FDA issues hold on much-debated Avandia study

[July 22, 2010]  WASHINGTON (AP) -- Federal health officials are barring new patients from enrolling in a safety study of GlaxoSmithKline's controversial diabetes pill Avandia, a week after a panel of experts ruled that the drug increases heart risks.

The Food and Drug Administration said it issued a "partial clinical hold" on the study to update researchers on the latest concerns about Avandia, which has been under scrutiny since 2007.

Last week a panel of experts voted that the drug appears to increase heart risks, but a majority ultimately voted to leave the drug on the market because the evidence was not definitive.

The FDA is currently reviewing the panel's opinions and deciding what action to take.

GlaxoSmithKline said in a statement it would halt recruitment for the so-called TIDE trial and update the study's chief investigators on last week's meeting. Patients already in the study will be permitted to continue participating.

The London-based drugmaker agreed to conduct the trial in 2007, after safety questions about Avandia were first publicized.

The TIDE study is designed to give a definitive assessment of whether Avandia's heart risks are greater than its chief competitor Actos.

Last week, the FDA's panel of outside advisers voted 20-10 that the trial should continue if Avandia stays on the market.

However, Avandia's critics have argued that the trial is unethical since current evidence already shows Avandia is riskier than Actos, which is made by Japan-based Takeda Pharmaceuticals.

Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, said halting enrollment in the trial was "the ethically correct thing to do."

Nissen first drew attention to Avandia's risks in a 2007 medical journal article estimating that patients taking Avandia were 43 percent more likely to experience heart attack than those taking other diabetes drugs or no diabetes medication. He noted that the FDA's advisory panel specifically voted last week that Avandia increased risk of heart attacks more than Actos.

"I still think there's a very good chance that the FDA will decide to remove Avandia from the market," Nissen said.

The TIDE study is supposed to enroll 16,000 patients, though safety concerns surrounding Avandia have slowed recruitment. Researchers reported last week that just 1,100 patients have volunteered for the study.

Dr. Robert Califf of Duke University, a researcher who is leading three major industry-funded diabetes studies, said there is still "tremendous uncertainty" about Avandia's balance of risk and benefit, and that not completing the study could leave a big hole in the information needed by patients and doctors.

Califf said the FDA's move is "a reasonable and rational step while the company gets its information together" but cautioned that it could push some current study participants to drop out.

The FDA said TIDE's researchers should update the informed consent forms used to describe the risks of the study to potential recruits.

But Yale University cardiologist Dr. Harlan Krumholz questioned how doctors could get patients to give truly informed consent to participate in a study "where the best-case scenario is that they are not harmed by the drug."

"I just wonder if patients in this trial really understand that the entire point is to determine if those randomized to the arm with Avandia are at higher risk," said Krumholz, who is also a professor at Yale.

Public Citizen's Dr. Sidney Wolfe said the FDA's move is an "important half-step," but said it would not help patients who are already enrolled in TIDE.

"It doesn't really speak to the health risks of the people staying in the trial," said Wolfe, who has petitioned the FDA to withdraw Avandia. "My guess is most, if not all the people in that study would drop out if they were given information about how much more dangerous Avandia is compared with Actos."

The American Diabetes Association said in a statement that the FDA's announcement only pertains to the TIDE trial and urged doctors "not to over-generalize this announcement to the use of Avandia in clinical care."

The FDA first approved Avandia in 1999 and it quickly became the top-selling diabetes pill in the world. However, U.S. sales have plummeted from $2.2 billion in 2006 to $520 million last year as safety concerns swirled around the drug.

The drug works by increasing the body's sensitivity to insulin, a key protein needed for digestion that diabetics don't adequately produce.

The FDA added a black box warning to the drug in 2007. New studies on the drug's safety combined with pressure from safety advocates has prompted the agency to take another look at the drug.

In coming months the FDA is expected to make a decision on whether to keep the drug on the market.

[Associated Press; By MATTHEW PERRONE and LINDA A. JOHNSON]

AP Business Writer Linda A. Johnson reported from Trenton, N.J.

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