Evelyn Pringle November 2007
On November 14, 2007, the FDA added a new black box warning to GlaxoSmithKline's diabetes drug Avandia, about a potential increased risk of heart attacks, in addition to the black box warning that was added in August 2007, about the increased risk of heart failure.
The FDA said the new warning would also apply to Glaxo's diabetes drugs Avandamet and Avandaryl, since they both contain the same active ingredient as Avandia.
However, Senator Chuck Grassley (R-Iowa), ranking member of the Senate Finance Committee, has asked the FDA to respond to accounts that on October 2, 2007, the agency convened a drug safety oversight board that voted to keep Avandia on the market by a one-vote margin amid considerations of a second warning.
In an October 26, 2007 letter to FDA Commissioner Andrew von Eschenbach he is also asking about the terms and conditions governing public notification with this sort of information.
"The Avandia case continues to present new rounds of questions about the way the FDA monitors and assesses drug risks and decides whether to let the public know about emerging risks," Senator Grassley said in an October 29, 2007 press release.
Among those who voted in favor of the drug's removal was the Department of Veterans Affairs and last month the Department announced that it was removing Avandia from its list of approved drugs and would severely limit its use. VA sales reportedly represent about 8% of total Avandia sales in the US.
On June 5, 2007, the NEJM published a paper entitled, "Rosiglitazone -- Continued Uncertainty about Safety," by Dr Jeffrey Drazen, Dr Stephen Morrissey and Dr Gregory Curfman, which drew more attention to some of the safety concerns about Avandia that were first reported in a study in the New England Journal of Medicine by Cleveland Clinic Cardiologist Dr Steven Nissen in May 2007.
The paper cited an analysis which indicated an increase of about 40% in the risk of myocardial infarction in patients receiving Avandia when compared to patients receiving either an oral diabetes drug such as metformin or a sulfonylurea or a placebo.
"Since rosiglitazone is widely used for the treatment of type 2 diabetes and since the analysis considered all publicly available data on the topic," the authors wrote, "we published the article to make health care professionals and their patients aware of these potential adverse effects."
On September 11, 2007, the Journal of the American Medical Association published two new studies on Avandia. One was a meta-analysis co-authored by Dr A Michael Lincoff and Dr Nissen of the Cleveland Clinic, that found Avandia's main competitor, Actos, appeared to protect diabetic patients from heart attacks, stroke and death by 18%. The second study, also a meta-analysis, by researchers led by Dr Sonal Singh at Wake Forest University, concluded that Avandia increased the risk of heart attack by 42%.
According to the November 2007 report by the Senate Finance Committee, FDA scientists presented an analysis at a July 30, 2007, safety panel meeting, which estimated that Avandia caused approximately 83,000 excess heart attacks since coming on the market.
The report notes that Dr John Buse, a medical researcher at the University of North Carolina, tried to sound the alarm about the increased risks associated with Avandia in 1999, and states: "Had GSK considered Avandia's increased cardiovascular risk more seriously when the issue was first raised in 1999 by Dr. Buse, instead of trying to smother an independent medical opinion, some of these heart attacks may have been avoided."
The committee found it most troubling that the plans to silence Dr Buse involved discussions by GSK executives at the highest levels, including CEO Jean-Pierre Garnier.
Citing relevant e-mails, the report says, "GSK executives labeled Dr. Buse a 'renegade' and silenced his concerns about Avandia by complaining to his superiors and threatening a lawsuit."
GSK also required Dr Buse to sign a letter claiming that he was no longer worried about cardiovascular risks associated with Avandia, which GSK officials referred to as Dr Buse's "retraction letter," and intended to use the letter to gain favor with a financial consulting firm that was evaluating GSK's products for investors, according to the report.
However, even though Dr Buse remained silent in public, he continued privately to voice his concerns about the problems with Avandia and wrote a letter to FDA Commissioner Dr Jane Henney on March 15, 2000, after he signed the retraction letter, warning the FDA about the risks of Avandia and describing GSK's abuse of clinical trial data.
"I remain concerned about the safety of rosiglitazone," he wrote, "in light of its consistent negative impact on lipids documented in the FDA registration data as well as a worrisome trend in cardiovascular deaths and severe adverse events in the subjects exposed to rosiglitazone versus active comparators."
Dr Buse also stated, "I think the FDA has to act forcefully to prevent the rampant abuse of clinical trial data by SmithKline Beecham."
