Monday, June 24, 2013

Bad Pharma: Suppressing Drug Data Is Most Dangerous of Bad Practices

Ben Goldacre is a British physician who has provided the general reader a detailed and often passionate look into practices that have become common throughout the medical field in his book Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients. While British himself, his data, examples, and claims apply to people of all countries.

Goldacre begins with this statement:

"Medicine is broken. And I genuinely believe that if patients and the public fully understand what has been done to them—what doctors, academics and regulators have permitted—they will be angry."

He then provides this explanation:

"We like to imagine that medicine is based on evidence and the results of fair tests. In reality, those tests are often profoundly flawed. We like to imagine that doctors are familiar with the research literature, when in reality much of it is hidden from them by drug companies. We like to imagine that doctors are well-educated, when in reality much of their education is funded by industry. We like to imagine that regulators let only effective drugs onto the market, when in reality they approve hopeless drugs with data on side effects casually withheld from doctors and patients."

Developing drugs for medicinal use is expensive and time-consuming. In an ideal world an independent agency would be involved in testing and validating the effectiveness of a given drug and comparing it against similar drugs to determine which is most effective. We do not live in such a world.

Most testing is performed by the drug companies themselves. There is a lot of money involved in getting a drug into the marketplace, and there is a lot of competition from other drug makers. Without effective regulation of such systems, ethics tend to fall to the lowest feasible level.

"Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analyzed using techniques which are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favor the manufacturer."

Biases in favor of a positive result for the drug under investigation are well-documented and can result from intentionally fraudulent practices as well as from mere irrational enthusiasm on the part of researchers and the medical community as a whole. Early testing of a new drug tends to be dominated by the manufacturer. Subsequent testing by independent agencies often obtains different results, but by then it is too late to matter much. For more on this topic see Medical Science and the Vanishing Truth.

When peoples’ lives are at stake one should be able to expect strong and effective regulators to be involved. Unfortunately, that is not the case.

"When trials throw up results that companies don’t like, they are perfectly entitled to hide them from doctors and patients, so we only ever see a distorted picture of any drug’s true effects. Regulators see most of the trial data, but only from early on in a drug’s life, and even then they don’t give this data to doctors or patients, or even to other parts of the government. This distorted evidence is then communicated and applied in a distorted fashion."

Incredibly, regulators allow embarrassing data to be buried from view as "valuable proprietary information." Drug regulators are subject to the same perverse incentives as regulators of the financial industry. They are subject to varying political winds. At one time they are being told that their main job is to protect the public; at another time they are told that their focus should be on facilitating the drug companies business by making the introduction of new drugs easier. Regulators are also subjected to the same lobbying practices as all other government actors. Goldacre believes bureaucratic turf protection is also an important factor in suppressing the dissemination of data to others who would have a stake in the analysis. And last, but not least, the easiest way for a regulator to make a lot of money is to quit regulating and take a remunerative position with a company being regulated. That being the case, it makes no sense to anger a potential future employer.

More on the issue of regulation specific to the FDA can be found in How the FDA Fails to Protect Us.

Medicines are dispensed by doctors. Patients like to believe that their physician is a source of reliable information.

"Doctors spend forty years practicing medicine, with very little formal education after their initial training. Medicine changes completely in four decades, and as they try to keep up, doctors are bombarded with information: from ads that misrepresent the benefits and risks of new medicines; from sales reps who spy on patients’ confidential prescribing records; from colleagues who are quietly paid by drug companies; from ‘teaching’ that is sponsored by industry; from independent ‘academic’ journal articles that are quietly written by drug company employees; and worse."

The drug companies spend astounding amounts of money on marketing. If the prescription of medications is based on knowledge of drug performance, then why would marketing be appropriate? Goldacre provides an appropriate perspective: the purpose of marketing is to confuse doctors and to avoid evidence-based decisions on the part of doctors.

