Years Ago, Agency Was Warned of a Drug’s Risks

By STEPHANIE SAUL and GARDINER HARRIS
A leading diabetes doctor sent the Food and Drug Administration a letter seven years ago that warned of the heart risks of the drug Avandia. And in the next year, the F.D.A. reprimanded the drug’s maker for playing down safety concerns, according to documents from 2000 and 2001.
The documents, found in a reporter’s search of the F.D.A.’s database, indicate that the agency had been warned of safety concerns with the Type 2 diabetes treatment Avandia, and that the drug’s maker, GlaxoSmithKline, was seeking to minimize Avandia’s risks, before some of the same cardiovascular concerns were brought to public attention on Monday in an article and an editorial in The New England Journal of Medicine.
The F.D.A. has acknowledged that the company alerted the agency to concerns about a cardiovascular risk as early as 2005, based on the company’s analysis.
Glaxo has challenged the significance of the data cited in the medical journal. And, along with the F.D.A., the company has said that it was too soon to draw conclusions that Avandia raises a Type 2 diabetes patient’s risk of heart attacks. But the documents from 2000 and 2001 indicate that concerns about the drug’s safety are by no means new.
The letter in 2000 to the F.D.A. was written by Dr. John B. Buse, chief of endocrinology at the University of North Carolina in Chapel Hill, who is about to become the president of the American Diabetes Association. His letter from seven years ago sounded an alarm about Avandia, citing “a worrisome trend in cardiovascular deaths and severe adverse events” among patients using the drug.
In a telephone interview yesterday, Dr. Buse said that his opinion of Avandia had not changed since he wrote that letter. But he added yesterday that regulators should not rush to judgment by withdrawing Avandia from the market. Instead, he said, they should wait for the results of a larger study now being conducted by Glaxo that is meant to study the drug’s cardiovascular risks.
Avandia has been used by an estimated six million people in the United States since the agency approved it 1999. At the time, the company promoted Avandia as a safer alternative to a similar diabetes drug, Rezulin, which was withdrawn from the market in 2000 because it caused serious liver damage in some patients.
A Harvard professor who is a critic of the nation’s drug approval process, Dr. Jerome L. Avorn, yesterday drew parallels between the regulatory histories of Avandia and Rezulin, which had been a popular drug in its day.
With both drugs, “there were signals of a very dangerous side effect that were ignored,” he said. “Then massive marketing created a tremendous uptake of the drug.”
Last year, worldwide sales of Avandia exceeded $3 billion, making it one of Glaxo’s top-selling drugs.
The New England Journal of Medicine article, by the influential Cleveland Clinic heart specialist Dr. Steven E. Nissen, warned that the use of Avandia might significantly increase the risk of heart attacks. The extent of those possible risks had not been previously identified to the public.
Dr. Nissen has said that, according to his analysis, any person with Type 2 diabetes has a 20.2 percent chance of having a heart attack during a seven-year period. But with Avandia, he says, that seven-year risk would increase to 28.9 percent.
Glaxo has challenged the significance of Dr. Nissen’s analysis, which was developed by combining the results of more than 40 studies of the drug. Dr. Nissen has acknowledged that such studies, called meta-analyses, have limitations and are not as valid as controlled clinical trials.
As a result of Dr. Nissen’s article, the F.D.A. issued a safety advisory on Monday, suggesting that patients taking the drug consult their doctors. The agency also said that it planned to hold a meeting of outside advisers to review the drug’s safety. Among the options would be leaving it on the market with an even stronger warning — the drug’s label already alludes to the possibility of heart risks — or blocking its sale.
Even before Dr. Nissen had started working on his paper, Glaxo alerted the agency in 2005 and in 2006 that internal analyses had shown an increased risk of heart attacks. But the company also submitted a study of patients that it said showed Avandia was no riskier than other diabetes drugs. None of this analysis was specifically communicated to the public or doctors, although the company posted it on a Web site.
On Capitol Hill yesterday, agency officials explained their handling of Avandia to more than a dozen House and Senate staff members.
The briefing did little to settle concerns among some in Congress that the F.D.A. had been slow to alert patients about the drug’s potential risks to the heart, according to several staff members who were present and who spoke on condition of anonymity because the briefing was confidential.
Dr. Gerald J. Dal Pan, who leads the F.D.A.’s office of surveillance and epidemiology, told Congressional staff members that some in his office had disagreed with the agency’s actions regarding Avandia’s potential heart risk, several of those present said. Agency safety reviewers had been overruled by those in charge of drug approvals, staff members said.
