Negative Drug Studies are Hidden, Thousands Die

September 26th, 2012
in Op Ed

“The Drugs Don’t Work”: How the Medical-Industrial Complex Systematically Suppresses Negative Studies

by Yves Smith, Naked Capitalism

We’ve written a lot about the scientism of mainstream economics, both at pill-bottleSMALLNaked Capitalism and in ECONNED, and how these trappings have let the discipline continue to have a special seat at the policy table despite ample evidence of its failure. As bad as this is, it pales in comparison to the overt corruption of science at work in the drug arena. Although this issue comes to light from time to time, often in the context of litigation, the lay public is largely ignorant of how systematic and pervasive the efforts are to undermine good research practice in order to foist more, expensive, and sometimes dangerous drugs onto patients.

Follow up:

Ben Goldacre, a British doctor and science writer, provides a short overview of one of the worst scams practiced by Big Pharma: that of suppressing negative research, in a new piece at the Guardian (hat tip John L). This is the overview:

Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques that are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer. 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 government. This distorted evidence is then communicated and applied in a distorted fashion.

In their 40 years of practice after leaving medical school, doctors hear about what works ad hoc, from sales reps, colleagues and journals. But those colleagues can be in the pay of drug companies – often undisclosed – and the journals are, too. And so are the patient groups. And finally, academic papers, which everyone thinks of as objective, are often covertly planned and written by people who work directly for the companies, without disclosure. Sometimes whole academic journals are owned outright by one drug company. Aside from all this, for several of the most important and enduring problems in medicine, we have no idea what the best treatment is, because it’s not in anyone’s financial interest to conduct any trials at all.

And the consequences are devastating. Data scientist Cathy O’Neil earlier discussed one case, that of Vioxx:

Yesterday I caught a lecture at Columbia given by statistics professor David Madigan, who explained to us the story of Vioxx and Merck. It’s fascinating and I was lucky to get permission to retell it here…

Yet Madigan’s own data strongly suggests that Merck was well aware of the fatalities resulting from Vioxx, a blockbuster drug that earned them $2.4b in 2003, the year before it “voluntarily” pulled it from the market in September 2004. What you will read below shows that the company set up standard data protection and analysis plans which they later either revoked or didn’t follow through with, they gave the FDA misleading statistics to trick them into thinking the drug was safe, and set up a biased filter on an Alzheimer’s patient study to make the results look better. They hoodwinked the FDA and the New England Journal of Medicine and took advantage of the public trust which ultimately caused the deaths of thousands of people.

And “deaths of thousands of people” is no exaggeration. When Vioxx was taken off the market, the US death rate fell and experts attributed it to the Vioxx withdrawal.

Goldacre explains that the sort of abuse that occurred with Vioxx isn’t an anomaly. One of the biggest ways pharmaceutical companies deceive doctors (even the ones like Goldacre who have the skills and take the time to read medical research) is by presenting them only with cherry picked studies, those that show good efficacy and low/no adverse side effects. Perversely, regulators don’t insist that they receive the results of all clinical trials on a particular drug and make the results public. This deliberately misleading disclosure is even more troubling as some economists keep maintaining that patients need to become more informed medical consumers and decide which treatments to buy and not buy. Ahem, major drug companies already spend more on marketing than on reasearch and doctors themselves, including vigilant ones like Goldacre, are snookered. How is the dumb chump public supposed to make sense of all this if medical professionals can’t?

Goldacre stresses the active suppression of negative research and mentions in passing a second flaw: limited duration of safety and efficacy studies. Typically clinical trials are at most four months in duration. That is not sufficient to see if they work over the long term and similarly, have long term side effects. Both have proven to be major issues with psychoactive drugs. Many appear to provide short-term changes, but the brain’s chemistry often adjusts to counter the operation of the drug, leaving the patient more or less back to where he started from. That often leads doctor to prescribe even more drugs. Similarly, important side effects are often missed in the original clinical trails. The now well known libido-suppressing effects of SSRIs (selective seratonin uptake inhibitors, the most widely prescribed type of anti depressant) weren’t captured in the initial clinical trials, first because it took a little while for patients to recognize what was happening, and then they were embarrassed to discuss it with their doctors. More generally, while the FDA (and I assume other national drug regulators) have a regime for tracking longer-term effects, it is not well enforced.

The entire Goldacre piece is a must read, and here are the some important parts:

In 2010, researchers from Harvard and Toronto found all the trials looking at five major classes of drug – antidepressants, ulcer drugs and so on – then measured two key features: were they positive, and were they funded by industry? They found more than 500 trials in total: 85% of the industry-funded studies were positive, but only 50% of the government-funded trials were. In 2007, researchers looked at every published trial that set out to explore the benefits of a statin. These cholesterol-lowering drugs reduce your risk of having a heart attack and are prescribed in very large quantities. This study found 192 trials in total, either comparing one statin against another, or comparing a statin against a different kind of treatment. They found that industry-funded trials were 20 times more likely to give results favouring the test drug.

He then discusses that broader studies (ones that were not drug specific) had similar findings. He continues(emphasis mine):

It turns out that this pattern persists even when you move away from published academic papers and look instead at trial reports from academic conferences….

How does this happen? How do industry-sponsored trials almost always manage to get a positive result? Sometimes trials are flawed by design. You can compare your new drug with something you know to be rubbish – an existing drug at an inadequate dose, perhaps, or a placebo sugar pill that does almost nothing. You can choose your patients very carefully, so they are more likely to get better on your treatment. You can peek at the results halfway through, and stop your trial early if they look good. But after all these methodological quirks comes one very simple insult to the integrity of the data. Sometimes, drug companies conduct lots of trials, and when they see that the results are unflattering, they simply fail to publish them.