"....we will see that pharmaceutical companies spend tens of billions of pounds every year trying to change the treatment decisions of doctors: in fact, they spend twice as much on marketing and advertising as they do on the research and development of new drugs. Since we all want doctors to prescribe medicine based on evidence, and evidence is universal, there is only one possible reason for such huge spends: to distort evidence-based practice...."

The regulators facilitate the marketers by not demanding that drug companies determine that their product is not only better than nothing, the current low bar for entry into the marketplace, but that it is also better than existing products. This facilitates the proliferation of similar drugs into the marketplace. The competition then is based not on relative effectiveness (unknown) but on advertising campaigns.

"....for several of the most important and enduring problems in medicine, we have no idea what the best treatment is, because it is not in anyone’s financial interest to conduct any trials at all."

Perhaps Goldacre’s biggest concern is the lack of comparative data. If a doctor has twenty drugs to choose from, how is she to make a valid choice? Clearly some will provide better long-term outcomes for patients than others. Knowledge of relative efficacy would produce one or two winners; lack of knowledge produces twenty winners. By not selecting the best performing drugs, doctors put the health of their patients in unnecessary risk.

Goldacre provides plenty of data and examples to illustrate this sorry state of affairs. He includes lengthy discussions of the sleazy and unethical (by normal standards—or even by political standards) activities of highly regarded members of the medical profession. He also details the criminal marketing activities for which numerous drug companies have admitted guilt. He views these as outrages that can and will be addressed as the public becomes more familiar with the harm that is being done to them.

"Bad behavior in marketing departments is unpleasant, but it’s the one thing that has already received public condemnation, because the issues are tangible, with covert payments, misleading messages, and practices that are obviously dishonest, even to the untrained eye. But for all that they may be disappointing, these distortions can be overcome by any good doctor."

Goldacre is most worried about the practice of suppressing the dissemination of data because it is deemed a business threat, an embarrassment, or just plain uninteresting. He provides an example from his own practice where he was misled by a company that withheld critical data. Goldacre reviewed the published data on an antidepressant, reboxetine, and that convinced him that it would be appropriate for a particular patient. He thought he had done everything a good doctor should do. Subsequently, he learned the following:

"Seven trials had been conducted comparing reboxetine against placebo. Only one, conducted in 254 patients, had a neat, positive result, and that one was published in an academic journal, for doctors and researchers to read. But six more trials were conducted, in almost ten times as many patients. All of them showed that reboxetine was no better than a dummy sugar pill. None of these trials was published. I had no idea they existed."

"It got worse. The trials comparing reboxetine against other drugs showed exactly the same picture: three small studies, 507 patients in total, showed that reboxetine was just as good as any other drug. They were all published. But 1,657 patients’ worth of data was left unpublished, and this unpublished data showed that patients on reboxetine did worse than those on other drugs. If all this wasn’t bad enough, there was also the side-effects data. The drug looked fine in the trials which appeared in the academic literature: but when we saw the unpublished studies, it turned out that patients were more likely to have side effects, more likely to drop out of taking the drug, and more likely to withdraw from the trial because of side effects if they were taking reboxetine rather than one of its competitors."

Nothing done by the drug manufacturer (Pfizer) was illegal.

"Because nobody broke any law in that situation, reboxetine is still on the market, and the system that allowed all this to happen is still in play, for all drugs, in all countries in the world."

As an aside, reboxetine was approved for distribution in Europe where, apparently, one good trial can negate any number of bad ones. It was not approved for use in the US, apparently because the FDA demands two positive trials to negate any number of bad ones. One assumes that Pfizer, try as they might, just couldn’t get a second positive trial.

We will conclude with Goldacre’s thought on "missing data."

"Missing data is different, because it poisons the well for everybody. If proper trials are never done, if trials with negative results are withheld, then we simply cannot know the true effects of the treatments we use. Nobody can work around this, and there is no expert doctor with special access to a secret stash of evidence. With missing data, we are all in it together, and we are all misled....evidence in medicine is not an abstract academic preoccupation. Evidence is used to make real-world decisions, and when we are fed bad data, we make the wrong decision, inflicting unnecessary pain and suffering, and death, on people just like us."

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