Evelyn Pringle June 10, 2007
On May 21, 2007, the New England Journal of Medicine reported a study that found GlaxoSmithKline's diabetes drug Avandia is associated with a 43% increase in heart attacks and possibly a 64% increase in cardiovascular death. The NEJM said it posted the article online ahead of its June 6, 2007 print edition because of its medical importance.
Experts point out that the studies analyzed for the NEJM report were not designed to look for heart risks, many were only 24 weeks long, and it may be that higher risks will appear after a longer term of use. Dr David Nathan, chief of diabetes care at Massachusetts General Hospital, who reviewed the paper for the NEJM, told the Associated Press, "This analysis is just scratching the surface of what may be there."
Avandia (rosiglitazone) was FDA approved in 1999 for the treatment of type 2 diabetes, a disease that affects between 18 to 20 million Americans.
When approved, Glaxo promoted Avandia as being safer than Rezulin, a diabetes drug removed from the market in 2000 after serious cases of liver damage developed in patients taking the drug.
Avandia is currently the top selling diabetes drug with total US sales of $2.2 billion in 2006, according to IMS Health, a healthcare tracking information firm. A one-month supply sells for between $90 and $170, the Associated Press reported on May 23, 2007.
"More than 6 million people worldwide," the Associated Press reports, "have taken the drug to control blood sugar since it came on the market eight years ago, and about 1 million Americans use it now."
The FDA is going to have an extremely tough time wiggling out from under the rug of blame for this regulatory failure. The situation "reflects very badly on the FDA and on Glaxo," Dr Nathan said. "It's the FDA's responsibility to be monitoring this stuff."
In an editorial that accompanied the study in the NEJM, Dr Bruce Psaty of the University of Washington and Dr Furberg of Wake Forest University wrote: The drug "represents a major failure of the drug-use and drug-approval processes in the United States."
They also state that "the rationale for prescribing rosiglitazone at this time is unclear," because when the drug was approved its benefits were "at best mixed."
Documents dating back 7 years show the FDA knew about the risks associated with Avandia and did nothing to protect consumers. The day after the new study appeared online, on May 23, 2007, Dr Sidney Wolfe, director of Public Citizen, a non-profit health research group, sent a letter to FDA Commissioner Andrew von Eschenbach, which described a July 16, 2002 FDA memo that showed FDA scientists had recommended that the label for Avandia be amended to include post-marketing reports of heart failure among patients taking the drug.
"The failure of the FDA to act on the recommendations made almost five years ago by its Division of Drug Risk Evaluation is yet another case in which the conclusions of scientists who are engaged in post-market drug safety review are not taken seriously enough or addressed soon enough," Dr Wolfe said in a press release.
"As a result," he stated further, "millions of people - to the detriment of their health - are prescribed drugs whose risks are dangerously understated, instead of being prescribed safer, equally or more effective alternative drugs."
According to the memo, in July 2002, the FDA had 25 adverse reaction reports in which the use of Avandia resulted in hospitalization for heart failure. By the fall of 2006, the number of cases had increased to 415, Public Citizen reports.
Another memo dated May 22, 2002, submitted to the FDA by Dr. Wolfe and Larry Sasich for an FDA Hearing on Risk Management of Prescription Drugs informed the panel that a Glaxo-employed physician had contacted Public Citizen to report that the company was concealing reports of serious problems found with the drug.
"This week," they informed the FDA, "we received an anonymous call from a GlaxoSmithKline physician who was alarmed at the failure of his company to require a black box warning concerning heart failure caused by Avandia."
"He maintained that the company currently has 450 reports of heart failure associated with the use of the drug and over 1200 reports of edema," the statement said.
Nearly two years earlier, on March 15, 2000, Dr. John Buse, an Associate Professor of Medicine and Director of a Diabetes Care Center in Durham, North Carolina, sent a letter to then FDA Commissioner, Dr Jane Henney, warning the FDA about the risks of Avandia and describing the abuse of clinical trial data by Glaxo.
"I remain concerned about the safety of rosiglitazone," Dr Buse 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 warned, "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 issues. "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 noted, "that such patients are excluded in clinical trials as I am a PI [Principal Investigator] in one of their trials."
Lawmakers in both Houses of Congress reacted to the news of another FDA regulatory failure immediately. On May 21, 2007 the US House of Representatives Committee on Oversight and Government Reform announced that a hearing would be held on June 6, 2007, at 10:00 am in Room 2154, Rayburn House Office Building, to assess the FDA's role in the evaluation of the safety of Avandia.
