According to a November 2007 report by the Senate Finance Committee, an analysis by FDA scientists presented at a July 30, 2007, safety panel meeting estimates that Avandia has caused approximately 83,000 excess heart attacks since coming on the market.
The report entitled, "The Intimidation of Dr. John Buse and the Diabetes Drug Avandia," summarizes the Committee’s findings regarding GlaxoSmithKline’s intimidation of Dr Buse, an independent scientist who first voiced concerns about Avandia back in 1999.
The Committee points out that Dr Buse is an expert in diabetes with extensive research experience in the thiazolidinedione class of drugs that includes Avandia and states: "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."
In November 2007, the FDA added a black box warning to GlaxoSmithKline’s diabetes drugs Avandia, Avandamet, and Avandaryl about an increased risk of heart attacks, and a boxed warning about an increased risk of heart failure was added in August 2007.
On October 26, 2007, Senator Chuck Grassley (R-Iowa), ranking member of the Finance Committee, sent a letter to FDA Commissioner Andrew von Eschenbach asking him to respond to reports 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 while considering whether to add a second warning.
"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 a press release the same day.
The Senator also asked the Commissioner to explain the conditions governing disclosure of this information. "I have yet to see any public notification of this vote," he states.
"Accordingly," he writes, "I would appreciate information from the FDA regarding the internal policies and procedures governing the DSOB and the terms and conditions governing the release of information from the DSOB to the public."
The Department of Veterans Affairs was among those who voted to remove Avandia from the market and has since removed Avandia from its formulary of approved drugs. On December 6, 2007, two pharmacy benefit managers, Prime Therapeutics and HealthTrans followed suit and announced the removal of Avandia from their formularies.
The studies verifying the dangers of Avandia have been non-stop over the past 6 months. On June 5, 2007, the New England Journal of Medicine published a paper by Dr Jeffrey Drazen, Dr Stephen Morrissey and Dr Gregory Curfman, which drew more attention to the safety concerns that were first reported in a study in the NEJM by Cleveland Clinic cardiologist Dr Steven Nissen and Kathy Wolski, in May 2007.
The paper cites an analysis which showed about a 40% increased risk of myocardial infarction in patients receiving Avandia when compared to patients receiving diabetes drugs such as metformin or a sulfonylurea or a placebo.
On September 11, 2007, the Journal of the American Medical Association published two more studies. The first, co-authored by Dr A Michael Lincoff and Dr Nissen, found Avandia’s main competitor, Actos, appeared to protect diabetic patients from heart attacks, stroke and death by 18%. The second, by Dr. Sonal Singh and researchers at Wake Forest University, concluded that Avandia increased heart attack risks by 42%.
On December 12, 2007, JAMA reported another population-based study by Canadian researchers of patients 66 and older with diabetes, that found thiazolidinedione treatment, primarily with Avandia, was associated with an increased risk of congestive heart failure, acute myocardial infarction, and mortality when compared with other combination oral hypoglycemic agent treatments.
According to the Senate Committee report, if GSK had 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 the 83,000 heart attacks may have been avoided.
The report says the Committee found it "most troubling" that plans to silence Dr Buse involved discussions by GSK executives at the highest levels, including then and current, CEO Jean-Pierre Garnier.
In response to a letter dated May 21, 2007, in which the Committee asked about the retaliation against Dr Buse, the report notes that GSK issued a press release to refute the allegations and the Wall Street Journal reported that, "[GSK] called the suggestion ‘absolutely false.’"
The Committee also points out that CEO Jean-Pierre denied having any knowledge about the intimidation of Dr Buse in a July 25, 2007 interview with The Philadelphia Inquirer, when in fact, emails written in June 1999, show GSK executives discussed Dr Buse in a series of emails they titled, "Avandia Renegade," and silenced him by complaining to his superiors and threatening to sue him. One email cited in the report states:
"The sentiment of the SB group was to write him a firm letter that would warn him about doing this again…with the punishment being that we will complain up his academic line and to the CME granting bodies that accredit his activities….The question comes up as to whether you think this is a sensible strategy in the future (we don’t really do too much work at UNC to make any threats)."
SB refers to SmithKline Beecham which is now GSK.
The report also cites an email by Dr Tachi Yamada, GSK’s head of research at the time, that was copied to Dr Garnier which discussed plans to retaliate against Dr Buse stating:
"I plan to speak to Fred Sparling, his former chairman as soon as possible. I think there are two courses of action. One is to sue him for knowingly defaming our product even after we have set him straight as to the facts-the other is to launch a well planned offensive on behalf of Avandia…."
According to the report, Dr Yamada did in fact call Fred Sparling, the chairman of Dr Buse’s department and GSK also demanded that Dr Buse sign a letter claiming that he was no longer worried about cardiovascular risks of Avandia, which GSK officials referred to as a "retraction letter."
