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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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February 22, 2010

Avandia: Off the Market or Not?

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Posted by Derek

The Senate report that leaked on Avandia (rosiglitazone) over the weekend has made plenty of headlines. It quotes an internal FDA report that recommends flatly that the drug be removed from the market, since its beneficial effects can be achieved by use of the competing PPAR drug Actos (pioglitazone), which doesn't seem to have the same cardiovascular risks. The two drugs have been compared (retrospectively) head to head, and Avandia definitely seems to have come out as inferior due to safety concerns.

There had been worries for several years about side effects, but the red flag went up for good in 2007, and the arguing has not ceased since then. According to another FDA document in the Senate report, there are "multiple conflicting opinions" inside the agency about what to do. The agency ordered GSK to set up a prospective head-to-head trial of Avandia and Actos, but other staffers insist that the whole idea is unethical. If the cardiovascular risks are real, they argue, then you can't expose people to Avandia just to find out how much worse it is. The trial is enrolling patients, but will take years to generate data, and Avandia will be generic by the time it reports, anyway. (Presumably, the only reason GSK is running it is because the drug would be taken off the market for sure if they didn't).

The FDA's internal debate is one issue here (as is the follow-up question about whether the agency should be restructured to handle these questions differently). But another one is GlaxoSmithKline's response to all the safety problems. Says that New York Times article:

In 1999, for instance, Dr. John Buse, a professor of medicine at the University of North Carolina, gave presentations at scientific meetings suggesting that Avandia had heart risks. GlaxoSmithKline executives complained to his supervisor and hinted of legal action against him, according to the Senate inquiry. Dr. Buse eventually signed a document provided by GlaxoSmithKline agreeing not to discuss his worries about Avandia publicly. The report cites a separate episode of intimidation of investigators at the University of Pennsylvania.

GlaxoSmithKline said that it “does not condone any effort to silence” scientific debate, and that it disagrees with allegations that it tried to silence Dr. Buse. Still, it said the situation “could have been handled differently.”

Well, yeah, I should think so. I don't know what the state of the evidence was as early as 1999, but subsequent events appear to have vindicated Buse and his concerns. And while you can't just sit back and let everyone take shots at your new drug, you also have to be alert to the possibility that some of the nay-sayers might be right. We honestly don't know enough about human toxicology to predict what's going to happen in a large patient population very well, and companies need to be honest with the public (and themselves) about that.

Comments (16) + TrackBacks (0) | Category: Diabetes and Obesity | Regulatory Affairs | Toxicology


1. PharmaHeretic on February 22, 2010 10:27 AM writes...

After this much adverse publicity, Avandia is likely DOA (withdrawn or not).

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2. alig on February 22, 2010 10:45 AM writes...

Avandia has lost 2/3 of its scripts since Nissen published his meta-analysis. The insurance companies have a good database of outcomes depending on which script a patient gets. Both Actos & Avandia are horrible when it comes to congestive heart failure. Actos has a slight advantage when looking at MI, but they both trend to more events. It'll be interesting to see how the new treatments (januvia et al) perform in real world settings.

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3. Kent G. Budge on February 22, 2010 11:34 AM writes...

I suspect rosiglitazone is dead. If I ever had to go on a glitazone, I would certainly go with pioglitazone rather than rosiglitazone. Still well-controlled with metformin at the moment.

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4. Anonymous on February 22, 2010 12:42 PM writes...

"In 1999, for instance, Dr. John Buse, a professor of medicine at the University of North Carolina, gave presentations at scientific meetings suggesting that Avandia had heart risks. GlaxoSmithKline executives complained to his supervisor and hinted of legal action against him, according to the Senate inquiry."

There is a small error in that story. GSK was formed in Dec. of 2000 so the alleged executives would have come from SmithKline Beecham where rosiglitazone originated. One of the post-merger jokes at GSK was 'What does GSK stand for? SmithKline - the 'G' is silent'.

I suspect that this news is causing little concern for management at GSK. They still have a few research centers left they can shut down to offset sales and litigation costs. They have no reputation to tarnish.

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5. peej on February 22, 2010 1:52 PM writes...

This story is goofy, because its so old. The report in question was written last year, before the RECORD trial was presented that basically showed Avandia to be safe regarding CV concerns. But it gets released/leaked now, so its a story.

Realistically, the drug is still pretty much dead, but this NYT story seems as irresponsible as GSKs threats to John Buse.

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6. Morten G on February 22, 2010 4:44 PM writes...

So GSK should have tried to sell Avandia to Takeda, yes/no? Avandia could have been taken off the market and Takeda would have no competition to Actos. Reduce liability, increase profit. Or was that a stupid idea? Too late now anyway.

