Jan 08 2011

Big Pharma rushes to catch up with off-labeling enthusiasm and re-invigorated placebos

There remains simple experience; which, if taken as it comes, is called accident, if sought for, experiment. – Francis Bacon

The phenomenon of an inert substance resulting in a patient’s medical improvement is called the placebo effect. The classic use of placebos in medicine—to boost the confidence of anxious patients—has been employed tacitly for ages. Nearly half of the doctors polled in a 2007 survey in Chicago admitted to prescribing medications they knew were ineffective for a patient’s condition—or prescribing effective drugs in doses too low to produce actual benefit—in order to provoke a placebo response.

There's gold in them there pills.

Placebos are widely used in medical research and medicine and the placebo effect is a pervasive phenomenon; in fact, it is part of the response to any active medical intervention. The placebo effect makes it more difficult to evaluate new treatments. Apparent benefits of a new treatment (usually a drug but not necessarily so) may not derive from the treatment but from the placebo effect. Oftentimes poor experimental design can result in placebos influencing research results. A report in the Annals of Internal Medicine that looked at details from 150 clinical trials, found that certain placebos used in the trials affected the results. For example, one study on cholesterol-lowering drugs used olive oil and corn oil in the placebo pills which in themselves have been studies for their effect on cholesterol levels. Indeed a convenient way to demonstrate a lack of efficacy (if that is the research agenda) is to simply select a substance for a placebo that doesn’t in reality behave like one.

Now, an article in Wired magazine caused quite a stir when it reported that the effects of a placebo were not terribly distinct from those of many well-regarded anti-depressants. Recent new techniques in data-mining reveal that even superbly managed trials were subject to runaway placebo effects. Part of the problem was that response to placebo was considered a psychological trait related to neurosis and gullibility rather than a physiological phenomenon that could be scrutinized in the lab and manipulated for therapeutic benefit.

Even a pill’s shape, size, branding, and price all influence its effects on the body. Soothing blue capsules make more effective tranquilizers than angry red ones. Ironically, Big Pharma’s attempt to dominate the central nervous system has ended up revealing how powerful the brain really is.

“To remain dominant in the future we need to dominate the central nervous system.” — Edward Scolnick, Research Director, Merck Pharmaceuticals

Replication of results is a standard procedure in the validation of any scientific discovery. An experiment or test can be carried out using the scientific method to answer a question or investigate a problem.

A second article in the New Yorker paints an even more disturbing picture that in fact something strange is happening: At a 2007 Brussels conference on anti-psychotic medicines neuroscientists, psychiatrists, and drug-company executives heard some startling news. It had to do with a class of drugs known as atypical or second-generation antipsychotics, which came on the market in the early nineties and which are exceedingly profitable.

If replication is what separates science from pseudoscience, where do we put all these rigorously validated findings that can no longer be proved? Which results should we believe?

Although initially touted as having few side effects, followup studies have found that atypical antipsychotics have serious side effects, including significant weight gain that can lead to diabetes and heart disease. An estimated $6 billion was spent in 2008 on off-label use of antipsychotic medication nationwide, of which $5.4 billion was for uses with uncertain evidence. These new drugs accounted for more than $10 billion in retail pharmacy U.S. prescription drug costs in 2008, representing the largest expenditure for any single drug class — nearly 5 percent of all drug spending, surpassing even blockbusters like statin cholesterol medications.

Most people think, ‘If my doctor prescribed this, the FDA must have evaluated whether this drug was safe and effective for this use.’ That’s not true. — Randall Stafford, M.D., Ph.D.

The U.S. government’s original stamp of approval for the new drugs was for treating schizophrenia, but they’re used more today for other conditions, including other psychoses, autism, bipolar disorder, delirium, dementia, depression and personality disorders. And while some of these uses have recently been approved by the U.S. Food and Drug Administration (FDA), many have not. For example, the FDA has approved quetiapine (Seroquel), the antipsychotic with the biggest U.S. sales, for treating schizophrenia and some aspects of bipolar disorder and depression. But the drug is also often used for the treatment of other mental health concerns, such as anxiety and dementia. This kind of use that hasn’t been specifically approved by the FDA is called “off label” prescribing, because a doctor is prescribing the drug for an indication not on the drug’s label. According to a 2004 study, a quarter of all residents of U.S. nursing homes had taken them. In 2008 the U.S. subsidiary of a Japanese pharmaceutical company has agreed to pay more than $4 million to settle charges that it illegally marketed an anti-psychotic drug, according to Forbes Online. Otsuka Pharmaceutical Co. Ltd.’s U.S. unit allegedly promoted its drug Abilify for pediatric use and to treat dementia-related psychosis among the elderly from 2002 to 2005, even though the Food and Drug Administration hadn’t approved the drug for such uses.

It appeared that the therapeutic power of the drugs appeared to be steadily waning. A recent study showed an effect that was less than half of that documented in the first trials, in the early nineteen-nineties. Many researchers began to argue that the expensive pharmaceuticals weren’t any better than first-generation inexpensive antipsychotics, which have been in use since the fifties, and in fact sometimes look even worse. Among the drugs are quetiapine, aripoprazole (Abilify), olanzapine (Zyprexa) and risperidone (Risperdal), each with annual U.S. sales exceeding $1 billion. [link]

For many scientists, the effect is especially troubling because of what it exposes about the scientific process. If replication is what separates science from pseudoscience, where do we put all these rigorously validated findings that can no longer be proved? Which results should we believe? Francis Bacon, the early-modern philosopher and pioneer of the scientific method, once declared that experiments were essential, because they allowed us to “put nature to the question.” But it appears that nature often gives us different answers.

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