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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: derekb.lowe@gmail.com Twitter: Dereklowe

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« Knowing What You Know. . . | Main | Pecunia Non Olet? »

May 31, 2007

The Avandia Wars Continue

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Posted by Derek

GlaxoSmithKline is breaking out the data to respond to the Nissen and Wolski NEJM paper on the possible cardiovascular risks of Avandia (rosiglitazone). In a letter published by The Lancet (PDF), the company's chief medical officer, Ronald Krall, defends the drug (and the company):

"GlaxoSmithKline did similar meta-analyses in 2005 and 2006 and found hazard ratios in the same direction as Nissen and Wolski. However, all these results are highly dependent on the methods used and the studies included, given the small number of events reported. For example, the actual number of myocardial infarctions in the Nissen and Wolski meta-analysis yields a very low frequency of events (0·6%), and the absolute difference in rates of myocardial infarctions between rosiglitazone and controls is less than 0·1%.

These observations support a view expressed by Nissen and Wolski them-selves: “a meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest.”

He then goes back over the data in the three large trials that bear on the question. Reanalyzed data from the ADOPT study still do not show a statistically meaningful cardiovascular risk for rosiglitazone versus the other two diabetes drugs in the trial (metformin and glibenclamide). (There's no placebo group - this is one of those head-to-head comparisons of a drug versus its strongest competitors, a type of study that some people believe never takes place). The second completed study, DREAM, looked at co-administration of rosiglitazone and the ACE inhibitor ramapril. There were four groups - placebo only, rosi and placebo, ramapril and placebo, and rosi plus ramapril. The first three showed no difference in cardiovascular events, but the last one did, for unknown reasons.

These two studies are in the Nissen/Wolski meta-analysis, of course, but as I noted originally, it was the sum of the smaller studies that gave them their cardiovascular warning. But when the statistically less powerful trials show one thing that isn't borne out by the larger ones, the issue is (at the very least) still in doubt. The letter also points out that the company's database mining of managed-care patients taking rosi has shown no increase in cardiovascular risks.

Other controlled studies are ongoing, the (now highly awaited) RECORD and another one called ACCORD. Both are designed from the start to address cardiovascular outcomes (which are a major complication in diabetic patients). Krall's letter lifts the veil a tiny bit on RECORD, saying that the independent review board has now completed an interim analysis of its cardiovascular data and concluded that the trial should continue. This would not be the case, you'd have to presume, were the numbers to clearly show increased CV deaths in the treatment group.

My take on this is that the company has a pretty strong case so far, certainly strong enough to wait for the ongoing trials to settle the issue. What never fails to disappoint me, though, is the way that stories like this are jammed into ready-made templates. Depending on the editorial writer, the appearance of the NEJM paper became "FDA Corrupt, Broken: Snores While Dangerous Drugs Kill Thousands", or "Giant Drug Company Sells Heart Attack Poison, Doesn't Give Hoot". Or maybe just "Drug Approval System Completely Broken - Again".

Now, Steve Nissen does sound the alarm a lot, but I have no doubt that his intentions are honorable. His paper, to me, was the equivalent of saying "Hey, you people may have a problem here. Did you know that?" GSK's response, then is "Yeah, we've looked at that, too, but we don't see it. Are you sure your numbers are good?" Meanwhile, the studies which should answer the question for good are already years into their runs. If this is our standard for a broken drug approval system, we've certainly become mighty fastidious over the years. For what it's worth, The Lancet agrees.

Comments (11) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Press Coverage


COMMENTS

1. John Johnson on May 31, 2007 8:33 AM writes...

You know, pharma does have a lot of problems, as does the FDA. The only problem with this situation is that people are looking for another Vioxx (and that name got dropped almost as soon as the ink dried on Nissen's article). So we get the 43% figure quoted over and over without any context, while the lawyers are starting their Avandia conferences and recruiting clients.

This is not the way to monitor drug safety. I can only hope that the drug safety reform efforts in Congress and the FDA are effective, not only to yank bad approved drugs off the market, but also to increase faith in the good ones.