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7. SteveM on February 22, 2010 7:25 PM writes...

Re: "companies need to be honest with the public (and themselves) about that."

Honest with the public? Big Pharma? Derek, you're joking right?

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8. PharmaHeretic on February 22, 2010 7:50 PM writes...

What do you say?
Sources of funding for Nobel Prize-winning work: public or private?

Funding is important for scientists’ work and may contribute to exceptional research outcomes. We analyzed the funding sources reported in the landmark scientific papers of Nobel Prize winners. Between 2000 and 2008, 70 Nobel laureates won recognition in medicine, physics, and chemistry. Sixty five (70%) of the 93 selected papers related to the Nobel-awarded work reported some funding source including U.S. government sources in 53 (82%), non-U.S. government sources in 19 (29%), and nongovernment sources in 33 (51%). A substantial portion of this exceptional work was unfunded. We contacted Nobel laureates whose landmark papers reported no funding. Thirteen Nobel laureates responded and offered their insights about the funding process and difficulties inherent in funding.

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9. Paul on February 22, 2010 11:28 PM writes...

You know things are bad when Washington politicians are implying you are lazy good for nothings and do your job for you. I don't think I can ever recall when a Senate committee actually hired its own researchers to answer a medical/drug safety question. Their conclusion, Avandia has caused 88,000 heart attacks! Of course it should be pulled, Actos, meanwhile is equally efficacious and does not have the associated cardiac toxicity concerns.

Paul Maher, MD MPH

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10. KinaseNerd on February 23, 2010 4:12 AM writes...

Somebody should look at the really interesting numbers: How much revenue did come from Avandia since 1999? That number will answer all your questions.

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11. Been There on February 23, 2010 6:14 AM writes...

There are alot of interests at play here and whether Actos is a better therapeutic agent has not been shown. What bothers me about the "John Buse Issue" is Dr. Buse never mentions how he spoke all across North Carolina for Takeda and Actos. He spoke from one side of the state to the other and made plenty of $$$, but I have never seen or heard Dr. Buse admit this in the spirit of transparency when he is interviewed in print or other forms of media. From pharma to Nissen to Buse to the FDA's Graham, there is not one entity that is not biased in someway...follow the $$$$.

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12. The Way It's Done In America on February 23, 2010 11:08 AM writes...

There is so much to say on thie one, where to begin, where to begin? If the drug is seriously flawed, then it should be removed from the market. There is no new data since the last FDA review. Yet, Avandia (in the US) is being pushed more into oblivion. But, does the data really indicate a seriously negative risk to benefit?

Most unfortunate is that the debate over Avandia is now fully entrenched in the policial arena, where statements become truth in an instant. (Of course, there are weapons of mass destruction in Iraq!) Those individuals who are (ir)responsible never have to pay an equivalent price, if it is Nissan, Buse, GSK senior executives, or the politicians in DC. Shrug it off, move on to another topic, another well-paying job.

No matter what the outcome of the new FDA evaluation in July, scientific information and proper statistical anlysis can only help those who want to have the drug removed from the market. Members of the House, that well known & highly respected bastion of scientific excellence, restarted the debate because they have issue with the FDA. Is that really so? Any consideration that all House seats are up for re-election in the fall, knowing that going after FDA and big-Pharma is the type of fail-safe discussion point to constituents? If there's an issue with FDA, then deal with FDA, but this is not the way to do it.

In the end, defendable or not, GSK cannot win in this public debate. If the drug is removed from the market, batten down the hatches. Enough said. If the drug continues to be made available the company will still have a tainted image that persists as long as here are Buse's, Nissan's and opportunistic politicians free to continue to hold-forth. It's the American way.

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13. dearieme on February 23, 2010 3:07 PM writes...

@PharmaHeretic: I'm glad to discover that even at the Nobel level it's your absolutely best ideas that the buggers won't fund.

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14. Joel Polowin on February 25, 2010 4:52 PM writes...

Are there people who have serious bad reactions to all of the competing drugs but not to Avandia? If so, they might prefer to take Avandia, knowing the cardiovascular risks. (I have several acquaintances who were left without usable treatment when Cylert was taken off the market, because they could tolerate it but not its competitors.)

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15. gowramma b on May 13, 2010 8:05 AM writes...

Sir, I am planning to do my Ph.D work in Rosigiltazone. Please give some suggestion to do my Ph.D work in Rosigiltazone or not.

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16. Petros on September 24, 2010 2:33 AM writes...

And now it's gone with simultaneous regulatory action in Europe and the US

The EMEA has withdrawn approval and the FDA has heavily restricted use

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