When it comes to origin stories, you won’t find many weirder than the one associated with the concept of placebo. “Placebo” is Latin for “I shall be pleasing”. In the 8th century, long before research-based medicine and the pivotal role of placebo in determining the efficacy of medications, the term was associated with funeral crashers who faked a connection to the deceased in order to partake of the funeral meal.
By the 18th century, the term had migrated into medicine. It was defined in Quincy's Lexicon-Medicum as “an epithet given to any medicine adapted more to please than to benefit the patient.” Physicians of the era liberally prescribed placebos in the form of sugar pills, pills made of bread, injections of water, and other sham treatments.
In the mid-20th century, researchers’ view of placebos began to shift. Anesthesiologist and medical ethicist Henry Beecher of Harvard Medical School published a paper in 1955 entitled The Powerful Placebo. It argued for the necessity of double-blind, placebo-controlled studies in order to accurately gauge the efficacy of medicines. Sugar pills were no longer just the last refuge of frustrated physicians hoping to assuage patients. They would play a critical role in clinical trials.
The Very Real Problem with Placebos
Today, we know that placebo medications and procedures can demonstrate startling efficacy, even where the “placebo” has no therapeutic effect. An extreme example of this was the phenomenon of “psychic surgery”, popularized in the Philippines in the 1970s. Warning, if you’re squeamish, turn away now!
More recently, this was reinforced in a trial of pain medications, where investigators analyzed patients’ responses to external heat or cold stimuli. They found that patients whose attention was distracted by an external stimulus were not very sensitive to pain, and thus more likely to attribute efficacy to the placebo. The authors of the paper recommended not including those patients in placebo-controlled trials focused on pain.
Typically, the placebo effect mainly involves relief of symptoms rather than affecting the underlying disease, which has serious implications for clinical trial data. After all, the efficacy of a treatment appears diminished when the efficacy of the placebo comparator is also notable. What’s an investigator to do?
Minimizing the Unwanted Impact of the Placebo Effect in Clinical Trials
Sponsors use a variety of techniques within their study designs to manage the placebo effect. These include:
Using a no-treatment control group to throw into stark relief the difference between placebo and the natural course of the disease
Filtering out placebo responders by using a placebo run-in period
Eliminating patient-reported outcomes by using biomarkers instead
With the rise of ‘patient-centricity’, patients have become more involved in trial design. Patients are receiving a greater level of education about clinical trials and the trial itself. Educating the patient about the placebo response can be another important tool in mitigating its effect. Thorough patient education can be key to ensuring that the placebo effect doesn’t discredit otherwise valuable data. Bringing patients’ attention to the phenomenon of the placebo effect and the impact it can have in establishing the effectiveness of a promising therapy may limit the observance of the placebo response in trial data. At Longboat, we are seeing an increased use of this method by sponsors through our ‘patient education’ modules.
Ultimately, acknowledging and effectively managing the placebo will help ensure “pleasing” results for our clinical trials.