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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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In the Pipeline

« Hmmm: The Gates Foundation Bails | Main | Midsummer »

July 13, 2010

Avandia: Was the Evidence Buried?

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Posted by Derek

The New York Times has added to the arguments over Avandia (rosiglitazone) this morning, with an above-the-fold front page item on when its cardiovascular risks were first discovered. According to leaked documents, that may have been as early as the end of 1999 - just a few months after the drug had been approved by the FDA.

According to Gardiner Harris's article, SmithKline (as it was at the time) began a study that fall, and "disastrous" results were in by the end of the year that showed "clear risk" of cardiovascular effects. (They must have been disastrous indeed to show up in that short a time, I have to say). He quotes a memo from an executive at the company:

“This was done for the U.S. business, way under the radar,” Dr. Martin I. Freed, a SmithKline executive, wrote in an e-mail message dated March 29, 2001, about the study results that was obtained by The Times. “Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK,” the corporate successor to SmithKline.

The only possible way I can see this being taken out of context would be if the rest of the memo talked about how poorly run the study was and how unreliable its data were - in which case, someone was an idiot for generating such numbers. But that puts the company in the situation of "idiots" being the most benign (and least legally actionable) explanation. Which is not where you want to be.

Without seeing the actual material, it's hard to comment further. But what's out there looks very, very bad.

Comments (29) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology


COMMENTS

1. AZzzer on July 13, 2010 9:48 AM writes...

John Patterson, ex-executive director for development at AstraZeneca, once said in an internal announcement, "please be careful with what e-mails you send to each other", also be careful what notes you take and post-its you leave..."

I guess snr mgmt every where is quite scared what the great scientists are capabale of - telling the truth!

Permalink to Comment

2. qetzal on July 13, 2010 10:02 AM writes...

I was under the impression that they'd be obligated to share those data with FDA, even though the drug was already approved, and even if the study was horribly flawed. Is that right?

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3. Anonymous on July 13, 2010 10:09 AM writes...

If Avandia goes bust, another executive bonus is a must!
Have no fear, there's still sites to close down here.
Send those scientists to the streets and plan another retreat;
There's too much stress in our management suite.
The South of France sounds good, Florida too or maybe even Hollywood.
We may have lied. We may have cheated.
Just fuel up the jet and get my mistress seated.
China will save us, Sirtris too.
Announce the reorg and we're back on cue.

Permalink to Comment

4. Kent G. Budge on July 13, 2010 10:15 AM writes...

Given that there are better alternatives out there -- I would unhesitatingly choose pioglitazone over rosaglitazone -- it seems clear that Avandia should come off the market.

But I find it odd that cardiovascular effects were not seen in what were likely lengthy clinical trials prior to approval, then showed up in very short order after. Is it simply a case of small sample size in the clinical trials?

Permalink to Comment

5. Vader on July 13, 2010 10:20 AM writes...

Right, Anonymous 3. There's just no doubt that if I was a major shareholder in GSK, with millions invested in the company, my first reaction to learning that the company had covered up data showing that our product was killing long-term customers would be ... to sacrifice more of my dividends to pay a bonus to the executives responsible for ruining my investment. Yeah, that makes perfect sense.

Permalink to Comment

6. Rorschach on July 13, 2010 11:58 AM writes...

I guess I'm just naive, because I work in R&D for a major drug company and I have no clue how something like this happens. After seeing products like fen phen, and Vioxx, how could anyone possibly think they could get away with this?

Permalink to Comment

7. Hap on July 13, 2010 12:01 PM writes...

#5: But I thought that that was how it always went. We have to reward our captains of industry for their leadership and make sure that they can stay securely at the helm until the ship is safely on the rocks or has finished capsizing.

Given that the evaluation of cardiovascular effects in their studies (I thought) seemed to be a judgment call, I don't know how they would have managed to get unambiguous data that rapidly and then 1) sit on it and 2) expect it to stay undiscovered. I guess they didn't they learn from the Northmeister.

I think reference to Gates' quotes during Iran-Contra is apropos - how did they know that they wanted to keep their study quiet without knowing that the news was likely to be bad? (Or is that just SOP?)

