Wednesday, June 06, 2007

More on Avandia: Why We Need to "Call Off the Dogs"

Stories about the glucose lowering drug rosiglitazone (Avandia, GlaxoSmithKline) and the controversy about its cardiovascular risks are still all over the media. We most recently posted about Avandia here.

Let us concentrate on just a few stories. First, on June 5, the Boston Globe focused on Dr Steve Nissen, who was lead author of the meta-analysis about the cardiovascular adverse effects of Avandia that lead off the controversy (see our post here). As Diedtra Henderson reported,

After the Avandia news broke, Robert Goldberg , a conservative pundit and vice president of the Center for Medicine in the Public Interest New York, posted a message on his blog,, that said Nissen is campaigning to become FDA commissioner in a way that 'makes him look craven and small.'

Told of Goldberg's blog entry, Nissen asked, 'Who would say such a thing?'

'I'm not running for anything,' Nissen added. 'I've got a great job here, and I'm not going anywhere.'

Goldberg, however, does have more clout than the average blogger. As a senior fellow at New York's Manhattan Institute , he once wrote that a front-runner to become FDA commissioner would so stymie the drug-approval process that the shorthand message to patients would be: 'Drop dead.' The candidate, Dr. Alastair J.J. Wood, foundered in the face of stiff industry opposition.

In an interview, Goldberg said the cardiovascular risks of such drugs as Vioxx have been highlighted by others, but Nissen is 'the most aggressive in promoting himself, whether he is accurately depicting the risks and benefits of products.'

As we have discussed before, the President of the Center for Medicine in the Public Interest, where Goldberg works, and which runs the blog called DrugWonks, is Peter J Pitts, whose day job is to be Senior Vice President for Global Health Affairs at the big public relations firm Manning, Selvage and Lee. Manning, Selvage and Lee has many big pharmaceutical accounts.

FDA spokesman Douglas Arbesfeld , in an e-mail to reporters days after Nissen's Avandia analysis was published by the New England Journal -- derisively dubbed him 'St. Steven ,' and wondered whether his feet were made of clay.

Arbesfeld, responding to a Boston Globe question about the e-mail message, said the correspondence -- sent using his FDA e-mail address -- reflected his personal views and not the agency's.

Douglas Arbesfeld, where have we heard of him before? Before he went to work for the FDA, he was a spokesperson for Johnson & Johnson, whose assignments included arguing with Dr Steve Nissen on the implications of more restrictive labeling for the drug nesiritide (Natrecor, made by Scios, a Johnson & Johnson subsidiary) (see the NY Times here, and our post here); and defending the company's Janssen subsidiary against charges it manipulated the TMAP guidelines in favor of atypical anti-psychotic drugs like its product risperidone, (Risperdal) (see the NY Times here, see our post here). Earlier, he worked for - you guessed it - public relations firm Manning, Selvage and Lee, and before that, pharmaceutical firm Rhone Poulenc Rorer (which merged into Aventis, which in turn merged into Sanofi-Aventis) (from "On the Move," AdWeek, January 11, 1999.)

Then there was this article in the New York Times by Stephanie Saul and Gardiner Harris,

A supervisor in the drug safety office at the agency said in an interview yesterday that she was rebuked last year after calling for a stronger warning label on Avandia and a competing drug, Actos.

The supervisor, Dr. Rosemary Johann-Liang, said that in March 2006 she approved a recommendation from a safety reviewer at the agency that the drugs be required to carry the strongest warning, a so-called black box warning, because they posed a risk of unusual swelling that could lead to heart failure.

But after officials at the agency who dealt more closely with Glaxo complained, Dr. Johann-Liang said she was ordered to retract her approval of the warning, lost her power to approve such assessments and no longer supervised reviews of the safety of Avandia and Actos.

'This was a very careful review that came to an inescapable conclusion,' Dr. Johann-Liang said in the interview. 'They decided to act like the review never happened and punish me for approving it.'

Senator Charles E. Grassley, Republican of Iowa, has investigated Dr. Johann-Liang’s accusations. Mr. Grassley sent a letter on Monday to the Food and Drug Commissioner Andrew C. von Eschenbach demanding that he investigate the case.

'I hope you recognized what is wrong with this picture,' Mr. Grassley wrote. 'I also sincerely hope that this is not standard practice within the F.D.A.'

