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Sunday, November 25, 2012

GSK's Misleading Avandia Study As Symptom of Bigger Problems of For-Profit Pharmaceutical Industry

The WashingtonPost today has an excellent article ("As drug industry’s influence over research grows, so does the potential for bias") on the basic problem of Pharma-funded research, which echoes some of what Dan Ariely says in "The Honest Truth About Dishonesty" (although my earlier posts on that book might have seemed critical, I am going to get through it, and it is a worthwhile read in many respects) about how it is very difficult for researchers with a financial stake in an outcome to do impartial research.

The article describes the fate of Glaxo-SmitkKline's Avandia, an anti-diabetes drug that was the clear victor in comparative trials described in a 17-page New England Journal of Medicine article in 2006.  Problem was, all eleven authors of the article received funding from GSK, and they all missed the fact that taking Avandia correlates to an increased risk of heart attack.  Because of that side effect, Avandia is now off the market.

[Aside -- This is one more example of how the modern Republican "free-market-uber-alles" mentality simply won't do.  The "free market" means that "capitalists" can purchase literally whatever they want -- including positive reviews of their drug products by respected scientists in a respected medical journal.  And although theoretically the fact that they might be liable for the harm caused if the "research" turns out to be wrong (or to miss something), that theoretical possibility counts very little against the immediate profits that can be realized by going forward with promoting and selling a blockbuster drug].

Here's an important quote from the article:

"The billions that the drug companies invest in such experiments help fund the world’s quest for cures. But their aim is not just public health. That money is also part of a high-risk quest for profits, and over the past decade corporate interference has repeatedly muddled the nation’s drug science, sometimes with potentially lethal consequences."

The article also notes:

"Years ago, the government funded a larger share of such experiments. But since about the mid-1980s, research funding by pharmaceutical firms has exceeded what the National Institutes of Health spends. Last year, the industry spent $39 billion on research in the United States while NIH spent $31 billion."

I'm quoting that because it's a shame that the article doesn't give exact statistics.  It's pretty weak to just say the government funded "a larger share" "years ago."  Based on the succeeding sentence, I assume it means that the government used to fund more research than Pharma, but there is a lot of data missing.

What saddens me is that this sort of "point" was not made in any significant way during the debate about Obamacare.  Instead, the legislation passed in part because the pharmaceutical companies were assured that they would be able to continue to do business as usual.   In fact, the more people get access to healthcare, the more Pharma will profit.

The last part of the Washington Post article is actually kind of sickening.

Apparently, GSK knew that Avandia caused increased levels of bad cholesterol and coronary blockage and yet suppressed that information.  The trial that was reported in the article -- ADOPT -- was done in response to a request by the FDA that GSK study potential heart problems with Avandia.  And yet the authors of the study (who, as above, already were financially-biased to begin with) were not told that this was an aim of the study (actually, the non-GSK authors and GSK disagree on this factual point), and were not told of about the information that GSK itself was actively suppressing on the subject.  The result was that ADOPT wasn't designed to detect cardiac issues; it was just a comparison between the benefits of Avandia and those of two older anti-diabetes drugs.

But on a close examination conducted by Steven E. Nissen, a Cleveland Clinic cardiologist, the data from ADOPT did show an apparent increase in cardiac risk, which was missed by the study's authors as well as the peer reviewers.  Nissen had seen potentially troubling results in an earlier study (called DREAM), but the sample size was too small to say anything definitive.  When he saw the same trends (increased cardiac events as well as increased levels of bad cholesterol) in the ADOPT study, he asked GSK for data from other studies relating to Avandia, and GSK refused.  Luckily much of that data was publicly available as a result of an investigation by Eliot Spitzer.

[Aside: As to GSK's refusal to release its data to Nissen, in principle, I could agree that the data is "proprietary" -- GSK paid for it, so it should be able to control it.  But that's just one more problem with having all the pharmaceutical research "privately funded."  If all the research were publicly funded, then the data would be free for everyone to look at, and everyone could study it and make independent evaluations of the risk.  And in effect, the data IS publicly funded, because it's bought and paid for by the patent system -- i.e. by the fact that we pay dollars for drugs that cost drug companies pennies to make.  Pharma keeps reminding us that the reason patented drugs costs so much is that they have to do all the expensive research.  That argument in effect concedes that the public is "paying" for the research.  The result should be that the public owns it.]

Nissen published his results in the New England Journal of Medicine. As part of the peer review process, Professor Stephen Haffner, a "Glaxo ally," received a confidential copy.  In an apparent breach of confidentiality, Haffner promptly faxed a copy to GSK, which then prepared a full-bore rebuttal, including a prematurely-released counter-study (called RECORD) designed to muddy the waters.  GSK's rebuttal did not withstand scrutiny, and Nissen was ultimately vindicated as more data came in.

And of course, despite its rebuttal, GSK knew all along that Nissen was on the right track.  From the article:

"More than 40 company executives would learn of [Nissen's article's] contents [as a result of Haffner's breach]. They prepared a meticulous response to its publication that suggested that Nissen’s results were plain wrong.

“'GSK strongly disagrees with the conclusions reached in the NEJM article, which are based on incomplete evidence and a methodology that the author admits has significant limitations,' the news release said.

"But internally, scientists and statisticians at Glaxo largely agreed with Nissen’s calculations, the company e-mails released by the Senate show.

"'To a great extent the numbers are the numbers, the Cleveland analysis is very similar to our own,' one of them reported via e-mail."

There are a rash of points beyond just the skewed-for-profit-research to be made for nationalizing the pharmaceutical industry.  I'll list them here briefly but will flesh them out (and more) in a subsequent post:

1.  The fact that drugs cost pennies to make, but millions if not billions to research.   The assumption is that the patent system is the only way to ensure that the research will be done.  But the patent system is very anti-free market -- it results in lengthy monopolies and suppression of competition legally for the term of the patent, and leads to all kinds of questionable practices designed to perpetuate the patent monopoly:

a.  Evergreening of patents

b.  Reverse settlements with generics in Hatch-Waxman litigation

c.  Special legislation to extend the life of lucrative patents

2.  Use of attractive Pharma Reps and other enticements to influence doctors to peddle specific drugs.

3.  Use of misleading (but "free speech") advertising to influence consumers.

4.  Steering consumers and doctors to patented drugs as opposed to off-patent versions.

5.  Inefficient and and suboptimal use of research dollars -- while competition is generally good, our pool of "research dollars" -- i.e. the premium the healthcare consumers and taxpayers (think Medicare and Medicaid) pay for research -- is very inefficiently spent, since it it divided among a number of pharmaceutical companies that are sometimes pursuing the same goals (and could thus benefit from knowledge of each others' research) and which are also pursuing the goals that are likely to be the most lucrative for them, as opposed to those that are in the best interests of public health.

And yes, nationalizing the pharmaceutical industry would not be easy, and it is difficult to predict that it will even achieve the best results.  After all, government is notoriously bad at running things.  The whole idea behind the patent system (and ancillary provisions like the Bayh-Dole Act) is that the government is not going to be good at getting needed innovations out to the public.

But I have to think that it can be done.  This is not about producing widgets, it's about saving lives.  A nationalized pharmaceutical industry might well attract the very people we want -- dedicated researchers whose life goals are to fight diseases and ease the suffering of mankind, and who have the tools and talents to make real progress on those fronts.  Right now, those people (the ones that don't work at the NIH) are working in the pharmaceutical industry, and getting mixed up in debacles like Avandia and Vioxx.  Wouldn't it simply be better to get rid of the distortions caused by the profit motive, and let them focus on getting the best medicines to the people?

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