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March 29, 2017

Reporting Evidence: Why The Coin Toss in Clinical Research?

Josephine P. Briggs, MD Director, National Center for Complementary and Integrative HealthLisa Helfert

By Josephine P. Briggs, MD
Director, National Center for Complementary and Integrative Health

At NIH’s National Center for Complementary and Integrative Health, which I lead, we, like all NIH Institutes and Centers, value what randomized controlled trials (RCTs) can offer in building a robust evidence base. I am also keenly aware that the field of complementary and integrative health can present many unmet research needs. Just walk down the dietary supplements aisle at your local market or see the many practices offered in your area and you know that many of these approaches are already in the marketplace. And Americans are spending approximately $30.2 billion out-of-pocket on these practices and products, including some that have real benefit and others for which there is little or no research about their potential benefits or risks. This, in many ways, increases the necessity for high-quality research in our field. Our ultimate goal is to offer consumers evidence-based information that draws on the best possible research, such as RCTs, so that consumers can make well-informed decisions about complementary and integrative health approaches.

One of the hardest things to explain about clinical research is why randomization is so often necessary. Most people who write about the biomedical research process are well aware that RCTs have a special place in the hierarchy of clinical research; they stand on a pedestal as the “gold standard.” Findings from RCTs provide the basis for evidence-based medicine and clinical practice guidelines and are almost always required steps in the drug approval process. They are essential. But why? Why do we need randomization to get answers? And why should patients enroll in a randomized trial? Why should a person let a decision about his or her own health care be made by the toss of a coin? And what are the safeguards that make this right and ethical?

Let’s start with the ethics. A core starting point in the design of an RCT is identifying two (or more) options that are balanced; that, in the opinion of experts, offer a coin-toss alternative. Clinical trialists call this equipoise—a state of knowledge in which the relative risk and benefits of the two options look to an experienced clinician to be about the same. This is the situation in which a physician would be ready to say to her patients, “I really don’t know which of these two choices is best.” Of course, another step in enrolling patients in clinical trials is making sure that people’s own preferences don’t make one option much better for them than another.

Equipoise is the starting point for the ethics of RCTs. Heads or tails. Randomization assigns patients to one of several treatments using a coin toss (or the modern computer equivalent). Many trials compare a new treatment with the best current standard of care. Some trials compare the treatment being tested to a “sugar pill” or placebo, an approach used particularly when there is no effective standard of care. But in all these cases, the relative merits of the study arms—the different options—should have a balanced set of risks and benefits.

That a trial has a placebo arm is often a sticking point. A person may wonder about enrolling in a study in which he or she might just receive a placebo or “sugar pill.” The surprising fact is that in many trials the placebo arm is either just as good—or sometimes even better. The placebo pill is chosen to be inert, and as a consequence has no negative side effects. Placebos are not used in all trials, but they are very important in studies in which subjective impressions of the participants are an important part of assessing effectiveness. We all know from personal experience that expectations color our perceptions. That is why wine tasting is done with hidden labels. And expectations turn out to influence our responses to medical care as well.