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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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May 5, 2010

Steve Nissen vs. GlaxoSmithKline

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Posted by Derek

You don't often get to see so direct an exchange of blows as this: Steve Nissen, of cardiology and drug-safety fame, published an editorial about GlaxoSmithKline and Avandia (rosiglitazone) earlier this year in the European Heart Journal. And GSK took exception to it - enough so that that the company's head of R&D, Moncef Slaoui, wrote to the editors with a request:

". . .(the editorial) is rife with inaccurate representations and speculation that fall well outside the realm of accepted scientific debate. We strongly disagree with several key points within the editorial, most importantly those which imply misconduct on the part of GSK and have identified some of these issues below. On this basis, GSK believes that it is necessary for the journal to withdraw this editorial from the website and refrain from publishing it in hard copy, until the journal has investigated these inaccuracies and unsubstantiated allegations.

Instead of doing that the EHJ invited Nissen to rebut GSK's views, and ended up publishing both Slaoui's letter and Nissen's reply, while leaving the original editorial up as well. (Links are PDFs, and are courtesy of Pharmalot). Looking over the exchange, I think each of the parties score some points - but I have to give the decision to Nissen, because the parts that he wins are, to my mind, more important - both for a discussion of Avandia's safety and of GSK's conduct.

For example, Slaoui disagreed strongly with Nissen's characterization of the company's relations with a coauthor of his, Dr. John Buse. Nissen referred to him as a prominent diabetes expert who had been pressured into signing an agreement barring him from publicly expressing his safety concerns, but Slaoui countered by saying:

The document that Dr Buse signed was not an agreement barring him from speaking but was a factual correction regarding data, which did not bar him from speaking at all. In fact, Dr Buse subsequently communicated his views regarding the safety of rosiglitazone to FDA.

Nissen's reply is considerably more detailed:

The intimidation of Dr John Buse by GSK was fully described in a report issued by US Senate Committee on Finance.3 The Senate Report quotes an e-mail message from Dr Buse to me dated 23 October 2005 following publication of our manuscript describing the risks of the diabetes drug muraglitazar. In that e-mail, Buse stated: ‘Steve: Wow! Great job on the muraglitazar article. I did a similar analysis of the data at rosiglitazone’s initial FDA approval based on the slides that were presented at the FDA hearings and found a similar association of increased severe CVD events. I presented it at the Endocrine Society and ADA meetings that summer. Immediately the company’s leadership contact (sic) my chairman and a short and ugly set of interchanges occurred over a period of about a week ending in my having to sign some legal document in which I agreed not to discuss this issue further in public. I was certainly intimidated by them but frankly did not have the granularity of data that you had and decided that it was not worth it’. In an e-mail to GSK, Dr Buse wrote: ‘Please call off the dogs. I cannot remain civilized much longer under this kind of heat’

This, to me, looks like a contrast between legal language and reality, and in this case, I'd say reality wins. The same sort of thing occurs when the discussion turns to the incident where a copy of Nissen's original meta-analysis of Avandia trials was faxed to GSK while it was under review at the NEJM. Nissen characterizes this as GSK subverting the editorial process by stealing a copy of the manuscript, and Slaoui strongly disagrees, pointing out that the reviewer faxed it to them on his own. And that appears to be true - but how far does that go? GSK knew immediately, of course, that this was a manuscript that they weren't supposed to have, but it was then circulated to at least forty people at the company, where it was used to prepare the public relations strategy for the eventual NEJM publication. I don't think that GSK committed the initial act of removing the manuscript from the journal's editorial process - but once it had been, they took it and ran with it, which doesn't give them much ethical high ground on which to stand.

Many other issues between the two letters are matters of opinion. Did enough attention get paid to the LDL changes seen in Avandia patients? Did the lack of hepatotoxicity (as seen in the withdrawn first drug in this class) keep people from looking closely enough at cardiac effects? Those questions can be argued endlessly. But some of GSK's conduct during this whole affair is (unfortunately for them) probably beyond argument.