Permalink to Comment

8. Watcher on July 13, 2010 12:11 PM writes...

That scientific journal, well referree'd publication, the NY Times has been a strong supporter of Nissan with negative articles on the Avandia debate for years. They published similar "exclusive" disclosures coincident with the last FDA Avandia review, which itself was forced by Nissan's poorly constructed and documented accusations. Such topics are easy targets for the NY Times, as defender of the public's interests.

While I am not a big supproter or defender of SB / GSK management, past or present, the Times can never lose with this approach, but patients in need of this drug, which may be imperfect as are most others, could suffer with it's withdrawal.

Dr. Nissan: I hope you never are in need of such drugs...but if you are I'm sure you'll take them with some amount of gratitude. I'd love to see you try to do better in trying to provide novel, first in class, therapies for areas of high medical need. To paraphrase an old adage....Those who can, do. Those who can't, criticize.


Permalink to Comment

9. Chemjobber on July 13, 2010 12:32 PM writes...

Kudos to #3; I request a poem for Pfizer.

Permalink to Comment

10. Hap on July 13, 2010 12:39 PM writes...

Avandia isn't either first or best in class, but a not-much-better (even by the standards of incremental innovation that is standard in the drug industry) drug. The point of a drug is to help people, and if it isn't clear that it does that, and adds risk, well, it doesn't seem like much of a help.

Even if Avandia is useful (probably unlikely at this point), GSK's record of dishonesty on the matter [what significance do we need to be OK, Dr. Nissen? You mean like (scribble, scribble) this?] doesn't seem to help either patients in need or the company. It makes it harder to see what Avandia is worth, and makes it hard for people to trust GSK when they have a useful drug, which would seem to be counterproductive if patients are your interest. If you have to be dishonest to get your drug out there, perhaps you are not really on the side of the angels.

Sorry about your stock, dude.

Permalink to Comment

11. Rev. Howard Furst on July 13, 2010 12:46 PM writes...

At today's advisory committee meeting, the analysis presented by Ellis Unger of the FDA indicated that the results of the Nissen meta-analyis of MI risk in patients taking Avandia was NOT supported by the all-cause mortality findings in the massive RECORD study, which were identical between the Avandia and control groups. Several other presentations noted the follies derived from meta-analyses versus randomized controlled studies.

Nissen was glad-handing with his buddies from Takeda (makers of Actos) before Unger spoke and repudiated his findings. However, Actos does in fact seem to be slightly safer than Avandia, though actual head-to-heads are sorely lacking.

Permalink to Comment

12. Anon on July 13, 2010 2:58 PM writes...

Let's get down what may be knwon here.

Has evaluation of GSK's files & study results found any data that has been withheld from FDA or other regulatory agencies?

Without such documentation, the implications in the Times article would look to be nothing but hearsay.

Permalink to Comment

13. BOB on July 13, 2010 9:08 PM writes...

@ Rorschach

I don't think business people worry about getting away with it. The side-effect is someone else's problem later, and I want my bonus now. It's been almost 10 years since that email was sent.

I think the attitude is this is the company's problem and screw it, I'll be retired by then.

Permalink to Comment

14. Peej on July 13, 2010 10:53 PM writes...

But Avandia IS useful! It does a billion in sales, despite virtually everyone who is prescribing it knowing about the CV risk profile..even if the CV risk profile is based on tenuous data.

Its simply another option for the millions of patients who need TZDs. Maybe it causes less edema than pio in some. Maybe its got better efficacy, or is tolerated better. Maybe the $100 per month discount vs. pio makes it attractive to some.

This point seems to be missed quite a bit. This drug should continue to be available, and the potential CV risk should be highlighted until it is proven to be absent.

Permalink to Comment

15. SinkingShip on July 14, 2010 5:11 AM writes...

I don't know much about T2D and avandia so can't comment on that but congratulations to the person who posted comment #3, a very witty (no pun) piece! It's spreading around GSK and raising some laughs! It sums up the general mood very nicely, well done!

Permalink to Comment

16. Hap on July 14, 2010 9:49 AM writes...

Could the execs have been panicking about interim data, or is the data not seen at all until the end of the study? If this is panic over interim data, maybe their fears weren't borne out, and so the emails could be simply the panicked CYA responses of executives.

