Since that recommendation was made in 1999, experts estimate that tens of thousands of patients have been harmed by Avandia, and they blame the FDA for not requiring Glaxo to conduct a thorough post-market study on the drug's heart risks.
Critics say the agency had many warnings. In March 2000, Dr John Buse wrote the FDA to request "cardiovascular safety trials in high-risk populations." In February 2003, the World Health Organization issued a warning about cardiac risks associated with TZD's, the class of drugs that include Avandia. A review in the NEJM a year later stated that, "data about the effects of TZDs on cardiovascular disease are urgently needed."
In August 2006, Glaxo provided the FDA and the European Medicine Agency with the results of several studies, including an analysis with findings similar to those published in the NEJM, and by October 2006, the product labels in Europe included a new warning. However, American Avandia users knew nothing of the risks until May 2007.
"Rosiglitazone represents a major failure of the drug-use and drug-approval processes in the United States," leading public health experts Dr Bruce Psaty and Dr Curt Furberg wrote in a NEJM editorial published on June 14, 2007, in comparing the Avandia situation to the Vioxx debacle in 2004.
"In view of the potential cardiovascular risks and in the absence of evidence of other health advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear," they stated in the editorial.
On July 24, 2007, Senators Chuck Grassley and Max Baucus, of the Senate Finance Committee, issued a press release to say they were investigating reports that FDA management had once again "muzzled" not one, but two senior safety reviewers who reported problems with Avandia.
"Based on our ongoing investigation," the Senators wrote, "it appears that FDA staff who voiced safety concerns about Avandia were removed from the very jobs that are supposed to protect the American public."
"Hardworking and knowledgeable employees at the FDA," Senator Baucus said, "strive to keep Americans and their health care providers informed about drug safety, but under Commissioner von Eschenbach's leadership it seems that drug manufacturers' interests may be allowed to trump science."
"The FDA undermines public safety every time it works to muzzle one of its own scientists," Senator Grassley stated. "It's time to stop this dangerous and repetitive practice where the FDA tries to shoot the messenger when it doesn't want to hear the message."
"The FDA must make decisions that are based on science and aim to protect the health of the American public," the press release states.
Experts say the rising number of risks found to be associated with Avandia outweigh any benefits of its use. A study in the July 17, 2007 Annals of Internal Medicine found that older and cheaper oral drugs for Type II diabetes were just as effective at controlling glycemia and improving lipid profiles as the newer medications.
The federal Agency for Healthcare Research and Quality commissioned the analysis in 2005. Dr Shari Bolen and colleagues of John Hopkins University reviewed data on 10 drugs from more than 216 published studies and systematic reviews for their report and found that second-generation sulfonylureas and metformin controlled blood glucose and other cardiovascular risk factors well.
The study found metformin to have the best risk-benefit profile. "Each oral diabetes agent is associated with adverse events that counterbalance its benefits," the authors wrote. "Overall, metformin seemed to have the best profile of benefit to risk."
"Large, long-term comparative studies on major clinical end points, such as myocardial infarction, chronic kidney disease, and cardiovascular mortality, are needed to determine definitively the comparative effects of the oral diabetes agents, especially in light of recent controversy regarding rosiglitazone," the authors concluded.
Another study by German researchers, first posted online on July 18, 2007, by The Cochrane Collaboration, reviewed the data from 18 published trials with 8,432 patients and also found that glycemic control was no better in patients taking Avandia than those given other oral anti-diabetic drugs.
The researchers found that Avandia might worsen complications of diabetes such as weight gain, swelling, bone fractures and heart disease. Dr Bernd Richter, of Duesseldorf's Heinrich-Heine University, who led the study, questioned whether it was even ethical to conduct any more clinical trials on Avandia.
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