Therapeutic Misconception: A 40-Year Saga of Inquiry Into How Research Subjects Understand Clinical Research Goals

By Mark Moran

Therapeutic misconception—when individuals enrolled in a clinical trial misunderstand or incompletely understand the difference between the goals of clinical care and those of a research trial—is prevalent throughout biomedical research, said APA past President Paul Appelbaum, M.D., at APA’s online 2021 Annual Meeting. He delivered the Adolph Meyer Lecture, titled “Therapeutic Misconception: A Psychiatrist’s 40-Year Journey.”

Appelbaum is the Elizabeth K. Dollard Professor of Psychiatry, Medicine, and Law and director of the Division of Law, Ethics, and Psychiatry at the Columbia University Vagelos College of Physicians and Surgeons.

The failure of patients to fully understand that when they enroll in a trial, they are not necessarily getting the best treatment for their condition is an ethical and practical problem that researchers should not lightly dismiss.

“It is not just an ethical problem,” he said. “I think there is a self-interested aspect for the research community as well. At some point, many research subjects discover the truth that they received a placebo, not the active medication; or that their physician was blinded to what medication they received; or they discover that the treatment was assigned randomly and not because someone thought it would be most beneficial.

“When that happens, people get angry,” he said. “People have brought lawsuits on the basis of having been deceived. When that happens [to a patient], that patient will never, ever again enroll in a clinical trial, and their family and friends and the community around them become suspicious. The medical community has an incentive to make sure no one enters a clinical trial without a full understanding of what they are getting into and the ways it differs from clinical care.”

Appelbaum showed that an educational intervention aimed at clarifying the distinction between clinical care and a clinical trial can make a difference without dissuading study subjects from participating. In a 2017 paper published in PLOS One titled “Reducing Therapeutic Misconception: A Randomized Intervention Trial in Hypothetical Clinical Trials,” Appelbaum and colleagues demonstrated that an educational video clarifying the concepts of placebo assignment, randomization, and patient and investigator blinding significantly reduced therapeutic misconception without affecting potential subjects’ willingness to participate.

“A simple and easily administered intervention may make a big difference in the quality of informed consent in psychiatric and other research,” Appelbaum said. “Researchers’ concerns that reducing [therapeutic misconception] would also reduce study recruitment appears to be unwarranted. I think this sets the stage for the application of these methods to actual clinical research.”

His lecture was a chronicle of a remarkable research endeavor that began in the early 1980s when Appelbaum first collaborated with Loren Roth, M.D., Emeritus Distinguished Service Professor of Psychiatry at the University of Pittsburgh, and Charles Lidz, Ph.D., professor emeritus of psychiatry at the University of Massachusetts, examining informed consent in psychiatric research. Out of that research the concept of therapeutic misconception was born; structured interviews revealed that even educated patients did not fully comprehend that they may not receive the best treatment or that their assignment to a certain treatment in the trial was not made because it was determined to be in their best interest.

Later, when some in the research community protested that the finding was to be expected in subjects with psychiatric illness, Appelbaum and colleagues showed that the same phenomenon existed throughout clinical trial research, for all manner of conditions.

Misconception arises out of the conflicting and unexpressed expectations of both study subjects and investigators. Appelbaum said investigators are clearly motivated to have people participate in a trial, but he said deliberate deception is rarely or never the case; rather, it is the kind of subtle messages conveyed in language that contributes to misconception. For instance, he noted that when describing a study to a potential participant, investigators are reluctant to use the word “experiment” even though, in fact, that is exactly what the patient is being asked to join.

From a niche area of inquiry largely unrecognized four decades ago, the concept of therapeutic misconception has come to be embedded in research ethics. Appelbaum said the story of this research endeavor is a testament to the importance of collaboration and long-term relationships and the value of sustained engagement with a research question.

“The initial publication about therapeutic misconception, which now has over 800 citations, was largely ignored when it appeared,” Appelbaum said. “It took more than a decade for the concept to begin to be absorbed into the research community. But the term therapeutic misconception is now so widely recognized that it’s often mentioned with no supporting citation—the ultimate tribute.” ■