Since 1999, there was evidence that Avandia caused an increased risk of heart attacks, but the drugmaker didn’t go out of its way to publicize the problem. In fact, the concern wasn’t widely broadcast until this month, when the New England Journal of Medicine published Steve Nissen’s controversial analysis indicating Avandia may cause a 43 percent higher risk than other drugs.

A similar review, begun in 2005 by Glaxo, found that Avandia raised the risk of reduced blood flow to the heart, including heart attacks, by 31 percent. The company gave the review to the FDA put it on its Web site last year along with 2,000 other studies.
And what’s the excuse for not doing a better job of highlighting the risk? The drugmaker says the Avandia studies, including its own, are flawed and, moreover, the company isn’t obligated, or legally required, to publicize every study done on its drugs.

“Why would you publicize it?” Glaxo ceo JP Garnier told shareholders at the annual meeting last week. “We don’t publicize every submission we make to the Food and Drug Administration.”

This seemingly off-hand comment, which Bloomberg News carried in an analysis this morning, is rather revealing, isn’t it? Glaxo’s line of defense seems to be that the Nissen study showing a 43 percent risk is flawed, and its own study shows a lower risk of 31 percent, but that’s flawed, too. So, in the end, why bother making a big deal out of it?

Beyond the Glaxo-bashing and the Nissen-smearing, JP’s reaction underscores a fundamental flaw - a willingness to look the other way when bad news about a drug becomes known. Granted, Glaxo is conducting another study that may prove more definitive. But as Bloomberg News writes, the drugmaker has a history of downplaying Avandia problems while advertising the hell out of it.

And as Morgan Stanley analyst Andy Baum wrote in a recent investor note, Glaxo’s “robust defense of Avandia safety and their conduct comes with a high risk if evidence of poor disclosure subsequently emerges.”

You can read the rest of the story here.

Glaxo, the world’s second-largest drugmaker after Pfizer, spent $849 million on consumer advertising last year, the most of any pharmaceutical company, according to Nielsen Monitor Plus.

The Cleveland Clinic report released in the New England Journal of Medicine caused Glaxo shares to decline 11.5 percent since then, cutting $17.6 billion from the company’s market value.

Avandia generated $3 billion for Glaxo last year, or 7 percent of total sales, and at least $12 billion since 1999. Analysts had estimated sales of $4 billion in 2007. The medicine helps the body better use insulin to lower high blood sugar, which in excessive amounts can cause complications such as heart disease, and kidney and eye damage. Glaxo says the treatment has risks similar to other oral diabetes medicines.

By 2005, the drugmaker had spent almost $200 million on advertisements advising U.S. consumers to ask their doctors about Avandia, its second best-selling product. Advertising included warnings contained in prescribing information, such as “Avandia may cause fluid retention or swelling, which can make some heart problems worse or lead to heart failure,” from a 2005 television commercial.

“It’s fair to say that from early on there have always been a few events of cardiovascular nature,” Glaxo Chief Medical Officer Ron Krall said May 21.

As far back as April 1999, executives of SmithKline Beecham Plc, which a year later merged with GlaxoWellcome Plc to become GlaxoSmithKline Plc, told the FDA that Avandia caused “minimal” cardiovascular side effects and “mild to moderate” fluid buildup. Fluid in the lungs or bloodstream can increase the heart’s workload.

The agency cleared the drug for sale the next month. Some advisory committee members called for more research on potential complications. In February 2001, after the drug was on the market, Glaxo agreed to an FDA request to change the drug’s prescribing label to warn doctors that Avandia, like other drugs in its class, can cause fluid retention.

Company sales representatives who knew the risks “denied their existence” three months later in oral presentations at the American Association of Clinical Endocrinologists’ meeting in San Antonio, Texas, FDA officials noted in a July 2001 letter to Glaxo.

The FDA told Glaxo in that letter that its marketers should stop denying or minimizing the increased risk of “heart failure or other cardiovascular adverse events” in patients taking the drug with insulin, according to the FDA’s Web site. The agency criticized Glaxo for continuing to “engage in false or misleading promotion of Avandia.”

Analysts at Citigroup and Morgan Stanley had noted possible cardiovascular side effects in notes to investors last year. “The key issue in addition to at least equivalent efficacy of Avandia to metformin and glyburide is cardiovascular safety,” Citigroup analysts wrote in a Nov. 23 report.

The next month, as results of a large-scale, company-funded trial were published, Glaxo executives said the overall risk of death, heart attack and stroke with Avandia was similar to other diabetes medicines.

Diabetes researcher Rury Holman of Oxford University in the U.K., an investigator in the $100 million company study, known as ADOPT, said in a Dec. 3 interview that the results would cause concern. “These people are early diagnosis, they haven’t got complications,” Holman said. “The fact that we’re seeing these cardiovascular effects in them, we can’t deny that. The concern when these data come out is you’ve got relatively healthy patients and still there’s a little bit of a signal.”

Earlier this year, cardiologist Steven Nissen and co- researcher Kathy Wolski of the Cleveland Clinic found Glaxo’s own analysis of Avandia studies while scouring the company’s Web site. The two uncovered the analysis after failing to gain the company’s cooperation for their review, Nissen said in an interview May 23.

“I just built this piece by piece until I had enough,” Nissen said. “Then I stumble upon the company’s own meta analysis deeply buried on their Web site, and it shows the same thing. It was a eureka moment for sure.”

Earlier this week, Glaxo began a campaign to challenge Nissen’s findings that helped its stock recover. Chris Viehbacher, the president of Glaxo’s U.S. pharmaceuticals unit, met with reporters May 30 to take exception to the report and the “sensationalizing” of it in media coverage. Krall wrote a May 30 letter to The Lancet which the company said “clarifies the safety record of Avandia.”

Since 1999, the company and the FDA have monitored and updated Avandia’s label for adverse events and continue to do so, the company said today in an e-mailed statement. “The totality of data provide clear evidence that Avandia has a comparable cardiovascular profile to other oral diabetes medicines and that these data are more scientifically rigorous and more clinically meaningful than the recently published meta analysis.”

The company’s failure to place as much emphasis on Avandia’s risks as it placed on the drug’s benefits may hurt it because of possible legal liability, Morgan Stanley analysts led by Andrew Baum said May 21 in a note. Avandia is facing competition from newer treatments, and reports of a heart risk may hurt sales by as much as 50 percent, analysts estimate.

GlaxoSmithKline’s “robust defense of Avandia safety and their conduct comes with a high risk if evidence of poor disclosure subsequently emerges,” Baum wrote.