By David Morgan
A U.S. Food and Drug Administration panel of outside experts reopened one of the biggest drug controversies in recent years on Wednesday at a meeting where they will decide whether to recommend lifting marketing restrictions on GlaxoSmithKline Plc's Avandia diabetes drug.
The two-day FDA advisory committee meeting is not expected to bring about a major boost in sales for the onetime multibillion dollar product. But its findings may help revive the credibility of the British drugmaker's original research and shed light on the current U.S. regulatory approach to the health risks posed by new medicines.
Avandia was once the world's best-selling treatment for type 2 diabetes, with annual sales of $3.2 billion. Its use was heavily restricted in 2010 because of the possibility of increased risk of heart attack and stroke. It was withdrawn from the market in Europe in 2010, and only 3,000 people in the United States take it today.
Glaxo has said it has no plans to promote Avandia again, even if the FDA panel recommends lifting restrictions on sales of the drug, whose generic name is rosiglitazone.
The advisory panel session focused on a debate over the value of a Duke University "readjudication" of Glaxo's Record safety study that forms the basis for the expert panel's deliberations over the next two days.
FDA staff said in briefing documents this week that the Duke analysis backed Glaxo's safety findings for Avandia but also found that scores of smaller trials raised questions over whether the pill increases heart risks.
Dr. Thomas Marciniak, medical team leader of FDA's Division of Cardiovascular and Renal Products, warned panelists that the readjudication by the Duke Clinical Research Institute (DCRI) cannot be considered independent. The effort was financed by and conducted in collaboration with the drugmaker, which has also paid thousands of dollars in consulting fees to Duke's lead investigator, he said.
"They got it right for what they were allowed to say," said Marciniak. Some Record documents were redacted, he said, and original records of potential adverse events were deleted.
"The readjudication was limited because it relies largely on the original database and source documents in collaboration with GSK," he added.
He offered to treat Glaxo Chief Executive Officer Andrew Witty and five of the CEO's colleagues to dinner at an expensive London restaurant if his views prove wrong.
Marciniak said it would have been better for FDA to handle all the data on Avandia with company authorization, pointing to concerns that the regulatory agency has less data on Avandia than the Duke researchers. That prompted panel members to express concern about how much proprietary data Glaxo has agreed to share with the agency.
No Avandia promotion
Researchers for Glaxo and DCRI defended Duke's reexamination of the Record study as comprehensive and independent and said that it showed no statistically important risk for heart-related deaths from the use of Avandia. Some FDA staff members also described the study as well planned and well conducted.
"There is no convincing evidence for systemic, systematic or intentional manipulation of efficacy or safety outcomes in Record," said Dr. Preston Dunnmon, an FDA official who reviewed the Record study, which spanned 4,400 patients across 25 countries, most of them European.
But members of the panel still questioned whether the reevaluation of Record offered an adequate assessment of the drug's safety profile.
"I'm not aware of any evidence definitively establishing cv (cardiovascular) safety," said Dr. Sanjay Kaul of Cedars-Sinai Heart Institute in California.
"I believe that based on the data that we have been provided, that we have identified all of the events that were reported," replied the Duke institute's associate director, Dr. Kenneth Mahaffey.
But Mahaffey acknowledged a potential bias in the underlying data because of the original study's open-label style and said the Duke team did not systematically investigate the information it received from Glaxo to ensure it was complete: "We just didn't have the ability to do that."
The panel's patient representative, Rebecca Killion of Washington, D.C., asked FDA officials whether they had received assurances from Glaxo that the information the company provided to Duke researchers had not been altered.
"Do we have evidence that there has been willful redaction and withholding of information? That's a very good question," replied Dr. Mary Parks, director of FDA's division of metabolism and endocrinology products.
But FDA officials pointed out that the data remains the property of Glaxo and is not subject to outside scrutiny. A Glaxo official later told the meeting that the company provided all the data it had to Duke.
Morningstar analyst Damien Conover predicted only a slight chance that the meeting will prompt the FDA to ease Avandia sales restrictions significantly.
"But if they do, that could signal that the FDA is a little more willing to accept more side effects than it has in the past," Conover said.
Glaxo has settled lawsuits filed by tens of thousands of U.S. patients who had taken Avandia and claimed the company failed to inform them about risks. Several thousand other cases remain pending. The company last July agreed to pay $3 billion to settle allegations that it failed to provide the FDA with safety data on Avandia and marketed other drugs improperly.
European regulators required the Record safety trial over concerns that drugs in Avandia's class - called thiazolidinediones, or TZDs - may increase the risk of heart failure.
The FDA clamped down on Avandia's use in September 2010 after an FDA advisory panel voted that the Record data raised significant concerns of a greater risk of heart attack and stroke than other treatments, including Takeda Pharmaceutical Co's Actos, another TZD.
Although the FDA allowed Avandia to remain on the U.S. market, it commissioned Duke to analyze results of the Record trial to better assess the drug's safety and to examine criticisms over trial design and how the data was handled.
In a briefing document released ahead of the two-day meeting, the FDA said the study's methods and analyses passed muster with the Duke group and that it appeared to agree that Avandia was not associated in the Record trial with increased risk of heart attacks and stroke.
Avandia sales had been on a downhill slide since 2007, when Dr. Steven Nissen, head of cardiology at the Cleveland Clinic, said a pooled analysis of 42 studies showed Avandia increased the risk of a heart attack by 43 percent. Sales of Avandia, which was approved in 1999, plunged after the negative publicity.
The FDA now requires heart-safety data before approving new diabetes drugs.