Comments (31) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Toxicology | Why Everyone Loves Us


COMMENTS

1. John on May 5, 2010 8:27 AM writes...

With respect to GSK's alleged intimidation of Dr. Buse, all Dr. Nissen has provided is a quote from Dr. Buse's stating his version of events. What is at issue here is the actual text of the agreement that Buse agreed to sign.

Since neither side has agreed to release the text of the actual agreement, I suspect that both sides are overstating their case.

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2. Petros on May 5, 2010 8:34 AM writes...

This episode is bad PR for the industry and especially GSK and its VP of R&D

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3. Hap on May 5, 2010 9:51 AM writes...

You have to also give points to the GSK legal and PR departments. They couldn't have possibly known that threatening a journal and attempting to get them to withdraw an editorial they didn't like and felt was untrue would not only not get the editorial withdrawn, but would also make their intimidation public with a partial repudiation of their arguments by the author of the original editorial. I mean, journals usually react well to being bullied, right?

This is a stellar example of counterproductivity for the GSK folks. I hope their oversight of big-money company purchases (*cough*Sirtris*cough*) is more competent.

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4. darwin on May 5, 2010 10:21 AM writes...

After bastardizing both Nissen and GSK, maybe we should direct the cross hairs on the Publisher. As data rolls out and articles submitted, journal delegate prospective pubs to peer reviewers. I know that this may be a suprise, but in fact I have heard that there can be undisclosed conflicts of interests in this process that can lend approval/decline of an article without merit. Readers will never know if there was impropriety attibuted to breach of ethics in this process. Given the statistical technique used, the responsible approach would have been to require Nissen to tone down the causal relationship inference based on metacrap analysis. Regardless of how this data shakes out in appropriately designed studies, it was not responsible to give him a podium to rant his anti-pharma droll. The media (and likely many of this journals audience)cannot disciminate speculation from fact.

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5. John on May 5, 2010 10:37 AM writes...

Hap, Its hard for me to imagine that GSK failed to anticipate that their letter would be published. This is the kind of stuff that lawyers think about 24/7.

The language of the letter is quite interesting in that they assert that Nissen is knowingly making false statements. In most states the libel laws do not allow the award of damages for the defamation of corporations, celebrities, and other "public persons" unless the plaintiff can show that the defendant KNOWINGLY made or disseminated false statements that were defamatory. So while there was no explicit threat that I saw in the letter, there is clearly an implicit threat of a defamation lawsuit. It would really be something if GSK actually sued a medical journal.

I don't know much about Nissen, but generally I tend to be skeptical of self-appointed defenders of the public interest. A search of Pubmed reveals that most of his publications revolve around being a pharma critic. If this is the theme that he is building his career around, doesn't this represent as much of a conflict of interest as the much reviled pharma rep-provided lunch? Everytime he comes to a negative conclusion about a drug, he builds his career and potentially gets his name mentioned in the NYTimes. If he evaluates a drug and finds that it is as safe as described in the company's clinical trial publications, no NYTimes article, probably no journal publication either.

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6. anon on May 5, 2010 10:39 AM writes...

Let's not forget that Nissen received funding from the main beneficiary of this chicanery, Takeda
May be purely coincidental, but...

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7. John on May 5, 2010 10:49 AM writes...

anon, can you provide a link???

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8. Hap on May 5, 2010 10:51 AM writes...

But they are likely to take serious PR hits in anything other than the long-term - fighting a libel suit against a publisher will probably embarrass them in everything but the long-term (if they win), and even then, may not obtain for them the vindication they desire. It will make it harder for their articles to be published, and will likely give more armor to people who already have little reason to like them and give them more of an available soapbox. On the other hand, when someone makes noises about a libel suit, I get the impression that they don't actually have the evidence to win such a libel suit, and rattling their sabers only because they don't have any bullets. While I don't think people take legal language as having any relationship to truth, they do likely regard its results as something closer to truth.

