FDA Bars New Patients From Avandia Study

Those already in the trial for the controversial drug may remain, for now.

July 21, 2010— -- WASHINGTON -- The U.S. Food and Drug Administration has ordered GlaxoSmithKline, the maker of Avandia (rosiglitazone) to stop enrolling patients in its ongoing head-to-head trial comparing the drug with rival Actos (pioglitazone).

Patients currently enrolled in the trial, called TIDE, can continue to participate, the FDA said in a statement posted to its website.

The decision comes after a 19-11 vote last week by the agency's expert advisory panel to keep the trial open. That vote came after the panel voted 20-12 to recommend the FDA allow Avandia to remain an option for patients with type 2 diabetes, despite an increased risk of heart problems associated with the drug. Most panelists want to see the controversial diabetes drug carry tougher warnings on its label.

The FDA required GlaxoSmithKline to conduct the TIDE trial following the agency's advisory committee in 2007 voting to keep Avandia on the market but beef up safety warnings. Practically since the beginning, the trial has been hampered by sluggish enrollment, possibly because of safety concerns.

In briefing documents released in advance of last week's advisory committee meeting, FDA reviewer Dr. David Graham called the trial "unethical and exploitative," as its main purpose is to look for safety issues with Avandia. He also said the informed consent form for the trial obscures the risks of Avandia while focusing too heavily on a more innocuous portion of the study -- a piece designed to detect vitamin D's affect on cancer.

Graham argued that the trial should be shut down.

"Is it ethical to enroll patients in a clinical trial where the goal is to prove harm?" he asked during last week's joint meeting of the Endocrinology and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee.

Doctors, Lawmakers Question Ethics of TIDE Trial

"Going into a trial as a human, you expect to get something good out of it," Graham said. "It's a bad deal trial. The best they can hope for is to not get a drug that causes a problem."

Congressional leaders also have voiced concerns over the TIDE trial. Sen. Max Baucus (D-Mont.) and Sen. Charles Grassley (R-Iowa) -- the chairman and ranking Republican of the Senate Finance Committee -- released a report in February that urged FDA to pull Avandia from the market. Graham, along with another FDA reviewer, contributed heavily to the Finance Committee report.

In addition to the report, Baucus and Grassley wrote a letter to FDA Commissioner Margaret Hamburg questioning the TIDE trial.

"After reading these documents, we would like to know what steps the FDA has taken to protect patients in the TIDE trial, and why this trial is allowed to continue," Baucus and Grassley wrote.

Despite concerns over the trial, the joint advisory committee voted last week keep the trial open, arguing that if Avandia stays on the market, then a head-to-head trial is necessary in order to keep an eye on potential signals that the drug may be unsafe. Several members favored retooling the trial's consent form.

The committee did not vote on whether to halt enrollment.

GlaxoSmithKline has argued at the advisory committee hearing that TIDE is ethical, the trial standards passed dozens of government review boards, and the consent form passed muster with hundreds of ethicists. Still, on Wednesday afternoon, the company confirmed it had halted enrollment in TIDE.

"This pause in enrollment will give clinical trial investigators and patients time to learn about the data presented to the FDA Advisory Committee and the Committee's recommendations," said Dr. Ellen Strahlman, GlaxoSmithKline's chief medical officer, in a statement.

"We are committed to working with the FDA in the best interest of diabetic patients," she said. "We believe that Avandia is an important treatment option for patients with type 2 diabetes."

Some Doctors Thinking Twice About Prescribing Avandia

The FDA is evaluating Avandia's safety data and reviewing the discussion from last week's two-day advisory committee meeting and will "update the public on the outcome of its review and its implications for Avandia and the TIDE trial when the review is complete," according to a statement posted to the FDA's website.

The FDA approved Avandia in 1999 to treat type 2 diabetes. Controversy over the drug began three years ago when Cleveland Clinic cardiologist Steve Nissen's 2007 review of data from 42 clinical trials found a 43 percent increase in heart attack risk among patients treated with Avandia.

The fallout from this review, as well as more recently released evidence against the safety of Avandia, has led some doctors to abandon use of this diabetes treatment.

"For my patients on Avandia, many of them have already asked to be switched to Actos," said Dr. Andrew Carroll, a family physician based in Chandler, Ariz.

"Based on prior studies I had read, I stopped prescribing Avandia about two years ago, and have been sticking with Actos," he added, saying that until the FDA makes a recommendation or further studies prove the drug is safe, he will be steering clear of Avandia.

Dr. John Sutherland, program director emeritus at Northeast Iowa Medical Education Foundation, said he has been slowly shifting his at-risk patients off Avandia, but said he has a few remaining patients on the drug.

Given the recent evidence that further risks were withheld by GlaxoSmithKline, he said that "we have made a decision to have all of [the few remaining patients on Avandia] switched to another therapy at this time."

Dr. Eric Larson, executive director of Group Health Research Institute, said he does not prescribe Avandia and even cancelled a research study on the drug after earlier reports of the drug's toxicity.

"The Senate documents and FDA hearings only confirm our earlier assessments of the safety of this drug -- it's gratifying to have our decisions confirmed but terribly disappointing that this hasn't been resolved earlier or even by now apparently," he said.

Though the drug has lost more than half of its sales since the 2007 study, it still generated more than $1 billion in revenue and was prescribed to 2.6 million Americans in 2009.

ABC News correspondent Lisa Stark contributed to this report.

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