Thursday, January 31, 2008

"Why I Sent It Is a Mystery" - More About Avandia, Conflicts of Interest, and Confused Thinking

We have posted frequently about the controversy about rosiglitazone (Avandia, by GlaxoSmithKline). Some of the distressing aspects of the case were various efforts made to keep information and opinions unfavorable to Avandia away from physicians, patients, and the public, including efforts involving obfuscation, deception, and intimidation. (For example, see this post about the "spinning" of Avandia and the ridiculing of Avandia critics, and this post about attempts to silence an early Avandia critic.)

So it is ironic that the latest Avandia controversy is about the premature release of a manuscript submitted for publication.

Recall how the story began, with the publication in the New England Journal of Medicine by Nissen and Wolski of a meta-analysis focused on cardiac adverse effects of rosiglitazone (Avandia, by GlaxoSmithKline) (see post here). The main achievement of the Nissen and Wolski meta-analysis [Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online here] was to be the first published article to combine data from all relevant clinical trials of rosiglitazone completed to date. Although two major trials of Avandia had been published, its manufacturer, GlaxoSmithKline, had performed many other smaller trials of the drug, most of which have not been published to date. They did eventually appear on a web-site run by GSK. However, this web-site was relatively obscure, and it was not created voluntarily, but in response to a settlement of legal action that alleged GSK had suppressed clinical research about its antidepresant paroxetine (Paxil). (See Steinbrook R. Registration of clinical trials - voluntary of mandatory. N Engl J Med 2004; 351: 1820-1822, link here and our post here). Nissen and Wolski found it, compiled the results of trials on Avandia, and combined their results with those of the few published trials in their meta-analysis.

Now it turns out one of the NEJM peer reviewers of the Nissen and Wolski manuscript leaked it to GSK well before the manuscript was published. From the News section of Nature,

17 days earlier [before the article was published], the reviewer, diabetes researcher Steven Haffner of the University of Texas Health Science Center at San Antonio, had faxed his copy of the article to Alexander Cobitz, a GSK employee whom Haffner knew from working on an earlier clinical trial of the drug.

This was a serious breach of the reviewers' code of conduct. Having reviewed many articles for many medical journals, (but not the NEJM), I can say with conviction that reviewers are forbidden from releasing unpublished manuscripts to anyone, with only one major exception. Reviewers can seek reviewing help from a colleague, as long as this is disclosed to the journal, and the colleague does not further release the manuscript.

As pointed out by an article by Stephanie Saul in the New York Times,

Under The New England Journal’s rules, reviewers are prohibited from disclosing an article’s contents before publication, as a way of protecting the exclusivity of the journal’s material and protecting the intellectual property of scientists who submit articles.

Besides violating The New England Journal’s rules, disclosing a pending article would also be considered a breach of professional ethics, according to Dr. Jerry Avorn, a professor of medicine at Harvard Medical School. Dr. Avorn said that he was not familiar with the specific allegations against Dr. Haffner.

So why did Dr Haffner do it? His explanation of why he sent the manuscript was at best incoherent.

'Why I sent it is a mystery,' Haffner told Nature . 'I don't really understand it. I wasn't feeling well. It was bad judgement.' Haffner says that Cobitz did not ask to see the draft and was 'probably a bystander'.

According to a report in, a GSK spokesperson rationalized Haffner's conduct thus,

Haffner, who consulted for GSK on Avandia, had concerns and questions regarding the methodology of the analysis and sent the article to GSK for advice from company statisticians.

This begs the question of why he did not simply note in his review his lack of expertise on the relevant statistical issues, or seek help from a statistician at the University of Texas.

So perhaps we should seek other explanations. Dr Haffner, it turned out, had a number of financial ties to GSK. As reported in Nature.

Haffner had earlier served on the steering committee of a GSK-sponsored clinical trial of Avandia. He says that he has given many talks for the company, although he declined to say how much he had earned from them. 'I've got a considerable amount of money. I didn't do it to raise my income or anything like that,' he says.

Furthermore, in the NY Times article,

Dr. Haffner, who had been involved in a clinical study that found Avandia worked better at controlling blood sugar than two other treatments, was quoted last year in the online medical publication criticizing the publication of Dr. Nissen’s study and of editorials that supported it in two other journals.

'The three major medical journals are becoming more like British tabloid newspapers. All they lack is a bare-chested woman on Page 3,' Dr. Haffner was quoted as saying.

