dmark consulting LLC

HSC: What’s the difference between Placebo and Placebo Effect?
David: A Placebo can be defined as a non-functioning test product used in a clinical trial with the subjects’ knowledge, while Placebo Effect is a physiological and/or psychological response to a non-functioning product which occurs because the patients believe it will help – patients are not aware of the non-functional nature. The nuance between the two definitions is further blurred because in the context of a clinical trial any change from baseline in the group getting the placebo is often referred to as “a placebo effect.”

HSC: Do Placebo Effects really exist?
David: A 1997 book “The Placebo Effect” [Harrington A (ed.), Harvard University Press] describes in scholarly detail the response to placebo treatments. There is convincing evidence that belief in the healer and the treatment can augment resolution of disease and/or amelioration of symptoms even if the actual treatment has no plausible mechanism of action. The nocebo effect is also described – that an expectation of sickness causes sickness. A given example: “80 percent of hospitalized patients given sugar water and told that it was an emetic subsequently vomited.”

HSC: Why use a Placebo treatment group in clinical trials?
David: People get better. Treating any temporary condition in an uncontrolled trial and claiming cause-and-effect is flawed for obvious reasons – it’s highly likely that the subjects will get better regardless of treatment. Yet studies on ulcers, infections, wound healing, and so on are conducted and reported this way. Even chronic conditions (arthritis pain, erectile dysfunction) have ebbs and flows. Reporting changes from baseline will bias the results in favor of the treatment.

People want to get better. Placebo-controlled clinical trials first appeared in the scientific literature circa 1915, but did not become common until around 1960. In uncontrolled evaluations of hundreds of substances and surgical approaches later proved ineffective, 25-80% of patients report improvements. Even in the context of blinded, controlled clinical trials, 40-45% of placebo-receiving arthritis patients report pain relief and 25-30% of men with erectile dysfunction report improved sexual functionality. To be considered effective, treatments have to work even better than placebos.

HSC: What else can explain a change for the better in a placebo-controlled trial?
David: The concept of a false baseline is poorly understood, but is responsible for much of the results inappropriately identified as a “placebo effect” in a clinical trial, especially for objective measurements such as blood pressure or cholesterol. Average cholesterol is 200 mg/dL, but on any given day an individual can be up or down 5% on their average plus the accuracy of the blood test can also be up or down 3%. Consequently, choosing >220 mg/dL as an enrollment criteria will capture many subjects who on that one day tested higher than their actual average cholesterol, meaning that when they are tested at the end of the trial their blood level is likely to test lower regardless of treatment. It’s like taking a photo of peoples’ head heights when they are jumping up and down and eliminating everyone under 6’6”. At the next measurement the average of the group will be lower. Drug company trials minimize this cholesterol measurement problem by taking three blood samples over 10 days, measuring each in duplicate, and using all results to establish baseline.

HSC: What is “power analysis” and who cares?
David: Determining the number of people to enroll is not a mysterious art. Nor should it be decided by budget constraints or patient availability. A biostatistician can look at expected effect and variability of the measurement and recommend group size to minimize false positives and false negatives. A smaller than desired study can “get lucky” (and get published), but it won’t have much credibility with the FDA when filing for a label health claim or responding to a warning letter.

HSC: What is an ingredient, supplement or functional food company to do?
David: Start small. A modest-sized before/after trial is just a beginning. Succeeding, the next step could be a cross-over study (half start with treatment and half start with placebo, then switch half-way through). Measurement methods should be modeled on drug trials. And so on, aspiring to adequately sized, high quality, placebo-controlled, double blind, randomized enrollment clinical trials. And remember that the key result is statistically significant difference from placebo at the end of the study.