Within the realm of drug-development efforts, the placebo-controlled clinical trial is considered to be the gold standard for demonstrating the efficacy of promising investigational therapies and medical devices. Using this trial methodology, a placebo, that is, a pharmacologically inactive or inert treatment (often called a “sugar pill”), is administered to one portion of the trial participants. This “control group” serves as a comparison to determine if exposure to the investigational product has produced any significant clinical improvements, safety issues, or side effects.

Sponsors or investigators compare the clinical and safety outcome data of participants receiving the active therapy versus those receiving the placebo, and if there is a significant difference showing a benefit with the drug or device, present those findings when seeking approval from regulators.

The placebo effect

People who are enrolled in a clinical trial often hope or expect that their condition will improve as a result of the effort. A phenomenon, the placebo effect, causes some patients who have received an inactive placebo treatment to experience and report some therapeutic benefit despite not receiving the active therapeutic agent.

Placebo effects are believed to result from a mix of psychological mechanisms and social conditioning (in terms of a person’s knowledge, hopes, beliefs, expectations, motivation and efforts to reduce their symptoms), as well as actual neurobiological effects.

Ethical considerations

The potential ethical implications associated with using a placebo in clinical research remain the subject of ongoing debate among healthcare professionals. Some argue that the use of a placebo provides an essential mechanism to help trial investigators recognize and quantify actual clinical impacts created by the drug or medical device being investigated. However, others argue that patients who participate in a clinical trial but are administered the placebo indeed miss the opportunity to be treated with a pharmacologic therapeutic intervention during the course of the trial, and given the nature of their disease or condition, this “lost time” could create negative health consequences for them. 

Some clinical trials are designed to demonstrate the advantage(s) of a novel therapy compared to an approved therapy that is already available to treat the same condition. Some argue that it would be unethical to create a placebo group of trial participants for certain diseases, as that would essentially guarantee that patients in a placebo control group would receive no treatment at all during the course of the trial. 

For these reasons, the U.S. Food and Drug Administration (FDA) provides guidance on when sponsors should consider using a placebo-controlled design, and how they should establish a detailed, science-based rationale for the trial design.

Blinding to reduce bias

To reduce the opportunity for bias, placebo-controlled clinical trials are often “blinded” (or “masked”). This involves withholding knowledge from both patients and trial investigators about which patients are assigned to which group—those receiving the active agent versus those receiving the placebo. Several options are available when it comes to blinding during trial design and execution:

  • Single blind: Trial participants don’t know which treatment group they are assigned to.
  • Double blind: Neither the patients nor trial investigators are aware of which treatment group they are assigned to.
  • Triple blind: The patients, trial investigators, statisticians, or person who analyzes the results of the trial are aware of which treatment groups participants are assigned to. 

A blinded study helps to reduce conscious or subconscious bias from being introduced during data collection or analysis. The goal of such rigorous effort is to safeguard the integrity of the data, so that only safe and effective drugs and devices are brought to market. 

This blog is intended to be informational in nature. The information and other content provided in this blog, or in any linked materials, are not intended and should not be construed as medical advice, nor is the information a substitute for professional medical expertise or treatment.

If you have any questions or concerns, please talk to your doctor. Never disregard professional medical advice or delay in seeking it because of something you have read on this blog or in any linked materials. If you think you may have a medical emergency, call your doctor or emergency services immediately.

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