En español | An advisory panel to the U.S. Food and Drug Administration (FDA) today cast a contentious vote to allow blockbuster diabetes drug Avandia to remain on the market. But the vote was split, and overwhelmingly negative in its judgment about Avandia’s risks, with 12 voting to withdraw the drug from the market altogether, 10 voting for it to be sold only with additional warnings and use restrictions, seven calling for some added warnings, and only three voting for no changes. One panel member abstained.
The FDA is not legally bound to adopt the recommendation, but typically does.
The recommendation comes after 11 years of brisk global sales of Avandia—including millions of U.S. prescriptions—earning well into the billions for its maker, GlaxoSmithKline (GSK). The panel decision also comes a month after a study in the Journal of the American Medical Association associated the drug with a significant number of cases of heart failure, heart attack, stroke, and death among diabetics taking it. Several previous studies have reached similar conclusions.
The 33-member panel of experts, which combines the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee, met all day Tuesday and Wednesday to hear presentations from FDA researchers and other doctors and scientists, as well as from GSK, on the cardiovascular safety of Avandia.
Avandia is used to lower blood sugar in people with type 2 diabetes. It’s usually prescribed as an add-on to traditional diabetes drugs, such as metformin. Indeed, a committee of diabetes experts in 2008 issued guidelines excluding Avandia, known generically as rosiglitazone, from any role in treating the disease. If called for, the committee said, doctors should prescribe Actos, another drug in the same class that has not been linked to cardiovascular disease.
The three years leading up to today’s climactic decision have seen mounting furor over Avandia’s risk profile. GSK has vigorously defended its safety. Some experts have insisted the data on heart risks are inconclusive and the drug should remain available. Others have cried foul at both the drugmaker and the FDA for failing to make patient safety a priority.
When it all started
The first salvo in this debate came in 2007, when Cleveland Clinic cardiologist Steven E. Nissen, M.D., published a meta-analysis—a statistical look at 42 drug trials taken together—that found a sharply increased rate of heart attack among people taking Avandia.
Largely in response to those findings, a joint FDA advisory committee later that year recommended adding heart risks to Avandia’s label, but voted almost unanimously—22 to 1—to keep the drug on the market.
Meanwhile the drug’s maker mounted a publicity campaign to counter concerns about Avandia, whose sales had plunged. Among other things, the company quickly published interim findings from its own ongoing trial comparing Avandia with other standard regimens, results that largely exonerated its drug of causing heart problems and strokes.
But 2010 has seen a steady drumbeat of official reports and medical journal articles casting further doubt on the drug and criticizing its defenders.
In late July, Nissen published a second meta-analysis examining results from 56 trials—and again, it showed Avandia users faced an increased heart attack risk. In the same week, outspoken FDA scientist David J. Graham, M.D., published a review of medical records from 227,571 Medicare beneficiaries who took Avandia or Actos from July 2006 to June 2009.
His analysis demonstrated a higher incidence of stroke, heart failure and death among Avandia patients.
A couple of recently published studies, however, would seem to provide reassurance on this score. One was an after-the-fact analysis of results of a study, presented last month at the annual meeting of the American Diabetes Association, which actually found a lower incidence of heart attack and stroke among Avandia patients. However, the original study was designed to look at a different set of questions.
Final results from the drug company’s own clinical trial, known as the RECORD trial, were published last year. While confirming an increase in heart failure with the drug, it showed no overall hike in cardiovascular disease or deaths.
“The totality of the evidence, from RECORD and other long-term studies, demonstrate no increase in the overall risk of these untoward outcomes,” the drugmaker emphasized in a report to the FDA in advance of the panel meeting.
Theoretically, a clinical trial—in which patients are assigned at random to a treatment or comparison group and followed—could be far more definitive than meta-analyses and studies plumbing databases of patient records. But it’s around the design and conduct of its trial that Glaxo has received perhaps the most damning criticism.
In preparation for this week’s advisory committee meeting to decide Avandia’s fate, the FDA conducted an unusually rigorous review of RECORD’s raw data. One reviewer, FDA scientist Thomas A. Marciniak, M.D., issued a scathing report to the committee. His central concern was that investigators and certain Glaxo staffers knew which patients in the trial were getting Avandia and which were not—and, whether deliberately or by unconscious bias, might have misclassified or dismissed cases unfavorable to the drug. Only 15 additional heart attacks among Avandia users would have changed the results so that they would have pointed to a statistically significant increase in risk.
“We count 25 patients with a potential MI [heart attack] and questionable handling favoring rosiglitazone,” Marciniak’s report said.
Last week, the New England Journal of Medicine published an editorial saying RECORD’s commercial sponsor “went around” the study’s data and safety monitoring board—the group charged with guarding patient safety—in order to rush out interim findings. Such “manipulations,” the editorialists ventured, call into question “the integrity of the whole clinical-trial enterprise.” The editors called for a new approach in which safety monitoring committees are established not by the trial sponsor, whether public or private, but by an independent public body.
Sen. Chuck Grassley (R-Iowa), long a gadfly to the pharmaceutical industry, has suggested similar reforms—chiefly the establishment of an independent body to monitor drug safety—at the FDA, which has been getting heat from all sides in the Avandia debate, and whose own staff has been sharply divided on the issue.
FDA employees who study a drug’s side effects after it has been on the market and used by the general population “should be able to express their opinions in writing and independently without fear of retaliation,” Grassley told a House subcommittee in April. “Instead, the FDA physicians and scientists committed to post-market monitoring of drugs have sometimes been suppressed. In the case of Avandia, it appears that they have been ignored.”
But by this week the views of Avandia critics both inside and outside the FDA had been published widely and received a great deal of attention.
Before the FDA advisers convened this week, David Juurlink, M.D., a University of Toronto specialist in the epidemiology of drug effects, predicted that whatever the panel decided, the FDA would have some tough questions to answer. If it doesn’t pull the drug from the market, he said, that would raise doubts about whether the agency is capable of protecting the public from unacceptable risks. “If they decide to remove the drug from the market,” Juurlink said, “the question they’ll have to answer to the public is, why did it take so long?”
Katharine Greider lives in New York and writes about health and medicine.
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