The U.S. Food and Drug Administration (FDA) today announced that it will significantly restrict the use of the diabetes drug Avandia to patients with Type 2 diabetes who cannot control their diabetes on other medications.
The new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia (rosiglitazone).
The FDA is taking this action today to protect patients, after a careful effort to weigh benefits and risks, said FDA Commissioner Margaret A. Hamburg, M.D. We are seeking to strike the right balance to support clinical care.
Rosiglitazone also is available in combination with other diabetes medications, metformin under the brand name Avandamet or glimepiride under the brand name Avandaryl.
Avandia, manufactured by GlaxoSmithKline (GSK), is in a class of drugs known as thiazolidinediones, or TZDs. It is intended to be used in conjunction with diet and exercise to improve glucose (blood sugar) control in patients with Type 2 diabetes mellitus.
The FDA will require that GSK develop a restricted access program for Avandia under a risk evaluation and mitigation strategy, or REMS. Avandia will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (pioglitazone), the only other drug in this class. Current users of Avandia who are benefiting from the drug will be able to continue using the medication if they choose to do so.
Doctors will have to attest to and document their patients' eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. The agency anticipates that the new rules will limit use of Avandia significantly.
Allowing Avandia to remain on the market, but under restrictions, is an appropriate response, given the significant safety concerns and the scientific uncertainty still remaining about this drug, said Janet Woodcock, M.D., director of the FDAs Center for Drug Evaluation and Research.
Also today, the FDA ordered GSK to convene an independent group of scientists to review key aspects of the companys clinical trial known as RECORD, which studied the cardiovascular safety of Avandia compared to standard diabetes drugs. During the course of the FDAs review of the RECORD study, important questions arose about potential bias in the identification of cardiovascular events. The FDA is requiring this independent review to provide additional clarity about the findings.
In addition, the agency halted the GSKs clinical trial known as TIDE and rescinded all of the regulatory deadlines for completion of the trial. The TIDE trial compares Avandia to Actos and to standard diabetes drugs.
Lengthy controversy
The FDA's action follows a long and contentious debate. In July, an FDA advisory panel said Avandia does, in fact, appear to increase the risk of heart attacks but a majority stopped short of asking that it be banned.
Twelve members of the 33-member panel considering the issue voted to remove the Type-2 diabetes drug from the market, ten voted to allow its continued sale but with changes to its label and restrictions, while seven members said the label should be changed. Only three panel members voted to allow continued Avandia sales with no changes or restrictions.
Health advocates have mounted a strong campaign against Avandia, saying its risks outweigh its benefits. However, some diabetes patients say they take the drug without any problems and asked the panel to keep it on the market.
After the committee vote, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, said: "Commissioner Hamburg should immediately order this drug off the market and stop the unethical international trial on it."
Meanwhile, some are questioning whether the drug company covered up Avandia's risks long before they became known. The New York Times published documents that it said showed SmithKlineBeecham - the firm's name in 1999 - buried a disastrous study that suggested Avandia posed greater heart risks than a competing drug.
As evidence of a smoking gun, the Times pointed to this 2001 email from Dr. Martin I. Freed, a GSK executive:
"This was done for the U.S. business, way under the radar. Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK," the email states.
2007 study
It wasn't until 2007, eight years after the study cited by the Times, that health researchers began to pose questions about Avandia's risks. That year a study by a Cleveland Clinic cardiologist, using data obtained from GSK, raised the first red flag.
The Times report says the documents it has uncovered demonstrate the company was sitting on incriminating data that surfaced soon after Avandia's introduction. In one document cited by the newspaper, GSK tried to add up the lost sales that would result if Avandia's heart safety risk became established. The document put the cost at $600 million over a two-year period.
The Times quotes a GSK spokeswoman as saying the company did not publicize the results of the 1999 study because they "did not contribute any significant new information."
Patients taking Avandia have, over the years, reported adverse effects of the drug to ConsumerAffairs.com.
"I was put on Avandia for type 2 diabetes at least two years ago," Patsy, of East Peoria, Ill., reported in 2008. "I started having dizziness and blackout spells not long after. My doctor said he didn't know what caused them. Three or four times I went to the ER where they got it resolved in from one to three days. The last time, in July of 2007, it did not resolve and still hasn't. I was told at that time I had congestive heart failure also and am being treated for that now."
Last week a medical reviewer for FDA said GSK's analysis of a study it used to justify Avandia's safety was completely misinterpreted. Dr. Thomas Marciniak, in a posting on the FDA web site, said the study actually shows the opposite of the company's position - Avandia may cause heart attacks.
Marciniak's review was part of an FDA effort to brief an expert panel today and tomorrow to determine whether questions about Avandia are serious enough to require its removal from the marketplace. GSK's analysis was part of its case that the drug should not be removed.
But in looking at the data, Marciniak wrote that the information in the study was so misinterpreted that it's hard not to conclude it was done on purpose. "One does not have to be a mathematician or to perform calculations to come to the conclusion that a combined look at all the trials of Avandia would demonstrate that it causes heart attacks," Marciniak writes.
