos. By 2013, that number had plunged to 9 percent.[1]

Placebo response, once dismissed as a nuisance, is now a field of research in its own right. Check out our podcast to learn more.

Full presentation:


[1] Tuttle AH, Tohyama S, et al. Increasing placebo responses over time in U.S. Clinical trials of neuropathic pain. Pain 2015;156(12):2616-2626.