Emails also show that on July 2, 1999, several GSK officials discussed sharing the "Buse retraction letter" with financial analysts who were evaluating GSK’s products for investors and the report notes that the emails were copied to GSK executives including Dr Garnier.
However, even though Dr Buse appeared to go silent in public after signing the retraction letter, he did voice his concerns in a letter to the FDA Commissioner on March 15, 2000, about the risks associated with Avandia and GSK’s misrepresentations regarding the clinical trial data on the drug.
In the letter, Dr Buse noted the drug’s "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."
He also urged the FDA to act forcefully to prevent the abuse of clinical trial data by the company. "I have been shown glossy materials claiming that rosiglitazone has been uniquely studied in patients with preexisting cardiac disease including patients with a number of associated conditions (such as unstable angina)," he stated in the letter.
Dr. Buse explained that he knew for a fact that these types of patients were excluded in the Avandia trials because he was the Principle Investigator in one. And while acknowledging that there are probably abuses by all companies that market drugs, he said, "there is something pervasive and systematic that I detect in my travel
s regarding the marketing of rosiglitazone."
Somehow, GSK obtained a copy of the FDA letter, and GSK executives faxed it among themselves with a cover note that read: "We need to address this as a company….Looks like Dr. Buse doesn’t buy into our lipid or cardiovascular story."
According to the Senate report, GSK then drafted a letter to Dr. Buse from one of its executives, Martin Freed, that stated: "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."
After that, the report notes that Dr. Buse appeared to remain silent for about two years, but voiced his concerns again in a private October 23, 2005 email to Dr Nissen, and described his treatment by GSK after his presentations at the meetings of the Endocrine Society and the ADA and suggested that Avandia may carry increased risks.
"Immediately," he wrote, "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."
"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," Dr. Buse told Dr. Nissen.
The Committee’s report says GSK’s behavior at the time that Dr Buse voiced his concerns and since the Committee first brought the allegations about Avandia to light was "less than stellar."
"Instead of acknowledging the misdeed to investors, apologizing to patients, and pledging to change corporate behavior, GSK launched a public relations campaign of denial," the report notes.
The Committee also points out that GSK’s concerns over Dr Buse reemerged in 2002, as his professional stature grew and in September 2002, one GSK official described him as the "most powerful Endocrinologist in the Carolinas…." and said, "[H]e is gaining power nationally and internationally."
In the report, the Committee notes concerns not only about the culture of leadership at GSK, but also a "fear that the situation with Dr. Buse is part of a more troubling pattern of behavior by pharmaceutical executives."
As an example, the report cites another case in which Stanford University researcher, Dr. Gurkirpal Singh, testified at a November 18, 2004 hearing on Vioxx, and said a Merck executive intimidated him by calling his superiors and warning Dr. Singh that Merck would make life very difficult for him if he persisted in his request for Vioxx data.
"Merck’s intimidation of Dr. Singh as it sought to protect Vioxx bears striking similarities to apparent threats by GSK against Dr. Buse to protect Avandia," the report notes.
In a November 15, 2007 speech on the Senate floor, Senator Grassley said the Vioxx hearing "turned the spotlight on systematic problems" at the FDA and described in detail how Merck had used power, influence and access to discredit safety expert Dr David Graham and said that it was "troubling" three years later to learn of another case where a drug company used power, influence, and access to intimidate a researcher.
On December 18, 2007, the Los Angeles based Baum, Hedlund, Aristei & Goldman law firm announced the filing of an Avandia lawsuit against GSK on behalf of Rogelio Larosa and his adult son, Eric, in the US District Court, Southern District of California accusing GSK of causing the death of Milagros Larosa, their wife and mother, due to negligence, fraud, breach of warranty and a failure to warn about the risks of Avandia.
The lawsuit alleges that GSK over-promoted Avandia, carelessly promoted it as safe and effective and refused to adequately warn the medical community and consumers about the risks associated with the drug until the FDA finally took action.
According to the complaint, over the course of a year, Ms. Larosa was hospitalized three times for heart problems, classified as myocardial ischemic events, before she had a fatal stroke.
She suffered the first heart blockage in December of 2004 and two more occurred in January 2005 and July 2005, with each requiring a heart bypass or "coronary revascularization" to restore oxygen and nutrients to her heart.
After the last blockage, Ms. Larosa had to be placed in a nursing home where she received constant care for 6 months until a stroke killed her on December 20, 2005. She was prescribed Avandia to treat Type 2 diabetes and she had no prior heart problems before taking the drug, according to the complaint.
Baum Hedlund attorney Roger Drake reports that there are currently about 50 state and federal lawsuits filed against GSK in the US.
The Larosa lawsuit will be consolidated with all the other federal Avandia lawsuits against GSK that were joined together in October 2007 by the Judicial Panel on Multidistrict Litigation, under the title, "In re Avandia Marketing, Sales Practices & Products Liability," with US District Judge Cynthia Rufe of the Eastern District of Pennsylvania overseeing the litigation.