In fact, Dr Haffner was one of the co-investigators for the ADOPT study, which compared rosiglitazone to metformin or glyburide, and was sponsored by GSK. [Kahn SE, Haffner SM, Heise MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-43. See link here.] In that article, Haffner disclosed,

Dr. Haffner reports receiving consulting fees from AstraZeneca and Takeda; consulting fees and grant support from Novartis and Pfizer; grant support and consulting and lecture fees from GlaxoSmithKline; consulting and lecture fees from Merck; and lecture fees from Sanofi-Aventis.

Furthermore, an article in the Philadelphia Inquirer noted,

Haffner is a national expert in diabetes. His university Web site calls him 'one of the highest-funded investigators, in terms of [National Institutes of Health] funding, in Health Science Center history.'

And we know that in this age of "greed is good" as the reigning philosophy in medical schools and academic medical centers, the biggest "tax-payers" like Haffner can do no wrong in the eyes of the administrators of these institutions.

So the Avandia story gets more complex, involving more people with more conflicts of interest, and not only suppression of research, but the breach of confidentiality of an unpublished manuscript submitted for publication.

Dr Haffner's nearly nonsensical explanation of why we went running to his fax machine to send the confidential manuscript to his part-time GSK employers is another reminder of the confused reasoning often displayed by people with conflicts of interest, even full professors of medicine who are supposed to be national authorities. As noted before, "people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult." Apparently becoming a consultant for a pharmaceutical company makes one susceptible to faxing confidential manuscripts in a fugue state, something like the sleep-driving pheonomenon reportedly caused by sleep medications like Ambien.

This latest development in the Avandia case is yet another argument that physicians should not only not accept pens, coffee mugs, and free pizzas from companies trying to sell their medical and health care products and services, but that academic physicians should shun all financial ties to these companies. (A physician who wants to work for a pharmaceutical, biotechnology, or device company should do so full-time, or not at all, in my humble opinion.)

Otherwise, prepare to appear on the national news blinking like a deer in the headlights, saying "Why I did it is a mystery."

ADDENDUM (31 January, 2008) - See also this post on the Clinical Psychology and Psychiatry Blog.


MedInformaticsMD said...
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Anonymous said...

I remain perplexed that these stories surprise people. No matter what scandal you look at there are physicians closely tied to industry trying to defend bad actions or dangerous drugs. Whether its VIOXX, Avandia, Vytorin, Drug-eluting stents or a list of others, you will find physicians who have lost any sense of independent judgment. And anyone who can get to and comprehend blogs like this one or pharmalot or a few other solid entries knows the reason. The financial ties are too substantial.

We like to blame industry but guys like Haffner are probably just as much to blame. From the industry side, the marketing team for a major medicine will conduct numerous "consulting meetings" where they will pay physicians to get their advice on topics. Sometimes the topics are compelling, but sometimes the topics are along the lines of "are we getting the right message out." So you get paind say $3,000 to sit around a table a comment on some promotional programs. Then the big brand also has speakers. A major brand will have upwards of 1,000 physician speakers. Now they will get paid around $3,000 to do a talk over dinner. And they can do many of these. In the cardiology area for example, you can easily find cardiologists who will take in say $50,000 in consulting fees then another 50 or 100k in speaker fees over a year. Now if that same cardiologist is working for 2 or 3 companies then you can see that he/she can be bringing in 100's of thousands of dollars a year (easily). It's the reality.

And yet we act surprised when one of these guys defends a company that did something wrong or tries to help them in a bind (or maybe just prescribes their products like crazy!).

We have to start breaking that link. I somewhat disappointed that I don't see calls for more transparency on the blogs.

I rarely see any support for the Physician Payments Sunshine Act” (S. 2029) introduced in the U. S. Senate by Senators Grassley, Kohl, Kennedy, McCaskill, Schumer, and Klobuchar. This bill would amend Title XI of the Social Security Act to “provide for transparency” in the relationship between physicians and manufacturers of drugs, devices, or medical supplies . . .

It does not appear that there is any energy behind the bill at all. I fear that it was introduced more as political gamesmanship than anything else. Still, people who want to see change should support initiatives like this.

I am not sure that this particular Act is the ultimate solution, but we certainly need some version of it. The entire industry and all the physicians know that their financial ties could never withstand public scrutiny, but they will forge ahead holding on as long as possible because the money to be made on both sides is simply too significant.

I urge the serious bloggers to do more on transparency. I have seen it close up and it's ugly.