Bloomberg News

Glaxo May Get Avandia Reprieve After FDA Panel Vote on Risks (1)

June 07, 2013

Glaxo Avandia Restrictions Should be Modified, FDA Advisers Say

GlaxoSmithKline Plc's Avandia diabetes drug. Photographer: JB Reed/Bloomberg

The perceived heart risks that torpedoed sales of GlaxoSmithKline Plc (GSK)’s best-selling diabetes pill Avandia may have been overstated and restrictions on prescribing the drug should be eased, U.S. advisers said.

A second look at a Glaxo study on the drug’s heart risk led a majority of the 26 members of a Food and Drug Administration advisory panel to yesterday recommend either modifying or removing the limits on prescribing and taking Avandia. The FDA isn’t bound by the advisers’ vote and will decide later.

Avandia’s reign atop the diabetes market began to end after a 2007 New England Journal of Medicine article found a 43 percent increased risk of heart attack in patients taking the medicine in a combination of results from smaller studies. A potential reprieve may be too late as sales of the former $3 billion-a-year drug fell to $9.5 million last year and London-based Glaxo’s patent expired in 2011.

“The train may have already left the station,” David Oakes, a panel member and professor in the University of Rochester’s Department of Biostatistics and Computational Biology, said after the vote. “I’m not sure what the practical results of this will be.”

Oakes voted to remove the restrictions.

Glaxo conducted its own study, called Record, after the 2007 findings that found Avandia doesn’t raise the risk of death, heart attack or stroke. The advisers said a reanalysis supports the argument that Avandia never carried an increase in overall cardiovascular risk. In a report June 3, some FDA staff also said the data conclusions appear to be supported by the reanalysis.

Glaxo Response

The panel discussion reflected confidence in the integrity and reliability of the company’s study that didn’t find an increased cardiovascular risk, Glaxo said in a 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” said James Shannon, Glaxo’s chief medical officer.

Glaxo rose 0.2 percent to 1,644 pence at 8:08 a.m. in London. The stock has returned 26 percent this year.

Avandia, approved in 1999 for U.S. sale, was taken up by an FDA advisory panel in 2007 that voted to place warnings on the box listing the potential for heart failure. The panel also recommended limiting some patient access to the drug instead of pulling it from the market. European regulators decided to withdraw the medicine from the market there.

Further Restrictions

The FDA further restricted access after a 2010 meeting, requiring doctors that prescribe the treatment and pharmacies that dispense the drug be certified. It also required patients to confirm they’re aware of how to safely use the drug.

Yesterday’s meeting asked the panelists to pick one of four recommended actions. Thirteen voted to modify the restrictions on Avandia, while five voted to keep them the same. Seven backed removing the restrictions and one said Avandia should be pulled from the market.

The reanalysis “moved the needle so that it seems appropriate to shift the burden of decision making to the physician,” Marvin Konstam, a panel member and chief physician executive at Tufts Medical Center’s Cardiovascular Center. “We ought to be shifting the burden back to the physician to look at the entirety of the data.”

Panel members who voted to change the restrictions didn’t all have specific suggestions for how they should be loosened.

Glaxo stopped promoting the drug in 2010. The company’s patent expired in 2011, and the FDA approved a generic version made by Teva Pharmaceutical Industries Ltd. (TEVA) in January, said Mary Anne Rhyne, a Glaxo spokeswoman.

Heart Guidance

The panel needed four tries to reach a conclusion amid confusion over whether the electronic system they use was counting the votes correctly. The final vote was taken on paper.

The debate in 2007 and 2010 over Avandia moved the FDA to require new diabetes drugs seeking approval be studied for heart risk. The FDA wouldn’t say whether it will revisit the guidance based on the reanalysis of Avandia.

“It’s a really interesting question but we’re not going to address that right now,” Curtis Rosebraugh, director of FDA’s Office of Drug Evaluation II, said.

The panel was split in discussion on whether Glaxo should do more study on Avandia to clear up lingering questions about the drug’s heart safety.

Duke Research

While another study should be done, given how long the drug has been on the market and how few people use it, that may not be possible, said Kenneth Burman, the panel chairman and chief of the endocrine section at Washington Hospital Center, said.

“In the real world this would seem difficult, indeed impossible,” Burman said during the meeting.

The FDA sought an independent assessment of Glaxo’s Record study, published in 2009, after questions were raised about the way the trial was conducted. Duke University School of Medicine’s Duke Clinical Research Institute in Durham, North Carolina, reviewed the trial.

Duke’s reanalysis found 186 cardiovascular deaths, heart attacks or strokes in the group of 2,220 patients who took Avandia in the Record study and 191 of the same adverse events among the 2,227 patients who took a popular drug combination typically used by Type 2 diabetes patients. Those numbers include 88 deaths and 72 heart attacks for those on Avandia compared with 96 deaths and 62 heart attacks for the other group.

Trial Design

While the results of Duke’s assessment were consistent with Glaxo’s original results, Thomas Marciniak, the medical team leader at the FDA’s Division of Cardiovascular and Renal Products, questioned whether the trial’s design biased the data, rendering Duke’s assessment moot in the debate over Avandia’s safety. Record wasn’t blinded, a method that prevents participants in the trial from knowing who is on what drug.

The question of whether the trial’s design affected the outcome “still remains,” Kenneth Mahaffey, associate director of the Duke research institute, said during the meeting.

Unblinding the trial was necessary because Avandia couldn’t be used with insulin, Murray Stewart, senior vice president of Glaxo’s metabolic pathways and cardiovascular unit, said. Duke researchers were given blinded data.

Glaxo originally conducted the Record study, which also found Avandia more than doubled the risk of heart failure, at the request of European regulators. The medicine was pulled from the European market and carries a black box warning in the U.S. that alerts patients of the potential for heart failure. U.S. patients also can only use Avandia if they were already on it or if they’ve determined with their doctor they aren’t able to take other drugs to control their blood sugar.

Glaxo agreed to a $3 billion settlement with the U.S. Justice Department almost a year ago involving a failure to report certain safety data about Avandia from 2001 to 2007 and promotion of two other popular drugs for uses that the FDA hadn’t approved. The company also agreed to pay $90 million to settle claims by 37 U.S. states and Washington, D.C., that it illegally promoted Avandia.

To contact the reporter on this story: Anna Edney in Washington at aedney@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net


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