FDA seeks warnings on 2 drugs

WASHINGTON — WASHINGTON -- Federal health officials have moved to put the strongest warning labels on two diabetes drugs, including Avandia, whose possible side effects were the focus of a heated congressional hearing yesterday in which the government and the drugmaker were accused of sitting on information about the health risks.

The Food and Drug Administration requested "black box" warnings for Avandia and the other drug, Actos, after a new study raised serious concerns that patients taking Avandia were at increased risk of heart attack.


Since the study's publication last month, the FDA has been criticized for failing to warn patients about the possible risks, as the agency failed to do before the withdrawal of the painkiller Vioxx. Congress is investigating why the FDA waited years to follow up on reports about Avandia's side effects.

The FDA's commissioner, Dr. Andrew C. von Eschenbach, said the agency wants to prominently warn patients taking insulin or suffering from congestive heart failure about the two drugs.


The FDA moved to strengthen the warnings May 23, but did not disclose having done so until yesterday. The agency has no authority to order label changes, so it asked the drugmakers to add the warnings. GlaxoSmithKline makes Avandia, and Takeda Pharmaceuticals North America sells Actos in the United States.

An FDA safety evaluator first sought the black box warning in February 2006, according to Sen. Charles E. Grassley, an Iowa Republican and prominent agency critic. Grassley said in a statement that an agency supervisor, identified by The New York Times yesterday as Dr. Rosemary Johann- Liang, was reprimanded for supporting the staff member and lost authority to sign off on any future warnings.

During the four-hour Oversight Committee hearing, Democrats assailed the FDA's failure to act more quickly on that information.

Rep. Henry A. Waxman, the committee chairman, described the delay as one of several "missed opportunities" to learn whether Avandia heightens the risk of heart attack. He said the agency could have taken steps in 2000, when a North Carolina doctor asked for a study of heart risks.

"Avandia is a case study of the need for reform of our drug-safety laws," Waxman said.

The California Democrat is sponsoring legislation to give the government power to order safety studies after a drug's approval. Now, the FDA can demand studies as a condition for approval but cannot compel companies to complete them.

Dr. John B. Buse, a professor at the University of North Carolina School of Medicine, had asked the FDA in 2000 to examine Avandia's effect on heart attack rates, citing his experience with the drugmaker. Buse, a president-elect of the American Diabetes Association, said that SmithKline Beecham, then the drug's manufacturer, tried to intimidate him when he first raised concerns about Avandia's risks during scientific meetings in 1999.

Buse said he received threatening phone calls from a SmithKline Beecham employee, whom he did not identify, saying that he could be held liable for a drop in the stock price that cost shareholders $4 billion. Buse said his department chairman at the time knew a high-ranking company official and also warned Buse.


"Please call off the dogs," Buse wrote to a SmithKline Beecham official. "I cannot remain civilized much longer under this kind of heat."

Rep. Elijah E. Cummings, a Maryland Democrat, released a copy of the faxed letter.

Moncef M. Slaoui, chairman of research and development at GlaxoSmithKline, said after the hearing that the company disapproved of threats.

"We invite, welcome healthy debate and never intend to use intimidation," he said. "I personally would not have acted the way that's been described."

Republicans accused Democrats yesterday of needlessly scaring patients and of vilifying a company when it wasn't at all certain that Avandia raises the risk of heart attacks.

"My concern with this process is sensationalization," said Rep. Chris Cannon, a Utah Republican.


Avandia and Actos come with warnings, but they are buried in the 29 pages of prescribing directions, clinical trial results and other information that accompany the drugs.

The FDA asked for the prominent boxed warnings, von Eschenbach said, because existing warnings haven't stopped doctors from prescribing the drugs for patients with congestive heart failure. Their hearts have trouble pumping, causing blood to build up near the heart and fluid to gather in the legs.

Von Eschenbach and other FDA officials could not quickly find - and then explain - the existing warnings during questioning in the packed Capitol Hill hearing room. Von Eschenbach passed the assignment to Dr. John K. Jenkins, head of the FDA's new drugs office, who eventually read from a table in the drug's information.

"I actually asked a couple of physicians to read it, and they couldn't tell me either," said Rep. Stephen F. Lynch, a Massachusetts Democrat.

GlaxoSmithKline and Takeda officials said the companies are discussing the proposed warnings with the FDA. Dr. Robert Spanheimer, Takeda's senior medical director, stressed that the changes would concern congestive heart failure, which is different from a heart attack, the subject of the current controversy.

Spanheimer said a recent study of 5,238 patients did not find higher rates of heart attacks among patients taking Actos for an average of three years.


Avandia has been sold to millions of patients with Type 2 diabetes since its approval in 1999. Its possible health risks attracted widespread attention three weeks ago, when The New England Journal of Medicine published a finding that the drug increased the risk of heart attack by 43 percent. Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, pooled data from various studies. A similar analysis by Glaxo- SmithKline also found an elevated risk. Nissen acknowledges that pooled reviews, called meta- analyses, are not as conclusive as large-scale clinical trials.

GlaxoSmithKline says other, better studies do not indicate a greater risk of heart attack. In October 2005, the company told the FDA about its meta-analysis indicating an elevated risk, and the drugmaker gave its findings to the agency in August 2006.

Rep. Darrell Issa, a California Republican, upbraided Nissen during tough questioning. Issa asked the prominent heart doctor whether he had jumped to conclusions and why he had asked members of Congress for help in getting the information for his analysis but not the FDA.

Nissen said he reached his conclusions after a careful review. He said the FDA is not permitted to provide proprietary data and that GlaxoSmithKline refused to provide it. Nissen said he asked Republicans and Democrats, and none provided information. He eventually found the data on the Internet.