Feb. 23, 2010 -- The end could be drawing near for GlaxoSmithKline's multi-billion dollar diabetes drug Avandia, if two U.S. Food and Drug Administration reviewers are successful in their bid to have the drug pulled from the market because of its link to heart problems.
The recommendations were released as part of a report from the Senate Finance Committee on the controversial drug.
While Avandia, known in medical circles as rosiglitazone, works as well as its competitor pioglitazone (Actos), the report concluded, use of the drug is responsible for a "substantial excess number" of heart attacks and heart failure cases that would not have occurred if patients were taking Actos instead.
"Rosiglitazone should be removed from the market," concluded Dr. David Graham and Dr. Kate Gelperin, both epidemiologists with the FDA.
In a statement released Monday, the FDA recommended despite the report that patients currently taking Avandia continue doing so unless their doctor tells them otherwise.
Graham, who has developed a reputation as a safety crusader and whistle blower critical of the agency's postmarket drug safety monitoring record, also raised early concerns about the anti-inflammatory drug Vioxx, which was subsequently removed from the market.
The fear that Avandia could be linked to an increased risk of heart attack and heart failure is not a new one. In 2007, then-president of the American College of Cardiology Dr. Steven Nissen raised the alarm when his analysis revealed that those taking the drug experienced a 43 percent higher risk of heart attacks and a 64 percent increased risk of dying from heart disease.
But the call for the drug's demise comes as Graham and Gelperin say that Avandia is responsible for about 500 additional heart attacks and 300 additional cases of heart failure each month than would occur if Actos were used exclusively.
Did GlaxoSmithKline Know of Avandia's Heart Risks?
Perhaps more troubling, committee chairman Max Baucus of Montana and ranking Republican Sen. Charles Grassley of Iowa suggest in the Senate Finance Committee report that GSK was aware of the cardiac risks associated with Avandia years before the evidence became public.
The drugmaker should have warned patients and the FDA about its concerns, but instead "intimidated independent physicians, focused on strategies to minimize findings that rosiglitazone may increase cardiovascular risk, and sought ways to downplay findings that the rival drug ACTOS (pioglitazone) might reduce cardiovascular risk," the senators wrote in a letter to FDA Commissioner Margaret Hamburg.
In a response published on its Web site, GSK rejected the report, which it said is inconsistent with "rigorous scientific evidence supporting the safety of the drug."
And in response to the charge that the company sought to intimidate doctors to tamp down warnings over the drug's risks, GSK spokeswoman Nancy Pekarek said, "We certainly don't condone any effort to silence scientific debate, but we will certainly correct inaccuracies if there is something said about our product that is inaccurate."
Still, in some ways the debate could be a moot point. Primary care doctors contacted by ABC News overwhelmingly said they already eschew the drug in favor of other options.
"I haven't prescribed Avandia for some time now, and I am not surprised that the recommendation is to pull it off from the market," said Dr. Albert Levy, assistant professor of medicine at the Mount Sinai School of Medicine in New York. "Any medicine with such a bad reputation is a potential life-threatening risk for the patient and a possible malpractice risk for the doctor."
Doctors, Diabetes Experts Split over Pulling Avandia
"I cut back on Avandia use when it was first linked to heart failure. This makes my willingness to use it even less," said Dr. Randy Wexler, assistant professor of Clinical Family Medicine at Ohio State University Medical Center in Columbus. "As a wise old doctor once told me, 'Don't be the first to use a new drug, and don't be the last.'"
"I doubt anyone is using this anyway," said Dr. Thomas Schwenk, chair of the department of Family Medicine at the University of Michigan Medical School. "[I] suspect many physicians -- including me -- thought it was already gone."
A few doctors, however, said the drug should remain as an option.
"I think it is safe enough to stay on the market, as long as the warnings are clear, which they are," said Dr. John Sutherland, program director emeritus of the Northeast Iowa Medical Education Foundation and Family Medicine Residency in Waterloo, Iowa.
And some diabetes experts noted that it has yet to be conclusively proven how, exactly, Avandia might bring about heart disease.
"We have known for some time that Avandia as well as Actos ... cause fluid retention, and that this can cause congestive heart failure in susceptible patients, when neither drug should be used," said Dr. Christopher Saudek, professor of Endocrinology and Metabolism at Johns Hopkins University School of Medicine in Baltimore. "The real question is whether Avandia causes more heart attacks, and the data there, in my mind, are inconclusive at best."
A Regulatory Failure?
The case itself could have implications beyond the doctor's office. Following the 2007 analysis, the FDA added a boxed warning to Avandia to address the heart risks. It also asked GSK to perform a cardiovascular safety trial to compare Avandia to other diabetes treatments such as Actos -- a trial that is still ongoing.
Around the same time, Baucus and Grassley began investigating how the FDA has handled rosiglitazone and whether GSK knew about the risk of heart attacks and heart failure that its drug posed.
Since 2007, the lawmakers have reviewed hundreds of thousands of pages of internal GSK documents and have spoken with GSK employees and anonymous whistle blowers, they said in a press release announcing the findings of their two-year investigation.
According to a letter Baucus and Grassley sent to FDA Commissioner Dr. Margaret Hamburg, their review uncovered a "alarming" analysis from a 2008 analysis conducted by two FDA safety reviewers who examined all available studies comparing rosiglitazone to pioglitazone.
Senators Take Aim at Drug Trial, Federal Regulators
Baucus and Grassley wrote in the letter that the reviewers concluded, "There is no evidence that rosiglitazone confers any unique health benefits over pioglitazone while there is strong evidence that rosiglitazone confers an increased risk of [heart attacks] and heart failure compared to pioglitazone."
Regarding the ongoing head-to-head trial pitting Avandia against Actos, the reviewers said "any proposed head-to-head trial of rosiglitazone vs. pioglitazone would be unethical and exploitative."
"After reading these documents, we would like to know what steps the FDA has taken to protect patients in [the trial], and why this trial is allowed to continue," the senators told Hamburg in their letter.
Defending the trial, GSK said it "has been approved by an independent review board and appropriate safety boards that are responsible for assessing the safety of conducting the trial."
FDA spokeswoman Karen Riley said, "The FDA takes very seriously concerns and issues raised in the recent inquiry from Senators Baucus and Grassley."
Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, issued a memo in December 2009 requesting that all appropriate offices within the Center rapidly evaluate the new data with the aim of presenting it to an FDA Advisory Committee in the summer of 2010, Riley said in a statement.
The agency posted an announcement about the July meeting on its Web site Monday. It will combine a panel of endocrinology and metabolic drug specialists with drug safety experts to examine the Avandia data that has been collected since 2007.
"FDA awaits the recommendations of the advisory committee, and in the meantime Dr. Hamburg plans to meet with FDA scientists and outside experts to gain a full understanding and awareness of all of the data and issues involved," Riley said.