There doesn't seem to be a benefit in GSK trying to intimidate unpleasant facts/untruths away, while there might be one in trying to confront them directly. The published criticism instead probably helps Nissen's status, cementing him as a brave confronter of (less than honest) drug company people - the intimidation makes them look worse than openly suing probably would have, and makes Nissen look better. If they knew that the letter would be published, it seems like they ought to know it would also be counterproductive.

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9. Hap on May 5, 2010 11:00 AM writes...

#7: see his directory entry - I think it notes he received money from Takeda.

It doesn't discount his conclusions (that's what data is for) but it's there, anyway.

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10. anon on May 5, 2010 11:04 AM writes...

John, check the original meta-analysis paper- Nissen lists Takeda for funding. You probably need a subscription to see it. Points to him for disclosure at least.

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11. John on May 5, 2010 11:36 AM writes...

Hap, I think you may be applying a double standard here.

It does appear that he has accepted money from Takeda. If he were out on the road promoting Actos, he would be immediately written off as having a conflict of interest. But by attacking Avandia, he is achieving the same end while being seen as a financially disinterested defender of the public interest. In terms of shifting market share, the effect is the same.

This is in addition to the career benefits that he gets by generating publicity for himself as a consumer advocate. How else would a cardiologist get his name mentioned in the NYTimes half a dozen times a year?

I'm disappointed but not surprised that the Takeda connection has not been mentions in the many NYTimes aritcles on this subject. There is no doubt in my mind that if he had published articles supporting the safety of a controversial drug, any money received from the drug's maker would have been mentioned front and center, or more likely, the study would not have made the news at all.

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12. Hap on May 5, 2010 11:57 AM writes...

I don't know that attacking a drug is the same as advocating a competitor - there might, for example, be other competitors. On the other hand, receiving money from one of the competitors should change the light under which one views his criticism. It doesn't, however, change the facts - that may be a legitimate point of criticism, however (people discount corporate data for conflicts of interest while not discounting individuals, though one argument in support of that position is the greater facility of large companies to fund experiments and to report only those that support their positions, something that individuals generally can't do as much). In general, medical journals can't afford to discount anyone's data - they just ask you to tell them, and figure to let the data speak for itself. That's probably still the best way - not to discount either's data based on their conflicts, but let their data talk for them.

Of course, the conflict hasn't been hidden - his connection to Takeda has been noted before here (though NYT's silence is not helpful). If GSK wanted to discredit him, that would have been a far better method than trying to threaten journals who solicit his opinions. It also doesn't exactly help GSK wrt Buse. Silencing your detractors is almost never a good idea, particularly if you have robust data to support your position. That's why the letter makes little sense to me - it seems better to openly confront your opponents if your data is good than to silence them semi-covertly, or worse, to openly intimidate them. Doing so implies GSK's data isn't good, and is counterproductive to them (since it will be remembered even if their later actions show their data to be good).

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13. John on May 5, 2010 12:25 PM writes...

Agreed, though I have also heard ("Office Politics for Dummies", an insightful but cynical and evil book)that one should never let criticism pass unrebutted.

I am not a Republican or a Fox News fan, but I do think that it is important to recognize the conflicts of interest that everyone brings to the table. The investigative journalist cannot afford to spend two weeks investigating an alleged corporate wrongdoing and conclude that everything is fine, this will not sell newspapers. Henry Waxman gets re-elected every 2 years by reinforcing his image as the defender of the public good, and so he keeps his office staff busy looking for corporate scandals, real or otherwise. Corporate money/profits is not the only, or even the most important source of conflicts of interest.

Likewise, I do not believe that anyone (with the possible exception of serial killers and lottery winners) becomes rich or famous by accident. You have to have a good plan and excellent execution. I believe Steve Nissen is executing his plan extremely well, but the rest of us need to recognize the conflict of interest that his ambition represents.

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14. Hap on May 5, 2010 12:37 PM writes...

