Therapeutic Misconception: A 40-Year Inquiry Into How People Understand Clinical Trials

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.

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.

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:

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.” ■