No senators attended the meeting, but some commented afterward on the F.D.A.’s handling of Avandia.
“It’s unconscionable that F.D.A. found serious medical risks arising with Avandia and raised no red flags,” said Senator Max S. Baucus, Democrat of Montana and chairman of the Senate Finance Committee.
Senator Charles E. Grassley, Republican of Iowa, said that the agency’s inaction and internal dissension was further proof that legislation was needed to separate the agency’s approval and safety-assessment functions. Mr. Grassley had proposed such an amendment to a drug-safety bill that recently passed the Senate, but it lost by one vote.
The House will soon take up its version of F.D.A. legislation. Several staff members said that Mr. Grassley’s amendment has won new life.
In his letter to the agency, dated March 15, 2000, Dr. Buse was highly critical of the drug maker’s marketing of Avandia, accusing the company of “pervasive and systemic” efforts to play down the drug’s risks and overstate its benefits.
The F.D.A. was conducting its own investigation of Avandia marketing and found that company representatives were denying the existence of changes on the drug’s label that the F.D.A. had already ordered, which were meant to flag Avandia’s risks to the heart and liver.
The agency sent the drug maker a warning letter in July 2001, citing misleading statements made by company representatives at a recent meeting of the American Academy of Clinical Endocrinologists, where the agency had sent undercover investigators. The F.D.A’s letter criticized company posters displayed at the meeting, saying they did not carry adequate warnings.
It was the third time that the agency had chastised the company about its promotion of Avandia. Because of the repeated warnings, the agency demanded that the company send out a letter to doctors specifically warning them of the risks. The company subsequently sent out that “Dear Doctor” letter on Sept. 6, 2001.
In statement yesterday, a Glaxo spokeswoman, Mary Anne Rhyne, said that the company had “strongly disagreed” with the allegations in Dr. Buse’s March 2000 letter, “which we found to be unbalanced and unsubstantiated.”
“We took the time to meet and talk with Dr. Buse at length about his concerns,” Ms. Rhyne’s statement continued. “We explained our reasons for why we disagreed with his characterization of the cardiovascular safety profile of Avandia.”
As for the F.D.A.’s July 2001 warning letter, Ms. Rhyne said, “Action was taken at the time to ensure representatives of the company were accurately reflecting the label for the product in any commercial activity.”
Dr. Buse, as one of two incoming presidents of the diabetes association set to take office in September, has been widely quoted in media reports this week on Avandia. In that role, he has struck a neutral tone on the drug and urged patients not to panic. And yesterday, he said that the F.D.A. and doctors should wait for Glaxo’s study of Avandia’s cardiovascular effects.
But as a private doctor, Dr. Buse said that he does not generally prescribe Avandia to patients. He has been an outspoken critic of the drug in medical education meetings, some of them sponsored by Takeda and Eli Lilly, which jointly market a competing drug, Actos.
He was also an investigator in a study comparing Avandia with Actos, sponsored by Eli Lilly, that showed Actos had better effects on cholesterol than Avandia.
Dr. Buse said yesterday that he wrote the letter in 2000 in response to an F.D.A. petition filed by Dr. Sidney Wolfe, a consumer activist, who had asked the agency to place warning labels on Rezulin, Avandia and Actos.
Dr. Wolfe’s Health Research Group, a part of Public Citizen, has long warned patients not to use any of those drugs. At the time, the F.D.A. was considering removing Rezulin from the market, and Dr. Buse objected. Rezulin was made by Parke-Davis, a division of the Warner Lambert Company.
“The way I felt about it, after several years of clinical availability of Rezulin, we kind of understood the problems with it,” he said, “and we didn’t understand the problems of Actos and Avandia.”
Dr. Buse analyzed data submitted to the F.D.A. in support of Actos and Avandia and came to the conclusion that there was a “hint, a whisper” of cardiac-related deaths with Avandia as well as evidence of negative effects on cholesterol.
Referring to Avandia by its generic name, rosiglitazone, and to Rezulin as troglitazone, Dr. Buse wrote in the letter, “I do not believe that rosiglitazone will be proven safer than troglitazone in clinical use under current labeling of the two products.” He added: “In fact, rosiglitazone may be associated with less beneficial cardiac effects or even adverse cardiac outcomes.”
In the 2000 letter, Dr. Buse asked the agency to call for head-to-head studies of all the drugs.
Yesterday, he said, “I would say that in the last several years, there has not been a study that’s made me feel better about this.”