Scientist says executive of Avandia firm tried to bully

WASHINGTON -- An executive of the company that makes the diabetes drug Avandia said a researcher who was among the first to link it to heart problems would be held liable for the $4 billion GlaxoSmithKline PLC lost in stock value as a result of his findings, Dr. John B. Buse testified before congressional investigators yesterday.

Buse told the House Committee on Oversight and Government Reform that he raised concerns about Avandia's connection to heart problems in 1999 , the year the Food and Drug Administration approved it for sale. He said the Glaxo executive, Dr. Tadataka Yamada, made the "disturbing" comment during a meeting Yamada had with Buse's department chair at the University of North Carolina. Afterward, Buse said, he faxed a letter to Yamada asking him to "please call off the dogs " because he feared he could no longer remain civil "under this kind of heat ." Buse, a UNC researcher, is incoming president of medicine and science for the American Diabetes Association's board.

The former Glaxo executive was "passionate about his work," Moncef Slaoui , Glaxo's chairman of research and development, said of Yamada, when questioned by the committee chairman, Representative Henry Waxman . "We regret that Dr. Buse felt pressured."

Yamada, who now works for the Bill & Melinda Gates Foundation , was participating in an all-day retreat, according to a foundation spokesman, and could not be reached for comment.

Buse's testimony capped a day marked by allegations of witness intimidation and an admission from the FDA that Avandia and Actos , a similar diabetes drug made by Takeda Pharmaceuticals North America Inc. , deserve the agency's strongest warnings for increasing the risk of congestive heart failure .

Avandia, the world's top-selling oral diabetes drug, has been under increasing scrutiny since May 21 when Dr. Steven Nissen , a Cleveland Clinic cardiologist, reported in the New England Journal of Medicine that patients in trials who took it had a 43 percent higher risk of suffering a heart attack , compared with people who took other diabetes drugs or sugar pills. Glaxo's own analysis of nearly four dozen studies found similar heart risks, as did a statistical analysis that the FDA conducted.

The "black box" warnings the FDA is requesting from Glaxo and Takeda would replace less prominent warnings the drugs already carry. Takeda yesterday committed to strengthen its warnings. Glaxo's Slaoui declined to comment because the firm is negotiating the change with the FDA.

The FDA's willingness to add a black box warning to Avandia is a sharp reversal that comes after the Senate and House launched inquiries into its handling of Avandia's heart risks and followed, by two days, Nissen's paper highlighting those risks. A supervisor who signed off on a February 2006 internal FDA memo suggesting such a label change for Avandia was rebuked by the agency, according to Senator Charles Grassley , Republican of Iowa.

The same day Nissen's study was published, Waxman, Democrat of California , called for a hearing before the oversight committee. He is trying to galvanize House support for an FDA reform bill he co sponsored. It would give the FDA authority that could have sped its actions on Avandia, including power to force changes to drug labels, greater power to require completion of postmarketing studies , and wider dissemination of clinical trial results.

Some 21 million Americans have diabetes, an ailment marked by the body's inability to properly use or produce insulin. Avandia, which generated more than $3 billion in revenue last year, is taken by 1 million Americans.

The public health impact of Avandia's cardiovascular side effects should have prompted faster action by regulators and the company, Waxman said.

Instead, Glaxo waited 11 months before telling federal regulators about clinical trial results linking Avandia to heart risks, and government officials ignored years of earlier warnings about the treatment, Waxman said. "Avandia is a case study of the need for reform of our drug safety laws," he said. "FDA needs the will, the resources, and the authority to be a more effective watchdog."

At the time of Avandia's approval, the FDA was more concerned about the drug's potential to cause heart failure , as well as the liver toxicity that forced a similar drug from the market.

"In retrospect," Avandia's link to heart attacks has evolved into an equally important cardiovascular side effect, FDA commissioner Andrew von Eschenbach testified. But the postmarketing study that Glaxo conducted, at the behest of the FDA, is not large enough to definitively address the drug's heart attack risks, officials said.

Diedtra Henderson can be reached at dhenderson@globe.com.