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| Fda (Photo credit: Wikipedia) |
Avandia = Rosiglitazone
After an intense two-day meeting that illustrated the challenges in determining drug safety, a divided FDA advisory panel voted to ease restrictions on the use of the controversial Avandia diabetes pill, which has been under the equivalent of regulatory lock and key for nearly three years.
Of the 26 panelists, 20 voted to either remove or somehow modify the existing REMS, or Risk Evaluation and Mitigation Strategy, which was established in 2010 following a protracted controversy over the extent to which the GlaxoSmithKline drug causes serious cardiovascular events. That debate emerged after a 2007 meta-analysis found a 43 percent greater risk of causing heart attacks and strokes (see this and this).
Despite the vote, uncertainty remains. The panelists were not in agreement on how to ease the REMS, one of many the FDA established in response to drug safety scandals. The Avandia program contains a medication guide and another component known as ETASU, or elements to assure safe use, which spells out terms for physician participation, patient enrollment and distribution requirements for pharmacies (here is the Avandia REMS).
“I do feel we should continue with the medication guide and communication strategy, and maybe it’s possible to eliminate the ETASU or soften it,” said Marvin Konstam, a panelist and director of the cardiovascular center at Tufts University School of Medicine. “This shifts the burden to physicians and allows him or her to use their judgment.” He was one of 13 panelists who voted to modify the REMS.
"I believe relaxing the REMS would put this on a more even playing ffield with other drugs with similar risks," said Elaine Morrato, an associated professor at the University of Colorado School of Public Health, who also voted to modify the REMS.
Several panelists also suggested that, given a re-adjudicated Glaxo (GSK) clinical trial suggesting the pill was not associated with a significantly increased risk of cardiovascular events, another study should be conducted to obtain outcomes data on adverse events. The FDA had ordered the re-adjudication of the so-called RECORD trial three years ago at the same time the REMS program was required.
There are, however, obstacles to running such a trial, including ethical considerations, given that REMS restrictions are in place which, combined with the negative publicity, drastically cut the population of patients who currently use Avandia. In the US, for instance, the number currently hovers somewhere around 3,000, down from 120,000 three years ago, according to Glaxo.
Moreover, there would appear to be little incentive for Glaxo to sponsor such a trial. The Avandia patent expired in 2011 and sales basically melted to less than $10 million last year, a far cry from the $3 billion or so in annual sales that the pill generated before the controversy erupted. Glaxo issued a bland statement about the vote and re-adjudication, but did not mention the possibility of another study.
“The train may have already left the station on this,” said David Oakes, another panelist, who is a professor in the department of biostatistics and computational biology at the University of Rochester Medical Center. “I’m not sure what the practical results of this will be.” He was one of seven panelists who voted to remove the REMS altogether.
Whatever direction the FDA takes will be closely watched, especially since the agency has been harshly criticized over its handling of the Avandia controversy. FDA officials, for instance, were made aware of undisclosed trial data, which became an issue for Glaxo and contributed to a $3 billion fine the drugmaker paid last year to the federal government to settle charges of bad corporate behavior. At one point, the FDA was also accused of suppressing a different Avandia study (back story).
More recently, one co-author of the 2007 meta-analysis, Steve Nissen of the Cleveland Clinic, accused the FDA of trying to save face by holding this week’s meeting and he noted that the FDA did not invite him to speak at the two-day meeting (back story). To some extent, though, he was vindicated in that some restrictions will remain in place and Avandia usage is unlikely to increase substantially.
But the re-adjudication, itself, became the focal point of some drama after FDA medical reviewer Tom Marciniak alleged that Duke Clinical Research Institute, which was tapped to review the RECORD trial, was biased because, he explained, the academic research organization relied on trial data that was supplied by Glaxo.
His remarks were contained in FDA briefing documents released earlier this week that revealed a remarkable spate of jousting between him and several of his supervisors. Not only did they tangle over the veracity of the re-adjudication process, but Marciniak was also chastised for “unprofessional language” he used to criticize Glaxo, the Duke team and some of his own colleagues at the agency (more here).
Despite the unusual clash, the FDA panelists largely felt that the re-adjudication process itself was credible (see Duke report here), even as they mostly agreed with FDA reviewers that the underlying RECORD trial contained design flaws. In fact, DCRI’s Ken Mahaffey, who was in charge of the re-adjudication, acknowledged the study did not provide strong evidence that Avandia is safe.
For this reason, FDA critics continue to maintain that Avandia restrictions should not be loosened. “The concern is that by lifting the restrictions, more people will get this drug and nothing that happened at the meeting today does anything to make the drug any safer,” says Sid Wolfe, who heads Public Citizen Health Research Group and who testified at the meeting. “I think it’s an unfortunate outcome. The FDA has been given a green flag, so to speak, and this could be to the detriment of some people.”
As for Glaxo, here part of the official statement: “We appreciate the committee’s thorough examination of the RECORD results and will continue to work with the FDA as it considers the recommendation of the committee,” says James Shannon, Glaxo's chief medical officer. "We continue to believe that Avandia is a safe and effective treatment option for type 2 diabetes when used for the appropriate patient and in accordance with labeling.”
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