Double-blind, placebo-controlled clinical trials

DEFINITION: Scientific trials in which a fake treatment (placebo) is used in conjunction with a real treatment and in which participants and researchers, through “blinding,” do not know which participants are receiving real or placebo treatments.

Overview

The double-blind, placebo-controlled study is the gold standard for determining whether a medical treatment works. With a few exceptions, new drugs must pass several double-blind studies to be approved by the US Food and Drug Administration (FDA). Conversely, when a drug already in use for a given purpose repeatedly fails to prove effective in double-blind studies, that drug is eventually discredited.

Herbs and supplements do not need FDA approval. Still, they, too, can be subjected to double-blind studies, and the results of those studies, whether positive or negative, can significantly impact the public. An article published in the International Journal of Epidemiology in 2007 highlighted problems with blinding and reporting methods in clinical trials and emphasized the need for methodological improvements. A subsequent 2021 review of clinical trials identified similar issues. However, double-blind, placebo-controlled trials are still considered the most effective and accurate method of determining the efficacy of a medical treatment.

History of Double-Blind, Placebo-Controlled Studies

In a double-blind, placebo-controlled study, some participants are given the real treatment while others are given a fake treatment designed to appear as much as possible like the real treatment (the placebo control). The assignment to real or fake treatment groups is accomplished by flipping a coin or using a random number generator. Participants and researchers are kept from knowing who receives real and fake treatment and are, therefore, “blinded.” The full technical name for these studies, randomized, double-blind, placebo-controlled trials, is often abbreviated as RCTs, or randomized-controlled trials. However, this abbreviation leaves out both placebo and blinding and is not discussed here.

The double-blind, placebo-controlled study was first conceived by German researchers in the 1950s to minimize the power of suggestion and other confounding factors. By the 1960s, the medical scientific community recognized that double-blind trials were essential to establishing treatment efficacy. However, it was not until the 1970s that pharmaceuticals were routinely required to pass meaningful double-blind studies to obtain FDA approval. (Many drugs approved before this time were “grandfathered” in.)

The rate of publication of double-blind studies of natural products grew at an astonishing pace. In the early 1990s, months could go by before a new double-blind study of a natural product was published; by the early twenty-first century, multiple such studies were published each week. Furthermore, while the typical study published in the early days of natural product testing involved a small number of participants, contemporary studies commonly enroll many more. Some studies are very large: Studies of vitamin E, beta-carotene, and other antioxidants, for example, have enrolled tens of thousands of participants.

As natural treatments began to undergo systematic testing, many proved ineffective. For example, in the giant studies just mentioned, vitamin E and beta-carotene proved ineffective for preventing heart disease or cancer. Others have also proven ineffective: garlic for high cholesterol, glucosamine for arthritis, and calcium supplements for osteoporosis.

Although some natural remedies have proved effective for treating specific medical conditions in double-blind, placebo-controlled trials, negative trials have sometimes discouraged supporters of natural medicine. However, one journal article cast doubt on these negative results, though it also cast doubt on all positive results. This 2007 article by Danish researcher Asbjørn Hróbjartsson and colleagues in the International Journal of Epidemiology was, essentially, a study of studies. Through extensive analysis of published studies augmented by interviews with some of the researchers who published those studies, Hróbjartsson and colleagues documented that the vast majority of researchers who perform double-blind, placebo-controlled studies failed to carry out a central, essential task: determining whether the blinding held firm. In other words, researchers did not check whether participants and observers could not distinguish the real treatment from the fake treatment.

It would not have been difficult to answer this question because one can simply poll participants and observers and ask them to guess. If the guesses come out correct no more than about one-half the time, then it would be fair to conclude that the blinding remained intact. However, researchers generally do not conduct such a poll, so they typically do not know whether the blinding remained intact. Knowing this, however, is essential to a study’s validity. If blinding does not hold—that is, if most people involved in the study figure out who is taking a placebo and who is taking the real treatment because, for example, the real treatment is smelly—then the study's validity is compromised. While Hróbjartsson’s work demonstrated that blinding was rarely tested in clinical trials, and when it was, the methods and reporting were often incomplete, the assertion that the study’s findings invalidated all double-blind, placebo-controlled trials is overstated. The study primarily identified areas where clinical trial methodology could be improved.

Importance of Blinding

Suppose the researchers conducting a study want to prove that an herb or supplement does not work. Such bias does not matter much if the study is truly double-blind, because researchers cannot tell who is getting the real treatment and who is getting the placebo; the outcome of the study is insulated from their preferences. However, once the blinding is broken, this protection disappears. For example, researchers disinclined to believe that glucosamine can help arthritis may unconsciously underestimate or under-report benefits in patients they know are taking glucosamine. This, in turn, could lead to a false outcome in the study, an apparent failure of a treatment that actually works.

The reverse is also true. For example, if researchers are biased in favor of the natural product (or drug) being tested, their predilections will likely cause them to see benefits not actually present—this is only human nature. However, when researchers do not know who is getting the treatment and who is getting the placebo, their bias has no effect. (Bias can also appear through the manipulation of statistics or dishonesty.)

Observer bias is just one of the confounding factors that double-blinding forestalls. Still, Hróbjartsson and colleagues found that most researchers did not poll their study participants to see if the blinding holds. Among those who did conduct such a poll, less than half actually found that the blinding had been maintained. This had implications for previously published studies but did not invalidate the efficacy of double-blind, placebo-controlled trials. 

In one sense, this is good news for supporters of natural medicine. A broken blinding may have flawed negative studies regarding natural products. In another sense, the same research deficiency identified by Hróbjartsson and colleagues means that positive studies involving natural products may also be invalid. Still, double-blind, placebo-controlled trials remain the gold standard in efficacy testing for prescription medications and natural treatments, and the problematic issues identified with blinding do not invalidate all previous studies. There has been a movement to improve methodologies and reporting and increase transparency in clinical trials. However, challenges like those identified by Hróbjartsson continue to persist.

Bibliography

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Hróbjartsson, A., et al. "Blinded Trials Taken to the Test: An Analysis of Randomized Clinical Trials That Report Tests for the Success of Blinding." International Journal of Epidemiology, vol. 36, no. 3, 2007, pp. 654-63, doi:10.1093/ije/dym020. Accessed 14 Dec. 2025.

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