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.
Interesting points raised, especially in context of cultural dynamics in pathology, and especially in pathogenesis.
Just want to add to the discussion the chronic hypocrisy re: which research is acceptable (or not) for US consumption. It’s notable that drug companies and others consider it legitimate to conduct research abroad when convenient (i.e., cheap), but it’s somehow acceptable that other bodies of research conducted abroad are considered less than legitimate until replicated in the US. Specifically, vast amounts of research (with good design and credible researchers) on complementary and alternative medicine are conducted in Europe and Asia, but the often-positive results of these studies are unwelcome to the AMA, the drug companies, and the insurance industry, so this substantial work is typically discounted through vague (and not so vague) charges that its legitimacy is questionable because it wasn’t undertaken in a lab in Bethesda.
Same old research dynamics: power and money = legitimacy, regardless of what the research actually says.
Wouldn’t it be nice to know a patient deeply, not just from a cultural perspective, but what it’s like to be a woman, a mother, divorced, with Schizophrenia, blind, talented… The list is endless. And not just applicable to psychiatry but all of medicine. But while you’re taking the time to read up and get to know, your patient suffers.
It’s easy to criticize research conducted on subjects from other cultures, but tell us a better way.
The “better way” is to do exactly what you say… get to know your patient in order to treat his/her suffering in the most effective (and safest) way possible. Quite the opposite of what is done in a typical clinical trial.
Just found your great site, from your comment on Carlat’s blog.
My twenty-something has some hard-to-treat symptoms, and I’ve been looking through clinical trials in the hopes of finding some nugget that will help him. This is my perspective on why clinical trials are being conducted overseas:
A trial will start with the participants being ratcheted up to the therapeutic dose of fluoxetine, lithium, or whatever and then, boom, half or a third of them will be switched to a placebo with no tapering of the active drug. The others might be put on a new drug that reacts badly with the first, etc.
I consider this patient abuse. Granted, this might have worked (ie been gotten away with) on the unsuspecting U.S./European public before the days of the Internet, but now? When we can read about Discontinuation Syndrome, lithium adverse drug reactions, etc.
If I”ve learned anything from this reading, it’s “don’t ever participate in a drug trial.” And since the drug trials are so short all those poor people will have to deal with the consequences of the rapid drug switches, long after the pharma people have packed up and gone home.
As a Psychiatrist who practiced in completely different cultures ( we’re talking about different continents,languages etc ) I can promise you that most of the difference lies in the expression of the symptoms rather than a difference in the symptoms themselves;
I have to agree with Moviedoc here: what is the better way? and when do you decide that you actually ‘know’ your patient well enough to treat them?
As someone who has only practiced in the US (albeit in some very different populations), I appreciate your cross-cultural perspective.
But “expression of the symptoms” vs “the symptoms themselves” is a tough distinction. It implies that the “symptoms themselves” are bona fide neural and/or psychological phenomena that simply manifest differently in different cultures, and I don’t really know that that’s the case. (Moreover, if “expression of the symptoms” differs from culture to culture, then wouldn’t that strengthen the argument against doing clinical trials overseas, since the way we recruit people is to include them according to their symptoms?)
Personally, I happen to agree that certain disorders (but not all) must have a fundamental neurobiological makeup which is independent of the society in which a person lives. Sort of like a Chomskian “universal grammar” or a Jungian archetype (OK, Dr Aanavi, feel free to weigh in on that gross oversimplification!). But our diagnostic tools are not sensitive enough to detect them, nor are they specific enough to eliminate false positives. In fact, I think pharmaceutical companies have capitalized on the fact that false positives abound, and can even find ways to create them overseas, as is well argued in Crazy Like Us.
Since you invited me to weigh in… 🙂
Perhaps there is something archetypal or universal in certain disorders–Jung described the archetypal realm as having two polarities in its manifestation: the spiritual (psychological, symbolic, etc.) and the somatic, so it makes sense that from that perspective threads of both poles would be evident. But in addition to cultural and social variation on the manifestation of a disorder, there’s some key discussion necessary re: cultural variability in what’s considered pathological, in what is permissible to express. Also, the chronological/historical context is an important variable–Gadamer’s idea of the “clearing” is a good example of this vis-a-vis the ways in which disorders seem to emerge at particular times (as well as places, cultures, etc.), as well as the work of Philip Cushman (Constructing the Self, Constructing America).
My two cents. And thanks, as always, for a great blog and challenging discussion.
I’m not answering the question posed to Dr. Belcaldi (as he or she may mean something entirely different) but our family has had some problems expressing/describing my son’s symptoms/side effects to his psychiatrist.
Once there was a big to-do because we had been using the term *muscle spasm* instead of *muscle cramp*, or it may have been the other way around. We thought those were the same thing but the doctor said there was a difference and he changed meds because of the difference. WTF.
Even when you speak the same language, some times there are problems with the translation.
Steve, you’re excellent. Wish you were my doctor.