He warned Dr Henney that Glaxo was overstating the safety of Avandia with respect to cardiovascular risks. "I have been shown glossy materials claiming that rosiglitazone has been uniquely studied in patients with preexisting cardiac disease," he wrote, "including patients with a number of associated conditions (such as unstable angina)."
"I know for a fact," he wrote, "that such patients are excluded in clinical trials as I am a PI in one of their trials."
"I am sure there have been abuses by representatives of all companies that market drugs," Dr Buse stated, "but there is something pervasive and systematic that I detect in my travels regarding the marketing of rosiglitazone."
The following month, GSK officials somehow obtained a copy of his letter to the FDA, and GSK drafted another letter to Dr Buse from executive Martin Freed stating: "I remain concerned about your ongoing aggressive posture towards rosiglitazone and SmithKline Beecham. In my opinion, you have presented to [FDA] several unfair, unbalanced, and unsubstantiated allegations."
The Senate report notes that Dr Buse remained silent for about two years, but on October 23, 2005, he again privately voiced his opinion about Avandia in an e-mail to Dr Nissen and described his treatment by GSK. Specifically, Dr Buse wrote:
"Steve: Wow! Great job on the muriglitazar article. I did a similar analysis of the data at rosiglitazone's initial FDA approval based on the slides that were presented at the FDA hearings and found a similar association of increased severe CVD events. I presented it at the Endocrine Society and ADA meetings that summer. Immediately the company's leadership contact[ed] my chairman and a short and ugly set of interchanges occurred over a period of about a week ending in my having to sign some legal document in which I agreed not to discuss this issue further in public."
Later in the email, Dr Buse wrote, "I was certainly intimidated by them but frankly did not have the granularity of data that you had and decided that it was not worth it."
"Again congratulations on that very important piece of work," he stated. "It makes me embarrassed to have caved in several years ago."
The report also describes GSK's behavior since the Committee first brought the allegations about Avandia to light as "less than stellar."
"Instead of acknowledging the misdeed to investors, apologizing to patients, and pledging to change corporate behavior," the report notes, "GSK launched a public relations campaign of denial."
Specifically, the report quotes a May 21, 2007, company press release entitled, "GSK Response to US Senate Committee on Finance," which states that the allegations raised by the Committee were "absolutely false," and a July 25, 2007 interview in The Philadelphia Inquirer in which CEO Jean-Pierre Garnier denied having any knowledge of the intimidation of Dr Buse.
The report also says the behavior of GSK during the time that Dr Buse voiced concerns was "less than stellar." Had Dr Buse been able to continue voicing his concerns, without being characterized as a "renegade" and without the need to sign a "retraction letter," it appears that the public good would have been better served.
The report notes serious concerns about the culture of leadership at GSK, but, even "more serious perhaps is our fear that the situation with Dr Buse is part of a more troubling pattern of behavior by pharmaceutical executives," the Committee states.
As an example, the report points out that Dr Gurkirpal Singh of Stanford University also testified at a Committee hearing in 2004 that an executive at Merck sought to intimidate him by calling his superiors and warned him that they would make life very difficult for him if he persisted in his request for data on Vioxx.
"Merck's intimidation of Dr. Singh as it sought to protect Vioxx," the report says, "bears striking similarities to apparent threats by GSK against Dr. Buse to protect Avandia."
During his November 15, 2007 speech on the Senate floor, Senator Grassley discussed the hearing on November 18, 2004, that followed the withdrawal of Vioxx, which "turned the spotlight on systematic problems" at the FDA.
"We found that the FDA maintained a cozy relationship with the drug industry and suppressed scientific dissent regarding agency actions on drug-safety," he said.
At that Vioxx hearing, Senator Grassley said the Committee heard about Merck using its power, influence and access to discredit FDA safety expert Dr David Graham and how Merck also tried to intimidate Stanford researcher Dr Gurkirpal Singh and warned him to stop asking for more safety data on Vioxx, despite the fact he was their consultant.
He called it "troubling" that three years later, "I am here with my colleague, Senator Baucus, to talk about another case where pharmaceutical executives used power, influence, and access to intimidate a medical researcher."
In essence, he said, another company wanted to put an end to another scientist who was voicing concerns about the cardiovascular risks associated with a drug. "So what we have here, are three cases where companies intimidated researchers who dared to express concerns about risky drugs," he pointed out.
The Committee's report also notes concern that this behavior may be more prevalent than evidenced in these two cases. "Corporate intimidation, the silencing of scientific dissent, and the suppression of scientific views threaten both the public well-being and the financial health of the federal government, which pays for health care," the report states.