Therapeutic Misconception: A 40-Year Inquiry Into How People Understand Clinical Trials
Abstract
From a niche area of research largely ignored 40 years ago, the concept of therapeutic misconception has become embedded in bioethical research.
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 Center for 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 the patient’s family and friends and surrounding community become suspicious.”
Importantly, in a 2017 publication three decades after he began researching the subject, 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 (see box below).
“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,” he said.
Problem Not Confined to Psychiatric 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.
Educational Video Decreases Misconception Without Diminishing Willingness to Participate in Trial
In a 2017 paper published in PLOS One titled “Reducing Therapeutic Misconception: A Randomized Intervention Trial in Hypothetical Clinical Trials,” APA past President Paul Appelbaum, M.D., 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.
Patients with diabetes mellitus, hypertension, coronary artery disease, head/neck cancer, breast cancer, and major depression were recruited from medical clinics and a clinical research volunteer database. The primary outcomes were therapeutic misconception, as measured by a validated, 10-item Therapeutic Misconception Scale (range = 10-50), and willingness to participate in the clinical trial.
They were randomized to one of two arms (stratified by disease group): a control arm that was intended to mimic a standard consent procedure for a hypothetical clinical trial and an experimental arm that provided a scientific reframing disclosure in the form of an educational video followed by the standard consent procedure for the same hypothetical trial.
A total of 154 participants completed the study with 74 (48.1%) randomized to receive the experimental intervention.
Therapeutic misconception was significantly lower in the scientific reframing group compared with the control group (26.4 versus 30.9) and remained so after controlling for education. Willingness to participate in the hypothetical trial was not significantly different between the intervention and control groups.
“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.”
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.
Some interviews revealed that even when participants understood the concepts of study research in the abstract, it did not quite translate to an understanding that they themselves would be subject to experimental methods. Appelbaum described an interview with a 25-year-old college-educated woman enrolled in a study comparing two medications and placebo for borderline personality disorder. Her understanding of the research was generally excellent: She recognized that the purpose of the project was to find out which treatment worked best, and she spontaneously described the three groups, including the placebo group, and indicated that assignment would be random and double blind.
When she was asked directly, however, how her medication would be selected, she said she had no idea. She then added, “I hope it isn’t by chance” and suggested that each subject would probably receive the medication needed. When she was asked what her understanding of “random” was, her response was entirely appropriate: “By lottery, by chance, one patient who comes in gets one thing and the next patient gets the next thing.”
But she then began to wonder out loud if this procedure were being used in the current study. Ultimately, she concluded that it was not.
In a 1987 paper in The Hastings Center Report, Appelbaum, Roth, and colleagues reported that in a survey of 88 participants enrolled in psychiatric research, 60% were unaware of randomized assignment; 50% believed their medication dosage would be adjusted according to their clinical needs; 44% did not recognize they might be assigned to an inactive placebo; and 40% expected assignment to be based on clinical needs.
Some in the research community protested that the phenomenon was to be expected among psychiatric patients. But data began to accumulate from other researchers in the 1980s and 1990s suggesting that wasn’t true, and in a 2004 report in IRB: Ethics and Human Research (now titled Ethics and Human Research), Appelbaum and colleagues found that therapeutic misconception was prevalent throughout clinical trial research, for all manner of conditions.
Validating a Measure of Therapeutic Misconception
The next milestone in this 40-year research endeavor was the development of a reliable tool for measuring therapeutic misconception; all previous research had relied on semi-structured interviews with participants. In a 2012 paper in Clinical Trials, Appelbaum, Lidz, and their collaborators tested and validated a 10-item scale measuring therapeutic misconception in three broad dimensions:
Individualization: This study is designed to give everyone the type of treatment and amount of treatment that best fits his or her individual needs.
Benefit: A researcher’s most important task is to make sure that the research will help the people who participate.
Study purpose: The purpose of the study is to provide each enrollee the best possible treatment available.
In a study of 220 subjects enrolled in clinical trials at four academic medical centers, 50.5% (n=101) of participants presented evidence of therapeutic misconception on at least one dimension: 24.50% (n=49) on the individualization dimension; 35% (n=70) on the benefit dimension; and 15% (n=30) on the purpose dimension.
“Although this will enable more systematic studies of therapeutic misconception prevalence and characteristics,” Appelbaum said, “the most important work will focus on reducing its incidence.”
He said misconception arises out of the conflicting and unexpressed expectations of both study subjects and investigators. 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 subtle messages conveyed in language—the words that are used and the words that are not used—that contribute to misconception. For instance, the acronyms used for some trials—BEST, MAGIC, MIRACL, PROVED—convey to potential study subjects the promise of health benefits if they enroll. And 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.
“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.” ■
