real patients…

Posted on Friday 23 December 2011

Antidepressant Clinical Trials and Subject Recruitment: Just Who Are Symptomatic Volunteers?
by Benjamin Brody, M.D., Andrew C. Leon, Ph.D., and James H. Kocsis, M.D.
American Journal of Psychiatry 2011 168:1245-1247.
[full text on-line]

… Why are placebo response rates so high? Some portion of the increase may be attributable to the broadening of inclusion criteria — subjects who are less depressed may be more likely to respond to placebos. Industry-sponsored trials that pay investigators incrementally by subject incentivize raters to inflate symptoms at screening visits preferentially over symptoms at midtrial visits. The incremental payments also discourage careful screening for exclusion criteria. Participation that is induced by cash payments may lead subjects to exaggerate their symptoms. Clinical trials have also become longer in duration, giving nonspecific factors more chance to accumulate. Another contributing factor to high placebo response rates may be the extent to which the volunteers in antidepressant trials are really generalizable to patients in clinical practice. Since the initial antidepressant trials in the 1960s, participants have gone from being patients who were recruited primarily from inpatient psychiatric populations to outpatient volunteers who are often recruited by advertisements. At times, these symptomatic volunteers have participated in other trials. When we contact potential participants to schedule screening, they often ask to be reminded which trial we are screening for or mistake our research trial for a different protocol in which they recently participated. The following stories illuminate some of the other problems we have recently encountered using symptomatic volunteers.

“Mr. A” participated in a trial of a biological marker for selecting medications in the treatment of depression. He improved over the course of the study, so it was surprising when he decided to discontinue his medication when the study concluded. A year later, he responded to an advertisement recruiting depressed subjects for a new clinical trial for an experimental antidepressant with a novel mechanism. But after we enrolled Mr. A in this new trial, the study monitor informed us that a subject with the identical birth date and initials had just completed the same trial at another local institution. Mr. A claimed that this was an honest mistake, but we were skeptical. Our suspicions were confirmed when we learned by happenstance that he was also enrolled in a trial as a healthy comparison subject at a neighboring institution.

“Ms. B” is another symptomatic volunteer who responded to an advertisement and enrolled in one of our trials. Three weeks later, we received a call from a colleague across town saying that Ms. B was already a subject in a trial at that site. This double enrollment was discovered when a pharmacy called the second site to verify a duplicate prescription for a controlled substance. Mr. A and Ms. B are two problematic volunteers whom we have identified in our own clinical trial program over the past year. We worry, however, that there may be similar subjects we are not aware of. In a fall 2009 article about the U.S. pharmaceutical industry moving clinical trials overseas, a Wyeth executive noted that “the trend toward placebo results and so-called failed trials is increasing in the United States. That means we are getting ‘fake’ patients, treatment-resistant patients, or patients who have been recycled from other studies”. Shiovitz et al. recently described similar cases of “professional subjects” and were told anonymously by trial sponsors that duplicate subjects in some protocols have been as high as 5%…

While it is always assumed that patients seen in clinical practice are seeking relief from suffering, the motives of the symptomatic volunteer are inherently more opaque. On the altruistic end of the spectrum, many may experience gratification from participating in biomedical research that contributes to our collective evidence base and will provide better treatments for future patients. Understandably, some volunteers desire free access to medical care or cash stipends. On the pernicious end of the spectrum, the “job” of an actively fraudulent volunteer is to have the correct diagnosis at study entry in order to collect a paycheck for answering questions and completing self-reports. No matter where on the spectrum these volunteers fall, these motivations and whatever underlying substrate propels them to pick up a telephone and respond to an advertisement may make them distinct from patients seen in clinical practice…

Considering my obsession with the Undurraga and Baldessarini article [Randomized, Placebo-Controlled Trials of Antidepressants for Acute Major Depression: Thirty-Year Meta-Analytic Review] [what was that all about?…, meta meta meta meta meta meta…], what could be more timely than this month’s commentary in the American Journal of Psychiatry about Clinical Trial volunteers? The article documents a few cases of professional patients, people enrolled in several trials at the same time – even using the term "fake patients." To use a metaphor I’ve used before, "For every roach you see, there are a hundred behind the walls." Of course these studies are filled with "fake patients." Being in Clinical Trials is no different that being a professional blood donor, just more lucrative [if you want to learn the ropes, just take a look at some of the videos on The Clinical Trials Guru run by  South Coast Clinical Trials. Where else could these subjects come from?

But before indicting the subjects for shopping around for Clinical Trials like it is a business, think about the fact that it is a business. The sponsoring drug company is in the business of getting their drug approved. The Clinical Research Center is in the business of enrolling subjects. The Clinical Research Organization is in the business of getting a successful Trial on the books for the FDA for approval. The Medical Writer is in the business of getting a publishable paper written. The guest author is in the business of padding a resume and pulling in some speaker fees. Why shouldn’t the subjects be in business too? It stands to reason. To expect mentally ill people to seek treatment by looking at newspaper ads and chance getting treated with a sugar pill or an ineffective drug is very unlikely scenario.
But it is a more pronounced problem for psychiatry, which lacks validated biomarkers and often relies on self-report for diagnosis confirmation.
It’s hard to avoid sarcasm here, the point being made is so obvious. But still, I appreciate these investigators writing this commentary, even though it is already obvious in the bizarre graphs that accompany the clinical trials, or the rising placebo responses so nicely documented in the article I’ve been reviewing recently. The solution would be a radical change in how we evaluate medications:
Perhaps the most effective way to address these problems is to increase the number of patients who self-present for treatment in clinical trials. Using fewer symptomatic volunteers would also mean using fewer for-profit research organizations, which do not treat patients and therefore rely heavily on advertisements for recruitment, and would institute a greater degree of responsible and transparent collaboration between industry and medical centers where real patients present for care.
Note the use of the term "real patients." If this is to remotely approximate science, it does seem like "real patients" ought to be the object of study instead of "fake patients" like Mr. A and Ms. B…
    December 23, 2011 | 11:19 AM

    Oh, my, that roach analogy really got to me!

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