Clinical trials that use patients that don't resemble our target patients are not just unreal, but deceptive and potentially dangerous.
The following originally appeared on the HCPlive Network blog Thought Broadcast.
A recent Vanity Fair article described the trend by American pharmaceutical companies to conduct more clinical trials outside of the United States and Western Europe. The writer and bioethicist Carl Elliott also detailed this trend in his book White Coat, Black Hat, and it has recently received increasing scrutiny in the media. While much attention has focused on the ethical concerns of overseas clinical trials, I’m avoiding that hot topic for now and arguing that we should pay some attention to questions of clinical relevance.
This is no small matter. The VF article reports that one-third of clinical trials by the 20 largest US-based pharmaceutical companies are conducted exclusively at foreign sites, and medications destined for use in the U.S. have been tested in almost 60,000 clinical trials in 173 countries since 2000. The reasons for “outsourcing” clinical trials are not surprising: cheaper costs, less restrictive regulations, more accessible subjects, and patients who are less likely to have taken other medications in the past, thus yielding a more “pure” population and, hopefully, more useful data.
At first glance, overseas clinical trials really shouldn’t be much of a problem. The underlying biology of a disease should have nothing to do with where the diseased person lives. Hypertension and hepatitis are probably quite similar, if not identical, whether the patient is in Boston or Bangalore. An article in this month’s Archives of General Psychiatry appears to reinforce this concept, showing that rates of bipolar disorder—as well as its “severity” and “impact”—are similar in a variety of different international settings. Hence, if you were to ask me where I’d do a clinical trial for a new bipolar medication, I’d probably go where it would cost less to do so (i.e., overseas), too.
But is this appropriate? Just because we can find “bipolar disorder” in the U.S. and in Uganda, does this mean we should we treat it the same way? Over at the blog 1boringoldman, Mickey has uncovered data showing that trials of Seroquel (an atypical antipsychotic) for bipolar depression are being conducted in 11 Chinese provinces. You can search the data yourself at clinicaltrials.gov (a truly fantastic tool, BTW) and find that many other psychiatric drugs are being tested worldwide, for a wide range of indications.
To a lowly community psychiatrist like me, this raises a few red flags. As I learned in my transcultural psychiatry lectures in med school and residency, the manifestations of disease—and the recommended treatment approaches—can vary dramatically based on the culture in which the disease appears. Even in my own practice, “bipolar disorder” varies greatly from person to person: a bipolar patient from a wealthy San Francisco suburb experiences her disease very differently from the patient from the poverty-stricken neighborhoods of East Oakland. A good psychiatrist must respect these differences. Or so I was taught.
In his book Crazy Like Us, author Ethan Watters gives numerous examples of this phenomenon on a much larger scale. He argues that the cultural dimensions that frame a disease have a profound impact on how a patient experiences and interprets his or her symptoms. He also describes how patients’ expectations of treatments (drugs, “talk” therapy) differ from culture to culture, and can determine the success or failure of a treatment.
Let’s say you asked me to treat Jiefang, a young peasant woman with bipolar disorder from Guangdong Province. Before doing so, I would want to read up on her community’s attitudes towards mental illness (and try to understand what “bipolar disorder” itself means in her community, if anything), learn about the belief systems in place regarding her signs and symptoms, and understand her goals for treatment. Before prescribing Seroquel (or any other drug, for that matter), I’d like to know how she feels about using a chemical substance which might affect her feelings, emotions, and behavior. I imagine it would take me a while before Jiefang and I felt comfortable proceeding with this approach.
There’s just something fishy about scientists from a multinational Contract Research Organization hired by Astra-Zeneca, flying into Guangdong with their white coats and clipboards, recruiting a bunch of folks with (western-defined) bipolar disorder just like Jiefang, giving them various doses of Seroquel, measuring their responses to bipolar rating scales (developed by westerners, of course), and submitting those data for FDA approval.
I sure hope I’m oversimplifying things. Then again, maybe not. When the next me-too drug is “FDA approved” for schizophrenia or bipolar depression (or, gasp, fibromyalgia), how can I be sure that it was tested on patients like the ones in my practice? Or even tested at all on patients who know what those diagnoses even mean? There’s no way to tell anymore.
The “pathoplastic” features of disease—what Watters calls the “coloring and content”—make psychiatry fascinating. But they’re often more than just details; they include the ways in which patients are influenced by public beliefs and cultural ideas, the forces to which they attribute their symptoms, and the faith (or lack thereof) they put into medications. These factors must be considered in any attempt to define and treat mental illness.
Clinical trials have never resembled the “real world.” But designing clinical trials that resemble our target patients even less—simply for the sake of bringing a drug to market quickly and more cheaply—is not just unreal, but deceptive and potentially dangerous.