If this is all there were, and the FDA had received the data as they were supposed to, it's pretty hard to believe that either they would have missed its significance at the time or not noticed the data in the subsequent hullabulloo (and someone in the "anti-Avandia" faction wouldn't have leaked said data). It would be good to see if FDA did miss the data, but it's far easier to believe in GSK's ill will than what would have to be comprehensive stupidity at the FDA.

Permalink to Comment

17. OldStager on July 14, 2010 9:53 AM writes...

Still no word on how the Avandia meeting with the FDA panned out?
For those interested, there's a nice piece on the story for the UK paper "The Guardian":
http://www.guardian.co.uk/business/2010/jul/12/glaxo-smith-kline-avandia-hearing
Little movement on the stock so perhaps they got a favourable ruling

Permalink to Comment

18. OldStager on July 14, 2010 9:53 AM writes...

Still no word on how the Avandia meeting with the FDA panned out?
For those interested, there's a nice piece on the story from the UK paper "The Guardian":
http://www.guardian.co.uk/business/2010/jul/12/glaxo-smith-kline-avandia-hearing
Little movement on the stock so perhaps they got a favourable ruling

Permalink to Comment

19. NorthwestT on July 14, 2010 10:22 AM writes...

So why is GSK's stock up over the last two days? Wouldn't the loss of $3 billion in sales be a material event for them? And based on the e-mail above, they are looking at 10 years of knowingly marketing a dangerous product. Makes me want to be a personal injury lawyer.

Permalink to Comment

20. Wiz on July 14, 2010 1:37 PM writes...

Stock is up lately because the effects of a bad FDA ruling on Avandia has already been factored into the price of the stock (because it has been in the media for so long).

Permalink to Comment

21. Bluto Blutarsky on July 14, 2010 3:22 PM writes...

The stock price is actually up in anticipation of the massive layoffs of GSK folks to justify the losses in revenue from the sale of Avandia (if there are actually any more sacrificial lambs left).

Permalink to Comment

22. Anonymous on July 15, 2010 2:32 AM writes...

Perhaps NYT and platiffs lawyers have equally poor, maybe more poor, incentives to interpert data than industry executives.

management bonus vs. plantiffs settlements?
i would say plantiffs settlements appear
much much larger.

"Since 2007 we have seen results from six controlled clinical trials looking at the cardiovascular safety of Avandia and together they show this medicine does not increase the overall risk of heart attack, stroke or death,"

Permalink to Comment

23. HarryB on July 15, 2010 4:29 AM writes...

Looks like end f the story for the moment, here's a summary:
http://www.guardian.co.uk/business/2010/jul/15/glaxosmithkline-legal-charge-avandia

Permalink to Comment

24. Hap on July 15, 2010 12:14 PM writes...

When I went to the NYT the day of the post, I didn't see mention of the article, and in the FDA discussions reported, they didn't mention anything about the possibility of withheld data. Did they already know about it, was the article somehow in error, or did I miss something (or more than one of those options, as well)?

Permalink to Comment

25. oldeurope on July 15, 2010 3:14 PM writes...

I find it interesting to see requests for withdrawing this drug on such a blog based on this hysteric discussion... CV effects in a short term trial... CV effects in a meta-analysis... give me a break thought there are some scientists here - ever took some lessons in statistics?

Permalink to Comment

26. Anon on July 15, 2010 8:15 PM writes...

1) This apparently was old news "leaked" from a Congressional report
2) No evidence that the data alluded to was withheld from regulatory access

Derek: You need to be more careful and less judgemental in what you post & write. You have shown a strong attitude against GSK in the past, and continue to do so in this posting. How about being a scientist as you try to project, instead of a quasi-politician, biased judge, and self-appointed jury?

Permalink to Comment

27. alig on July 16, 2010 6:24 AM writes...

Is it too late for Glaxo to un-merge with SmithKline?

Permalink to Comment

28. Anon on July 16, 2010 12:16 PM writes...

#27: Still fighting the Civil War, I'd guess.

You'd also want to undo Welcome & Glaxo...if you are from the Welcome side....

Permalink to Comment

29. Anonymous on August 1, 2010 5:33 PM writes...

It's called spin off. GSK should spin off the stuff. they are too larege. cut the fat!

Permalink to Comment

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