Conflicts of interest need to be taken into account, but they don't kill data - if Nissen's conclusions aren't correct, then there's no reason not to bounce them on that basis alone. If, however, they point at something real, then they have reality, regardless of his conflicts or character. In this case, GSKs actions don't exactly contradict his conclusions, and don't do credit to their drug or company. Hence my problem with their letter - shooting yourself in the foot is not an effective defense against someone shooting at you.

In the case of stupid people or complex (or judgment-laden) analyses, people tend to rely on factoids to make judgment, so technical rebuttals may not have the desired effects. People who buy drugs or invest in drug companies are unlikely to have direct knowledge of drug development, and so they rely on expert opinions which may have significant biases - in the absence of knowledge and unbiased commentary, people are likely to follow their internal biases to determine whose opinions and evidence to rely on. The goodwill that has been burned up the last decade or so most affect the prospects of drug companies here.

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15. Marilyn Mann on May 5, 2010 12:49 PM writes...

Hi Derek

The link in your first paragraph takes you not to Nissen's editorial but to the editorial by the editors of the European Heart Journal that was published simultaneously with the Nissen and GSK letters.

The Nissen editorial was published February 12 and was entitled "The rise and fall of rosiglitazone." Here's a link.

http://eurheartj.oxfordjournals.org/content/early/2010/02/11/eurheartj.ehq016.extract

Best,
Marilyn

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16. John on May 5, 2010 12:58 PM writes...

Hap, the only caveat I would add to your comments is that with respect to the Avandia data, my impression is that the argument is not about facts but about interpretation. So I don't think GSK can rebut Nissen just by showing its data.

GSK's allegations of "mistatement of facts" appear to revolve around Nissen's allegations about GSK's behavior responding to criticism of Avandia. I think we could have a lively and interesting debate about whether either party's allegations of misbehavior not directly related to the reporting of clinical data belong in a scientific journal, but I guess I should get some work done today.

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17. MTK on May 5, 2010 1:02 PM writes...

Why did Nissen find it necessary to include the "Steve: Wow! Great job on the muraglitazar article." part of the email from Buse?

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18. Alig on May 5, 2010 2:37 PM writes...

What also needs to be recognized is Nissen is calling for a halt to the study that directly compares Avandia and Actos. Is he afraid that a double blind study may refute his meta-analysis?

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19. Hap on May 5, 2010 2:39 PM writes...

In the "Odds Are, It's Wrong" article, the weakness of meta-analyses (because of the different characteristics of the individual studies and thus the machinations necessary to generate a common basis for comparison) was noted using antidepressant studies as an example (I don't know where they got the repudiation study). That might be one possible useful caveat for GSK to remind people of, and for the people reporting on the discussions (NYT?) to have asked about.

Interpretations of data probably belong in a journal. Misstatement/lies/libel etc. probably do belong in a courtroom.

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20. Josh on May 5, 2010 4:16 PM writes...

Dr Nissan is on a mission here and his editorial is indeed neither academic nor scientific. He needs to defend vigorously his original Avandia meta-analysis - which has been critiqued as flawed and inappropriate in its design and execution (not just by GSK, but the epidemiology community as well). He also wants to pre-empt an upcoming FDA Advisory Board which will again evaluate Avandia's safety. GSK took a risk of being criticized for suppressing 'academic freedom' but I think it was worth it for them to throw down a marker and say, enough of Medical journals treating Dr Nissen as some 'impartial' defender of the public - he's a partisan in this (and almost every other battle he enters) and all medical editor's really do need to reconsider if he can be portrayed as academic expert opining on the facts without bias.

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21. Josh on May 5, 2010 4:16 PM writes...

Dr Nissan is on a mission here and his editorial is indeed neither academic nor scientific. He needs to defend vigorously his original Avandia meta-analysis - which has been critiqued as flawed and inappropriate in its design and execution (not just by GSK, but the epidemiology community as well). He also wants to pre-empt an upcoming FDA Advisory Board which will again evaluate Avandia's safety. GSK took a risk of being criticized for suppressing 'academic freedom' but I think it was worth it for them to throw down a marker and say, enough of Medical journals treating Dr Nissen as some 'impartial' defender of the public - he's a partisan in this (and almost every other battle he enters) and all medical editor's really do need to reconsider if he can be portrayed as academic expert opining on the facts without bias.