A spokeswoman for the agency, Susan Cruzan, said it was investigating the accusations.

Finally, the Associated Press just reported (via the San Diego Union-Tribune here) about today's Congressional hearings by the Committee on Oversight and Government Reform of the US House of Representatives,

Dr. John Buse told lawmakers that after he drew attention in 1999 to heart problems among some patients using Avandia, SmithKline Beecham, which later combined with GlaxoWellcome, warned him that some executives wanted to hold him accountable for a $4 billion drop in the company's stock.

In a letter to SmithKline distributed at the hearing, Buse wrote: 'Please call off the dogs. I cannot remain civilized much longer under this kind of heat.'

Buse, who is head of endocrinology at the University of North Carolina and is set to become president of the American Diabetes Association, said he eventually signed a clarifying statement with the company that was used to ease concerns from investors.

In Buse's letter to the Committee he stated

There was a trend toward increases in serious cardiovascular events and cardiovascular deaths with Avandia as compared to active comparators. Neither was statistically significant. I could not find evidence for such trends with Rezulin and Actos.

I recognized that this was potentially an explosive issue and went to rather extreme ends to make sure that I was not making an error including sharing the results and the slides I was going to present with research scientists from SmithKline Beecham (SKB), the manufacturer of Avandia. Those discussions were cordial and helpful.

Couched with many caveats, I presented the issues outlined at least twice in June of 1999. In the week that ensued, there were a number of phone calls in this regard from SKB. During these calls, it was mentioned on two occasions that there were some in the company who felt that my actions were scurrilous enough to attempt to hold me liable for a loss in market capitalization..... In the end I offered to help the company with further studies and signed a clarifying statement drafted by SKB which was to be used to with the investment community

Is there a pattern here? In one of our earlier posts on the Avandia affair, we noted that the extent that this is a suppression of research case has been overlooked. Many of the clinical trials that Dr Nissen used in his meta-analysis were trials sponsored by GSK which were only made public because GSK had been forced to set up a web-based clinical trials registry by a 2004 settlement of a lawsuit brought by Eliot Spitzer, who charged that GSK had suppressed clinical research about its antidepressant 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.).

The pattern above also seems to be one of attempts to intimidate any one who questions the safety of Avandia. These attempts have gone from verbal ridicule to threats of litigation, and official government action. There also seem to be some interesting linkages among those doing the intimidation to pharmaceutical companies and public relations firms who have them as clients, even if those linkages are not always openly stated.

Of course, intimidating people who blow the whistle about drug safety concerns is bad not only for the whistle-blowers, but for patients and doctors whose decisions about which treatments to give ought to be based on critical review of the best possible clinical evidence, not evidence that is filtered by secrecy and intimidation to only reflect vested interests of the makers of the treatments.

As we have mentioned before, pharmaceutical companies (and other health care corporations) may be regarded by the public as "shifty." If such companies want to regain public trust, they need to call off their dogs, lest nobody can "remain civilized."

ADDENDUM - Pharmalot has links to many documents used in the Congressional hearing here.


Anonymous said...

Does Dr. Buse really exhibit the integrity needed to lead a charitable organization like the ADA that supposedly represents the interests of ALL diabetics?


Anonymous said...

Melody: Sadly, your question is based on false premisses. One would think - as I once did - that integrity would be required, but once you start viewing the ADA as more of a marketing tool (guess who funds it?) than a charitable organization, it makes more sense.

Don't get me wrong, I am sure there are plenty of people on board who volunteer and/or work for the ADA for nothing other than the most charitable and sincere reasons. However, you do not reach the highest levels in such organizations any more because of your integrity.

Anonymous said...

I agree with this completely, thanks for the post.

SandipM said...

Great to see all these connections and linkages exposed. Thanks.

Anonymous said...

I have worked for GSK and other smaller and other large comapanies on the past. I am aware of difficult decisions that companies have to make every day. I don't know if this Avandia issue is a real issure or not, but I do know that I did believe at the time that GSK was more concerned with "integrity" than the others. They preached that you should not just "meet the minimum requirements" as in my other experiences. I didn't believe the concept at first, but I began to believe that they were sincere in the end. This could be a legitimate concern, but I am not sure this can be the whole picture. It is interesting though. I am sure with all of the attention we will soon see what is true and what is fiction soon.