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2. Insider on May 31, 2007 12:34 PM writes...

Between Vioxx and this debacle one should not forget the glitazars.

Pargluva was a low point and seminal as to how we all got here.

Derek - you are on record about Pargluva.

Care to comment?

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3. Analytical Chemist on May 31, 2007 3:04 PM writes...

Regarding the mention of Vioxx, I have a slightly different perspective on Vioxx, and the lessons to learn from it. First, contrary to common belief, Vioxx was not a bad approval by the FDA. It turned into a PR nightmare for both Merck and the FDA due to later revelations and mishandling of the PR by Merck management and the resulting feeding frenzy in the media, but I stand behind the original decision of the regulators to approve this product.

The health issues with Vioxx are extremely subtle and only visible when the statistics were powered to a higher than normal level. Many times the cardiovascular risks for Vioxx came out equivalent to placebo, and even in the study that eventually killed Vioxx decisively, the drug was equivalent to placebo through a year and a half of this very large study. Merck is a very ethical company, and anyone who says differently has never seen it from the inside. Good comanies like Merck can make mistakes like this without being unethical--that's the real lesson of Vioxx.
Avandia just reinforces the same message.

Is Vioxx safe enough to be on the market? Is Avandia? That's a judgement call that should ballance a small risk against the potential benefits of the drugs. I know a lot of patients who wish they still had Vioxx for their pain, even with its risks.

Could we have known what we know now about Vioxx before it was approved? Maybe, but there's a cost associated with that kind of confidence. Ultimately, we need to decide as a society whether we want ultimate confidence at a much higher cost or if we can accept a reasonable level of managed risk in the interest of getting new therapies to patients in a timely and affordable manner.

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4. david on June 1, 2007 1:11 AM writes...

Nissen may not have meant to harm, but his paper is little more than a butcher job. The methodological weaknesses are so great that one must wonder if the NEJM editors appreciate the impact the paper's publication had on markedly reducing the Journal's reputation. Drug safety is built on solid, interpretable data. This paper had little of that. Not to mention that anything less than a 100% increase in an adverse event in such a context is difficult to attribute to a given factor. There are simply too many confounders. I think the Lancet agreed with those comments, too. At least the Lancet got the science right.

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5. The Pharmacoepidemiologist on June 1, 2007 1:23 AM writes...

Actually, Vioxx was a fine approval, but in 2001, the FDA/Merck had plenty of indication that the label needed to be changed to warn of the increased risk of cardiovascular events.

Is Merck really that ethical? I think there's a good question about that. It wouldn't let it's own scientist co-author a paper suggesting a problem with one of its products. That's an ethical company? It fought tooth and nail not to deal with Vioxx once the problems had been found. And it wasn't just a randomized trial, as Analytical Chemist suggests, which caused the alarm on Vioxx. David Graham's epidemiologic study in August 2004 set the ball rolling. Though much of the pharmaceutical community seems to think that the only data worth having in the label is from a randomized study, the public and the FDA are swayed by compelling epidemiologic data, which Graham's data were. There was more than a doubling of risk, and it's unlikely therefore that confounding alone could account for the increase.

Perhaps Analytical Chemist would like to return to the days before thalidomide, when the pharmaceutical industry couldn't even be bothered with keeping records of who was exposed to what agent during development programs. That's why we have regulations about INDs today. More than 200,000 people in the United States received thalidomide tablets during a seeding study, when the manufacturer thought FDA was going to approve it. The manufacturer kept no records of who received the drug. Sure, thalidomide was never marketed in the US, but there was a lot of exposure.

The FDA exists for one simple reason: the pharmaceutical industry is the most profitable industry in America. And as long as those profits are plowed back into research (and not marketing), it will remain as such. And that's why there's an FDA.

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6. Buddha on June 1, 2007 8:03 AM writes...

I am not sure that I buy Pharmacoepidemiologist's cynical logic on the reason for the existence for the FDA. Last I checked, the FDA existed to protect the consumer of pharmaceuticals. By the way, the pharma industry was the 5th most profitable U.S. industry in 2006, not 1st (http://money.cnn.com/magazines/fortune/fortune500/performers/industries/return_on_revenues/index.html).

