Healthy Skepticism Library item: 14931

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Publication type: news

Mundy A, Favole J.
Glaxo's Emails on Avandia Reveal Concern
The Wall Street Journal 2009 Jan 14
http://online.wsj.com/article/SB123190610976680477.html?mod=googlenews_wsj

Full text:

When a study linking GlaxoSmithKline PLC’s diabetes treatment Avandia to increased heart-attack risk was published in
2007, the pharmaceutical giant publicly responded by denouncing the researchers’
conclusions. But internal emails indicate some of the company’s own scientists were concerned that Glaxo’s data were
showing the same thing.

“The numbers are the numbers, the analysis is very similar to our own,” wrote the company’s senior consultant in an
email days before the study was published in the New England Journal of Medicine. He added that Glaxo couldn’t
“undermine” the figures but might find a way to explain them.

The journal’s study, which found a 43% higher risk of cardiovascular events for patients taking Avandia, caused the
drug’s sales to plunge.
It also triggered congressional investigations into Glaxo’s marketing of the drug and the Food and Drug Administration’s
response to the safety concerns.

Glaxo added a “black-box” warning to Avandia in November 2007 that says the drug can cause or exacerbate congestive
heart failure. The company and the FDA continue to say Avandia is a valuable option for patients when used properly. In
a recent interview, Janet Woodcock, director of the FDA’s drug-review division, said Avandia has been “convicted without
a trial.”

Glaxo also says it didn’t conceal the fact that it conducted its own meta-analysis and found a trend that was similar to
that in the New England Journal study by Cleveland Clinic cardiologist Steven Nissen.
It points to a letter published in the Lancet on May 30, 2007, in which Chief Medical Officer Ronald Krall said:
“GlaxoSmithKline did similar meta-analyses in 2005 and 2006 and found hazard ratios in the same direction” as Dr.
Nissen. The company adds that it gave full information on its data analyses to the FDA.

A leading Republican senator, Sen. Chuck Grassley of Iowa, has been pushing the FDA to ask Glaxo to withdraw the drug.
He is preparing a report that may be released soon containing excerpts from Glaxo documents about the company’s efforts
to defend its drug from the New England Journal study, according to people familiar with the situation.

Sen. Grassley’s report is likely to draw the attention of plaintiffs’
lawyers, who have filed suits on behalf of about a thousand patients who are allegedly suffering heart-related problems
after taking Avandia.

The study by Dr. Nissen for the New England Journal was supposed to be kept under wraps until its release on May 21, but
Glaxo obtained a copy on May 3 from a doctor, Steven Haffner of the University of Texas, who was reviewing it for the
medical journal. Dr. Haffner had been a Glaxo consultant on Avandia since 2000 and received $433,000 from Glaxo between
2000 and August 2007. He confirms giving Glaxo the study, though he says doing so was “a terrible mistake.”

Dr. Nissen says that when he was visited by top Glaxo scientists, including the chief medical officer, just days before
publication, they tried to get him to rethink his concerns. “They never revealed that they had obtained a copy of our
manuscript and had concluded that our findings were irrefutable,” he says. “Instead, they attacked the validity of the
study and the motives of both the authors and the NEJM.”

As soon as Glaxo got Dr. Nissen’s draft, its researchers began a detailed analysis, according to the email excerpts. On
May 4, one wrote, “There is no statistical reason for disregarding the [Nissen] findings as presented.” Glaxo declined
to make employees involved in the emails available for comment. The Wall Street Journal hasn’t viewed the full emails
from which the extracts were drawn.

In a May 8, 2007, email, Moncef Slaoui, the director of Glaxo research, told several executives: “FDA, Nissen and GSK
all come to comparable conclusions regarding increased risk for ischemic events, ranging from 30% to 43%!”

Glaxo spokeswoman Nancy Pekarek says Dr. Slaoui used imprecise language in his internal email when he said that Nissen
and GSK came to comparable conclusions. She says Dr. Slaoui was more precise in written testimony to Congress when he
said that the company didn’t agree with Dr. Nissen’s conclusions and thought that his methodology had significant
limitations.

Glaxo responded to Dr. Nissen’s study by putting out interim results of a study called Record. But there were questions
at Glaxo about whether putting out the Record results might backfire. “What’s to stop [Nissen] adding the events from
Record to his meta-analysis and reenforcing his view?” one scientist wrote. Nonetheless, Glaxo sent interim Record
results to the New England Journal for publication in late May.

The medical journal questioned the initial draft from Glaxo. “The editors feel strongly that your data do not support
the statement that the Record results for MI [myocardial infarction or heart attack] contradict the Nissen
meta-analysis,” said one reviewer in an email to Glaxo. “This statement must be removed or modified.”

The revised draft of the article was published in the New England Journal on June 5. It said Avandia might be linked to
increased heart risks but didn’t increase the likelihood of heart attack or death. At the time, Dr. Slaoui called the
article “very reassuring to doctors and patients.”

But the medical journal also included an editorial by Massachusetts General Hospital endocrinologist David Nathan, who
said the study “fails to provide exculpatory evidence” about Avandia, in part because too many patients had dropped out
of the Record trial.

Glaxo says it didn’t disagree with Dr. Nissen’s data but with his decision to draw conclusions from the data. “GSK
believes that a full and scientific evaluation of all the data does not confirm the safety questions originally raised.”

The FDA is also facing questions about its handling of Avandia. On June 6, 2007, at a hearing before Sen. Grassley on
Avandia, the FDA’s commissioner, Andrew von Eschenbach, defended the agency’s refusal to remove the drug from the market
or radically strengthen its warning label.

He said the FDA was doing its own analysis, which wasn’t complete. An FDA press release said the agency had recently
received data from Glaxo about its meta-analysis of 2005 and was reviewing it.

But the agency received the company’s analysis the year before the New England Journal study’s release, according to
Glaxo emails and a Glaxo statement Tuesday. The FDA declined to comment.

Some doctors were worried early on about cardiac events in their patients taking Avandia. Doctors at a Maryland hospital
told Glaxo’s predecessor company in 2000 that they saw dozens of cases of cardiac issues in patients taking Avandia,
including some cases of congestive heart failure. In a letter to the hospital, the company dismissed the analysis as
inconclusive, and asked a hospital executive to stop the doctors from talking with others about Avandia.