Committee chairman, Rep Henry Waxman (D-CA) extended an invitation to the author of the NEJM article, cardiologist, Dr Steven Nissen of the Cleveland Clinic, to testify at the hearing and discuss his article.
Dr Nissen and statistician Kathy Wolski, MPH, evaluated 42 studies involving nearly 28,000 patients and compared the 15,560 patients who were using Avandia to the patients who were not using the drug. The study found there were 86 myocardial infarctions in the Avandia group and 72 in the control group and there were 39 deaths from cardiovascular causes in Avandia patients compared to 22 in the control group.
Rep Waxman also sent a letter to FDA Commissioner Andrew von Eschenbach requesting his testimony at the hearing. In addition, he instructed the Commissioner to provide the Committee with specific information from August 1, 2005, to the present to include: (1) A chronology of actions taken by FDA in relation to the cardiovascular safety of rosiglitazone; (2) All communications between GlaxoSmithKline and the FDA relating to cardiovascular safety of rosiglitazone; and (3) All internal FDA analyses, slide presentations, and memoranda relating to the cardiovascular safety of rosiglitazone.
"In complying with this request," Rep Waxman advised the Commissioner, "you should produce all responsive documents in your possession, custody, or control."
Rep Waxman also told the Commissioner, "you should submit a written certification, signed by you or your counsel, stating that: (1) a diligent search has been completed of all documents in your possession, custody, or control which reasonably could contain responsive documents: and (2) all documents located during the search that are responsive have been produced to the Committee or identified in a privilege log."
And last but not least, Rep Waxman sent a letter to Glaxo CEO, Dr Jean-Pierre Garnier, asking him to appear. "We request that you come prepared to discuss your company's actions with regard to the cardiovascular safety of Avandia," the letter states.
Over in the US Senate, Senators Max Baucus and Chuck Grassley, Chairman and Ranking Member of the Senate Committee on Finance, which has jurisdiction over the Medicare and Medicaid programs, issued a public statement and sent letters to the FDA and Glaxo demanding they provide specific documents and other information to the Committee.
"What we are learning about the handling of Avandia," Sen Baucus said in the statement, "by both GlaxoSmithKline and the FDA is appalling and unacceptable."
"Both the drug company and the FDA," he said, "have some major explaining to do about what they knew about Avandia, when they knew it, and why they didn't take immediate action to protect patients."
"We need to know if this is another Vioxx," Senator Grassley stated, "where the FDA sat on its hands and endangered lives."
"The FDA," he continued, "has talked a good game about how it's beefed up post-market
surveillance over the last two years, but a case like this undermines that claim."
Experts say the new study findings are alarming because two-thirds of the people with type 2 diabetes die of heart problems. In a May 21, 2007 letter to Christopher Viehbacher, President, US Pharmaceuticals, GlaxoSmithKline, Senators Baucus and Grassley wrote, "It is troubling, to say the least, that by taking Avandia, diabetics may be increasing their risk of the very adverse event that they hope to prevent by controlling their blood sugar."
"To make matters worse," they advised, "American taxpayers have spent hundreds of millions of dollars on this drug through the Medicare and Medicaid programs."
"One of the most immediate concerns to us," they told Mr Viehbacher, "are reports that GSK employees silenced one or more medical professionals who attempted to speak out about the potential for cardiovascular problems with Avandia."
"This allegation is very serious and warrants further investigation," the Senators wrote.
According to plaintiffs attorney, Karen Barth Menzies of Baum Hedlund, a law firm that has been litigating drug related cases against Glaxo since 2001, ""The relationship between FDA and the drug industry is disturbing. We've seen internal correspondence between GSK and the FDA that would cause anyone to question the objectivity and regulatory effectiveness of the FDA. Apparently the FDA has failed yet again to protect the public - to the benefit of pharmaceutical industry profits. This failure, and FDA's derogatory attitude towards Dr. Nissen's study, should sound an alarm to all healthcare providers, patients and legislators that the problem is systemic. Patient safety commands serious change in the agency and the industry."
Already, legal conferences are being scheduled to discuss the legal implications of this latest drug safety scandal. Karen Barth Menzies is an invited speaker at an upcoming legal conference regarding Avandia. The conference will include Avandia's background, the science behind the drug, its side effects as well as the FDA's role in regulating Avandia.
(Evelyn Pringle is a regular columnist for OpEd News and investigative journalist focused on exposing corruption in government and corporate America)