The first question is clinical: what are the benefits and harms of rosiglitazone as a treatment of Type 2 diabetes, and therefore for which patients under what circumstances should this drug be used?
The second question is about policy: what barriers, if any, have prevented physicians and patients from getting the best possible answer to the first question, and what can be done about them?
Regarding the second question, keep in mind that 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.
It is to the credit of Nissen and Wolski to figure out how to do this. It is not to the credit of GSK that they sat on the data from these trials, only put it on this web-site when compelled to do so, did not make any effort to publicize the web-site, and did not publish a meta-analysis done by company scientists that showed qualitatively similar results to that done by Nissen and Wolski (see post here).
However, the spin cycle now in progress does little to answer these questions. Instead, it seems to obfuscate them. The latest revolutions in the cycle are...
GSK published a full-page advertisement in major newspapers including a letter to Avandia patients. The relevant parts of the letter are:
We at GlaxoSmithKline are proud to be the makers of Avandia. As leaders in diabetes, we understand that managing your type 2 diabetes is not easy. We also understand the confusion and concern you may have experienced following recent press coverage about the safety of Avandia. GlaxoSmithKline stands firmly behind Avandia.
Avandia is the most widely studied medicine for type 2 diabetes. GlaxoSmithKline has conducted an unprecendented number of clinical trials in order to continuously monitor the safety of Avandia, including its impact on the cardiovascular system. The response to this commitment from well-informed experts and researchers has been encouraging.
Like any medication, Avandia is not appropriate for all patients. Your doctor is the best resource for information about your health and is in the best position to determine if Avandia is right for you.
Be asssured, GSK gives you all our full commitment to providing you and your doctor with the facts about the safety of Avandia.
The letter obviously contains no specifics. It provides no new information about the benefits and harms of Avandia. It appears that the last sentence in the second paragraph was meant to be key, "the response to this commitment from well-informed experts and researchers has been encouraging." What it means, however, is completely obscure.
So all GSK seems to have done with the letter is provide vaguely soothing words without meaningful specifics.
Meanwhile, the Financial Times reported on the words of the GSK CEO, Jean-Pierre Garnier (via MSN Money here).
Jean-Pierre Garnier, chief executive of GlaxoSmithKline, the UK-based pharmaceutical group, on Wednesday lashed out at a leading medical journal for 'mixing science with politics' in publishing articles attacking its diabetes drug Avandia.
As his company's share price continued to fall, Mr Garnier told the Financial Times in an interview that New England Journal of Medicine papers raising safety concerns with Avandia were 'smearing the drug' as they 'pick and choose their numbers as they are trying to make a case the FDA [the drugs regulator] is not doing its job'.
Similarly, during the Congressional hearings last week, the New York Times reported that
Representative Darrell Issa, Republican of California, said the committee was coming dangerously close to 'politicizing science.' And he closely questioned Dr. Steven E. Nissen, a cardiologist at the Cleveland Clinic whose May 21 article in The New England Journal of Medicine questioned the safety of Avandia.
'This does look like in fact that this was a political concoction to anecdotally go after a company, and I object to it,' Mr. Issa said.
I suppose Rep Issa could have objected that the Congressional hearings in which he was participating were "politicizing science," but how a meta-analysis focused on particular adverse effects of a popular drug might be political is beyond me.
But it is one way to distract from the content of the article and the substantive clinical and policy issues it raises.
Note the similarity between the opinions of Rep. Issa and GSK CEO Garnier.
Furthermore, a commentary in the Washington Times by Peter J Pitts and Robert Goldberg took another swipe at Dr Steve Nissen. After starting out by charging that Nissen "positioned himself as the nation's de facto drug regulatory czar." The writers sarcastically labelled him as the "Patron Saint of Drug Safety," and "Saint Steven the Pure." They then went on to chastise Nissen for his involvement in two commercially sponsored studies, one on a drug "designed to reduce the level of fatty plaque deposits (atherosclerosis) in a person's arteries, sponsored by Atherogenics, the other on "a synethetic version of good cholesterol," sponsored by Esperion. Neither trial was apparently sucessful.
Nissen had not hidden the fact that he did commercially sponsored research. The relevance of his role in research on cholesterol lowering drugs to his meta-analysis of Avandia is unclear.
Pitts and Goldberg listed their primary affiliation as the Center for Medicine in the Public Interest. Pitts is its President, and chief blogger on the CMPI site DrugWonks. However, Pitts' day job is to be Senior Vice President for Global Health Affairs at the big public relations firm Manning, Selvage and Lee. Manning, Selvege and Lee has many big pharmaceutical accounts, as listed on the CommuniqueLive.com site. As Senior Vice President for Global Health Affairs, Pitts is presumably responsible for all these accounts. Thus, his livelihood seems to depend largely on his ability to convey the pharmaceutical industry's point of view. Pitts seems to be continuing in his role as a stealth health policy advocate which we first discussed in this post here.
And where else have we heard Nissen sarcastically derided as a would be saint? The Cleveland Plain Dealer reminded us,
Sen. Sherrod Brown and other lawmakers are questioning conflict-of-interest policies at the Food and Drug Administration, where an agency official with ties to the drug industry attacked industry watchdog Dr. Steven Nissen of the Cleveland Clinic.
FDA communications consultant Douglas Arbesfeld recently sent journalists a flaming e-mail about Nissen, who was the co-author of a study in the New England Journal of Medicine that raises safety questions about the diabetes drug Avandia.
The e-mail referred to Nissen as 'St. Steven' and included an anonymous blog item that accused the doctor of criticizing manufacturers that don't support drug trials at the Clinic, according to ABC News online.
Brown and four other lawmakers said in a letter Thursday to FDA Commissioner Andrew von Eschenbach that Arbesfeld 'may be using his position with the FDA to settle old scores with Dr. Nissen.'
It noted that Nissen and Arbesfeld had been adversaries in an earlier controversy over the safety of a Johnson & Johnson heart drug. Arbesfeld was a spokesman for Johnson & Johnson at the time.
The lawmakers said Arbesfeld's e-mail may give the impression the government encourages smear campaigns against independent scientists. Their letter asks the commissioner to explain policies on hiring from drug companies and potential conflicts of interest.
An FDA spokeswoman did not respond to requests for comment Friday.
Disputing whether Dr Steven Nissen is a saint, sinner, or something else only seems to distract from the substantive questions I raised above. It is interesting that the "Saint Steven" references were made nearly simultaneously by the Vice President in charge of health care (mainly pharmaceutical) accounts of a large public relations firm and a FDA spokesperson with many previous ties to the pharmaceutical industry.
So the spin cycle revolves merrily on about the Avandia case, throwing off obfuscation after obfuscation that distract from the central issues of the case. But maybe if the pharmaceutical industry really wants to avoid being labelled "shifty," (see post here) it could damp down the enthusiasm of its advocates for endlessly spinning this case, and address the real substantive issues: what are the harms and benefits of Avandia? were data about the drug suppressed, and if so, how can we prevent this from happening in the future.
ADDENDUM (14 June, 2007) - To those visiting via links from Clinical Psychology and Psychiatry, KevinMD, Notes from Dr RW, PharmaGossip, Retired Doc's Thoughts, and Question Authority with Dr Peter Rost: We thank those bloggers for their kind words. Welcome to Health Care Renewal. Our goal is to discuss threats to physicians' and other health care professionals' core values, especially those due to concentration and abuse of power. We do end up talking a lot about questionable practices by the pharmaceutical industry and its leaders, but there are many things to question about the management and operations of other health care organizations. Please have a look, and feel free to comment.