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7. The Pharmacoepidemiologist on June 1, 2007 8:25 AM writes...

I wouldn't characterize my comments as cynical. Realistic, not cynical. And by the most profitable, I mean over a sustained period. THe most recent year, 2 years, 3 years...hardly qualifies as typical of the pharm industry over the past 50-100 years. (And profitable is a function of margin, not net income.)

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8. Analytical Chemist on June 1, 2007 11:05 AM writes...

Such is the pervasive perception of Vioxx toxicity due to the bad PR of Merck's voluntary recall, that people loose sight of the fact that the recall was voluntary and there was an active discussion in the FDA about whether it should be reintroduced in the market with a black box warning. Ultimately that was a PR question, rather than a clear cut safety one. Is Vioxx really much different from Celebrex (still on the market and making $$ due to good PR moves by Pfizer) or Arcoxia (sold ex-US, but not approved in the us due to, I believe, PR concerns at the FDA)? Myself, I think Merck's ethics are represented by the masochistic step of the voluntary recall that was a very costly PR nightmare. It would have been ethical if they had simply slapped a black box on the label. Compare this with Pfizer's more moderate move of discontinuing DTC ads.

Pharmacoepidemiologist, people at Merck truly believed that there was no safety problem with Vioxx, and the long term study that killed it was done to prove this clearly. They felt that 1) the data from Graham and Nissen was of dubious validity (much as in the current Avandia case) and 2) that the equivalence to placebo previously shown was the more valid result. They were ultimatly proven wrong, but their willingness to invest in large probative clinical trials demonstrates their good faith. Otherwise, they wouldn't have done the study to prove or disprove the issue and left it a grey area.

Being wrong is not the same thing as bad ethics.

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9. Rob on June 1, 2007 11:52 AM writes...

I do agree with your overall point that this is more sloppy than malignant in intent. I too doubt that Nissen was just standing on the soap box. Lost in this conversation, however, is the fact that glycemic control has enormous benefits to patients from a mortality and morbidity standpoint. This is the big difference between the Vioxx case and Avandia. Vioxx was more of a quality of life drug, offering relief from pain, but no concrete increase in life expectancy. Avandia, however, improves glycemic control and that has been strongly correlated with improved survival and lower morbidity from serious complications of diabetes. Patients who stop this medication and worsen their control will be harmed. That was not the case with Vioxx.

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10. The Pharmacoepidemiologist on June 2, 2007 5:47 PM writes...

I'm not suggesting a lack of ethics by most of the folks at Merck. Gilmartin is worth a separate discussion in that respect--he was neither a scientist nor a health care provider, so my expectations of him, as a businessperson, aren't particularly high to begin with. Just my opinion. I also have a problem with forcing someone to remove their name from a paper with data they were quite involved in collecting and analyzing. As I recall, Merck wasn't particularly happy when the Wall Street Journal (hardly an anti-business hack operation) reported the story. (At least I think it was the WSJ.)

As for the Graham study, it was pretty well vetted at the Bordeaux ISPE (pharmacoepidemiology society) meeting in 2004, and I think it's safe to say it passed pretty nicely. Merck can believe what it wants to believe, but there was sufficient data in 2001 to have justified a label change. But that would have interferred with those marvelous marketing efforts.

Let's face it, Vioxx should have sold maybe $500 million a year, and that wasn't good enough for Merck, so it got pushed well beyond where it should have been, its safety issues were magnified as a result, and it was withdrawn from the market. It was the same thing as happened with Lotronex. I'm not so convinced Avandia is in the same camp. The risks just aren't there. If they were, we wouldn't be arguing about a less than 100 percent increase in risk, we'd be marvelling at the 200-300 percent increase.

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11. Jimbo on June 3, 2007 7:50 PM writes...

About how ethical Merck was - I remembered an old NPR report on that. Fortunately, the transcript is still available:
http://www.npr.org/templates/story/story.php?storyId=4696609

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