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22. another anon on May 5, 2010 5:21 PM writes...

What I don't understand is why Derek Lowe is so fixated on this topic. In fact, why do so many of his postings deal with GSK's activities? Seems to be an inordinate number.

It's curious, that there don't ever seem to be any posting related to activities of his current employer.

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23. anon1 on May 5, 2010 6:13 PM writes...

Every high level physician comes with conflicts of interest. Nissen is no exception. He has been on many payrolls throughout his career- including GSK and Merck both of which he has since vilified with data pointing to ischemic risks. There is no doubt he has an agenda but it is driven by personal ambition, not Takeda dollars. His data may have its limitations, but let's not forget both GSK and the FDA came to similar conclusions in their own analysis

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24. Sili on May 5, 2010 7:06 PM writes...

Seems to be an inordinate number.
"Seems" doesn't cut it. Numbers, please.

I'ven't been a reviewer, but shouldn't whoever sent that fax be slapped down?

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25. SMILES on May 5, 2010 10:08 PM writes...

To another anon:
What's your point to ask Derek to say something about his current employer? Get him out of job? Do no evil, please! If you know something Re his current employer, spell it out here or somewhere by yourself.

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26. Amber on May 5, 2010 11:53 PM writes...

I really dont understand why the NYT will not publish the fact the Dr Nissen is payed by takeda to promote actos. Lets be real here Avandia and actos are pretty much the same freaking drug. If one has a side effect so does the other.
I think he got turned down be GSK to be a big national speaker and now he is pissed and taking it out on GSK. That is just what I think.

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27. Roy on May 6, 2010 6:43 AM writes...

Steve Nissan is hungry for publicity, and hyping safety is only a means to achieve the end ! We have seen him doing many meta-anlaysis in the past, but what matters at the end is drug benefits the patients now, and not a probable statistical analysis.

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28. anon1 on May 6, 2010 2:39 PM writes...

Amber you may not realize this but none of the TZD drugs are the same. Do either actos or avandia have liver toxicity issues? Yet rezulin did so following your logic actos and avandia must have them as well. Why did Nissen blow the whistle on Vioxx and Vytorin? Well according to your logic he was in the pockets of Pfizer and Abbott as well...this is a slippery slope you are creating Amber

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29. befuddled on May 6, 2010 6:09 PM writes...

@#6, 9, 10, 11, 12, 26 et al.

For the record, the link Hap helpfully pointed out says this:

"Dr. Nissen reports that he has consulted for the following companies and has them donate all honoraria or consulting fees directly to non-profit organizations so that he receives neither income nor a tax deduction."

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30. Im not saying on May 6, 2010 10:28 PM writes...

Nissen has significant biases. I remember him giving talks on that Pfizer HDL drug and stating how wonderful it was in glowing terms after getting huge grants to do IVUS research on it. He seemed oblivious to the fact that IVUS was less predicive of outcomes than retrospective metaanalyses.

Nissen donates all his honoraria to HIS own foundation. Sounds fishy to me, and I can guarantee his research funds are paying for his salary/travel/Porsche.

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31. Jonathan Shuster on December 4, 2013 5:07 PM writes...

Steven Nissen, by his own admission, secretly wiretapped 3 GSK visitors when they visited his office in Cleveland in May 2007. This is not a criminal offense in Ohio, but is a federal civil offense if it involves interstate commerse, something readily self-evident.

He also was funded by Takeda (makers of Avamdoa rival Actos) on at least two studies.

Finally, he was head of the FDA hearing when Vioxx, Bextra, and Celebrex were looked at for cardiotoxicity in 2004. Celebrex survived, and the Cleveland Clinic (Nissen's home base) got a contract of about $100,000,000 to study Celebtrex vs. Nsaids.

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