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FDA panel favors keeping c on market.

GAITHERSBURG, MD. -- The oral diabetes agent rosiglita-zone should remain on the market, albeit with some warnings about an increased cardiac ischemia risk, said a majority of the members of a joint meeting of the Food and Drug Administration's Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management advisory committees on July 30.

The combined panels voted 20-3 that rosiglitazone (Avandia) increases ischemic risk, and 22-1 that the drug, a thiazolidinedione, should stay on the U.S. market.

"The committee felt relatively uniformly that there was some risk associated with the use of rosiglitazone in certain diabetic patients," panel chairman Dr. Clifford Rosen said in a postmeeting briefing with reporters.

Dr. Rosen said panelists were most concerned about increased risk of ischemia, heart attack, and death in patients taking insulin along with rosiglitazone. Several committee members suggested a contraindication or label warning for use with insulin. A few others suggested a black box warning on increased potential for heart failure, for which there is already a warning. Several panelists also said that patients with advanced cardiovascular disease or who regularly used nitrates probably should not use rosiglitazone.

"These are the people for whom clinicians are going to have to think twice before prescribing [rosiglitazone]," said Dr. Rosen, a senior staff scientist at the Maine Center for Osteoporosis, St. Joseph Hospital, Bangor.

An endocrinologist on the committee, Dr. David S. Schade of the University of New Mexico, Albuquerque, argued before the panel voted that Avandia should stay on the market. Clinicians "absolutely ... need to have a thiazolidinedione on the market," Dr. Schade said. If rosiglitazone

was withdrawn, the panel might later regret having taken away an option, he said, noting that the other thiazolidinedione currently available--pioglitazone (Actos)--also has some safety concerns, notably a signal of an increased risk of bladder cancer.

In a statement, the American Association of Clinical Endocrinologists (AACE) said that it welcomed the FDA panel's recommendation that rosiglitazone stay on the market, but that "at the same time, AACE recognizes the strong statement of the panel that the drug may increase risk of cardiovascular disease." However, AACE said, "physicians can continue to treat persons with diabetes who are well controlled with Avandia, knowing that it has been shown useful and effective in controlling glucose."

The expert advisers drew their conclusions primarily from three meta-analyses of some 40 studies: one by Avandia manufacturer GlaxoSmithKline (GSK), another by the FDA's biostatisticians, and the third by Dr. Steven Nissen, medical director of the Cleveland Clinic (N. Engl. J. Med. 2007;356:2457-71).

Dr. Nissen was a nonvoting consultant, and his data were barely discussed, because the "FDA analysis of the data, including patient level data [provided by GSK], is more robust than would be possible for an analysis utilizing study-level data alone" according to the FDA's briefing document.

The trials in the meta-analyses included mostly short-term data. GSK also provided longer-term data from three outcome studies and several epidemiology studies.

Dissension Within FDA

The FDA usually follows its advisory panels' advice. With rosiglitazone, however, the agency's next move is not so clear. There is division within the FDA over whether the drug should stay on the market.

Dr. David Graham, an associate director for science and medicine in the Office of Surveillance and Epidemiology, said rosiglitazone should be withdrawn. Dr. Graham, who sounded the alarm about Merck's rofecoxib (Vioxx) in 2004, said rosiglitazone may have been responsible for 66,000-200,000 excess cardiovascular deaths, nonfatal heart attacks, and strokes from 1999 to 2006. The drug offers no unique short-term benefits for glycemic control and has not demonstrated long-term reductions in micro- or macrovascular complications, Dr. Graham said.

His boss, Office of Surveillance and Epidemiology director Dr. Gerald Dal Pan, agreed that the "balance of the benefits and risks do not favor rosiglitazone."

But Dr. Robert Meyer, director of the Center for Drug Evaluation and Research's Office of Drug Evaluation II, which oversees the approval of endocrinology drugs, said "there is a fundamental disagreement within CDER." He added: "I do not have an opinion on what regulatory action should be taken on Avandia."

The agency will "move this forward as quickly as we can," Dr. Douglas Throckmorton, CDER deputy director, told reporters after the meeting. "Obviously, this is a high priority."

GSK said it would continue to provide the FDA with information. "We welcome this decision as positive for patients," said Dr. Ronald Krall, GSK chief medical officer, in a statement after the meeting.


The FDA convened the joint panel primarily to assess the three meta-analyses.

In them, GSK found that the hazard ratio for myocardial infarction was 1.59; the FDA reported a ratio of 1.5, and Dr. Nissen a ratio of 1.43. For cardiovascular mortality, GSK reported a ratio of 1.91, the FDA 1.7, and Dr. Nissen 1.64.

Each group used a slightly different set of studies and a slightly different approach in reaching their conclusions.

Joy Mele, an FDA statistician, said the agency concluded that there was a nominally statistically significant increased risk of myocardial ischemia with rosiglitazone, compared with placebo, especially in patients taking nitrates or ACE inhibitors. There did not seem to be an increased risk in the studies comparing rosiglitazone with metformin or a sulfonylurea, although the results were not as clear, Ms. Mele said.

Panelist Dr. Curt Furberg agreed that the risk was very clear in the placebo-controlled studies. The active treatment-controlled trials "add confusion," said Dr. Furburg, a professor in the public health services department at Wake Forest University, Winston-Salem, N.C.

Katherine Flegal, a panel member and scientist at the Centers for Disease Control and Prevention's National Center for Health Statistics, said that she was concerned about the quality of the data, and the inconsistency among the three analytical approaches.

But Dr. Nissen said, "No matter how you cut the data, you get this 30%-40% increase in myocardial ischemia."

Longer-Term Studies

At the outset, GSK's Dr. Krall said the company believed that all three meta-analyses were flawed, and that more definitive conclusions could be gleaned from three long-term trials: RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes), ADOPT (A Diabetes Outcome Progression Trial), and DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone).

GSK said it expected more answers on cardiovascular disease (CVD) risk to come from RECORD, an ongoing, open-label, 4,447-patient trial with a 4- to 6-year follow-up. That study uses "in-stream" adjudication to evaluate adverse events. Interim data show a greater absolute number of CVD events, but the hazard ratio is lower than in the meta-analysis for myocardial infarction, sudden death, and cardiovascular mortality, said Dr. Murray Stewart, GSK vice president of clinical development.

Dr. Karen Mahoney, a medical officer in FDA's division of metabolism and endocrinology products, said it appeared that hazard ratios were somewhat lower, except for congestive heart failure. But, she noted, the RECORD data were preliminary.

Dr. Graham claimed that RECORD was not sufficiently powered to provide real data on CVD risk.

Seeking to tease out rosiglitazone's risks and benefits, Dr. Graham presented data from a study of pioglitazone recently submitted to FDA by its manufacturer, Takeda. According to Dr. Graham, the PROactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events) showed that pioglitazone did not increase CVD risk, and thus might be a safer alternative.

But some panelists complained that PROactive had not been shared with them, and did not like being asked to compare the two drugs on the basis of FDA's preliminary review of that study.


Associate Editor, Practice Trends
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Title Annotation:News; Food and Drug Administration
Author:Ault, Alicia
Publication:Internal Medicine News
Geographic Code:1USA
Date:Aug 15, 2007
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