Because researchers are free to bury any result they please, patients are exposed to harm on a staggering scale throughout the whole of medicine. Doctors can have no idea about the true effects of the treatments they give. Does this drug really work best, or have I simply been deprived of half the data? No one can tell. Is this expensive drug worth the money, or has the data simply been massaged? No one can tell. Will this drug kill patients? Is there any evidence that it’s dangerous? No one can tell. This is a bizarre situation to arise in medicine, a discipline in which everything is supposed to be based on evidence.

And this data is withheld from everyone in medicine, from top to bottom. Nice, for example, is the National Institute for Health and Clinical Excellence, created by the British government to conduct careful, unbiased summaries of all the evidence on new treatments. It is unable either to identify or to access data on a drug’s effectiveness that’s been withheld by researchers or companies: Nice has no more legal right to that data than you or I do, even though it is making decisions about effectiveness, and cost-effectiveness, on behalf of the NHS, for millions of people.

In any sensible world, when researchers are conducting trials on a new tablet for a drug company, for example, we’d expect universal contracts, making it clear that all researchers are obliged to publish their results, and that industry sponsors – which have a huge interest in positive results – must have no control over the data. But, despite everything we know about industry-funded research being systematically biased, this does not happen. In fact, the opposite is true: it is entirely normal for researchers and academics conducting industry-funded trials to sign contracts subjecting them to gagging clauses that forbid them to publish, discuss or analyse data from their trials without the permission of the funder.

This is such a secretive and shameful situation that even trying to document it in public can be a fraught business. In 2006, a paper was published in the Journal of the American Medical Association (Jama), one of the biggest medical journals in the world, describing how common it was for researchers doing industry-funded trials to have these kinds of constraints placed on their right to publish the results. The study was conducted by the Nordic Cochrane Centre and it looked at all the trials given approval to go ahead in Copenhagen and Frederiksberg. (If you’re wondering why these two cities were chosen, it was simply a matter of practicality: the researchers applied elsewhere without success, and were specifically refused access to data in the UK.) These trials were overwhelmingly sponsored by the pharmaceutical industry (98%) and the rules governing the management of the results tell a story that walks the now familiar line between frightening and absurd.

For 16 of the 44 trials, the sponsoring company got to see the data as it accumulated, and in a further 16 it had the right to stop the trial at any time, for any reason. This means that a company can see if a trial is going against it, and can interfere as it progresses, distorting the results. Even if the study was allowed to finish, the data could still be suppressed: there were constraints on publication rights in 40 of the 44 trials, and in half of them the contracts specifically stated that the sponsor either owned the data outright (what about the patients, you might say?), or needed to approve the final publication, or both. None of these restrictions was mentioned in any of the published papers.

When the paper describing this situation was published in Jama, Lif, the Danish pharmaceutical industry association, responded by announcing, in the Journal of the Danish Medical Association, that it was “both shaken and enraged about the criticism, that could not be recognised”. It demanded an investigation of the scientists, though it failed to say by whom or of what. Lif then wrote to the Danish Committee on Scientific Dishonesty, accusing the Cochrane researchers of scientific misconduct. We can’t see the letter, but the researchers say the allegations were extremely serious – they were accused of deliberately distorting the data – but vague, and without documents or evidence to back them up.

Nonetheless, the investigation went on for a year. Peter Gøtzsche, director of the Cochrane Centre, told the British Medical Journal that only Lif’s third letter, 10 months into this process, made specific allegations that could be investigated by the committee. Two months after that, the charges were dismissed. The Cochrane researchers had done nothing wrong. But before they were cleared, Lif copied the letters alleging scientific dishonesty to the hospital where four of them worked, and to the management organisation running that hospital, and sent similar letters to the Danish medical association, the ministry of health, the ministry of science and so on. Gøtzsche and his colleagues felt “intimidated and harassed” by Lif’s behaviour. Lif continued to insist that the researchers were guilty of misconduct even after the investigation was completed.

So get this: doctors that revealed not the content of any of the work they did, but some of the key features of the research contracts, were harassed, with the clear intent of getting them fired and damaging their reputations.

Goldacre also has a long discussion of “off label” uses of drugs, and GlaxoSmithKline presented studies that showed paroxetine, an anti-depressant, was effective in children, even though if you included the studies they hid, you would have to conclude that its efficacy was not proven. And because this was an off label use, GSK didn’t have to report about the side effects, namely, increased risk of suicide. Goldacre writes:

How is it possible that our systems for getting data from companies are so poor, they can simply withhold vitally important information showing that a drug is not only ineffective, but actively dangerous? Because the regulations contain ridiculous loopholes, and it’s dismal to see how GSK cheerfully exploited them: when the investigation was published in 2008, it concluded that what the company had done – withholding important data about safety and effectiveness that doctors and patients clearly needed to see – was plainly unethical, and put children around the world at risk; but our laws are so weak that GSK could not be charged with any crime.

Again, please read the entire article and circulate it widely. The way to start to attack this is to demand more transparency, say by requiring any drug company that gets NIH funding to make all its drug research contracts and studies public. A credible threat is the only way to force this miscreant industry to begin to behave responsibly.

Related Articles

Analysis and Opinion articles by Yves Smith

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