WASHINGTON — The suffering persisted for more than two years. Initially, there were four known victims. Then 21. Then 33. Finally, 63 confirmed fatalities.
All the while, federal authorities watched, waited and hoped the deaths would stop.
It was not until a disparate collection of physicians inside the U.S. Food and Drug Administration waged a remarkable revolt that the agency was forced to reverse course. These specialists--dubbed the "Termites" by one medical officer--combined meticulous research and bluntly worded e-mail messages to upbraid their government superiors for contributing to the needless deaths of patients.
How the Termites prevailed in toppling Rezulin, a blockbuster diabetes drug that generated $2.1 billion in sales, illuminates one of the most important reversals in FDA history.
A reconstruction of Rezulin's rise and fall shows that senior government officials repeatedly played down the drug's propensity to cause liver failure and death. Before it was withdrawn on March 21, the FDA assured doctors and patients that Rezulin's potential benefits in lowering blood-sugar levels outweighed its grave risks.
Diary entries, internal correspondence and interviews with participants reveal the pivotal roles of separate factions inside the FDA: the Termites, spearheaded by the efforts of Dr. David J. Graham, and the agency's most senior officials, led by Dr. Murray M. "Mac" Lumpkin.
As deputy director of the FDA's drug-evaluation center, Lumpkin helped make Rezulin the nation's fastest-approved diabetes pill and, to the end, resisted its withdrawal.
Lumpkin said that he had no misgivings about keeping Rezulin on the market for so long. The drug finally was pulled, Lumpkin said, only when it became "outmoded" in comparison to newer pills for adult-onset diabetes.
After listening to Lumpkin defend the handling of Rezulin on May 19 at an FDA advisory committee meeting, one panelist, Dr. Jules Hirsch of Rockefeller University, shook his head.
"I don't share the point of view of a wonderfully happy outcome, of how well the system has worked," Hirsch said. "Because a lot of people died of this thing. And a lot more people than we know died."
Indeed, the FDA's sustained support of Rezulin had consequences: 63 confirmed deaths from liver failure and thousands of liver injuries. Because adverse events from prescription drugs are reported voluntarily, typically by doctors and hospitals, Rezulin's estimated toll is perhaps 10 times higher, experts say.
As the deaths kept escalating, the FDA responded by recommending multiple regimens of blood testing, called "monitoring," as a means of safeguarding patients from liver failure. From the fall of 1997 through mid-1999, the FDA and the manufacturer, Warner-Lambert Co. of New Jersey, agreed to four liver-monitoring recommendations.
Yet no scientific proof existed then, or now, that monitoring would protect Rezulin patients, according to the FDA's own research and interviews with physicians.
"It was a hope," said Dr. Srini R. Vasa, a liver specialist based in Kansas City, Mo., who treated three Rezulin patients with liver failure, two of whom died. "There were a lot of lives lost and a lot of lives changed. . . . It did not make the drug safer."
The FDA has overseen withdrawals of nine prescription drugs since fall 1997, an unprecedented number within such a short span. However, of those nine, the agency granted "fast-track" approval to only one: the oval, tan pill marketed as a diabetes breakthrough.
Rezulin thus becomes a touchstone for federal policymakers and for the doctors, patients and family members so directly affected by the government's decisions.
This chronology of the struggle over Rezulin is based on previously undisclosed documents and scores of interviews conducted over the last three years with government and private physicians.
Doctor Learns of Liver Failure Deaths
Anxiety washed over him in a flash.
It was a Friday afternoon in early October 1997 and Dr. Robert I. Misbin had just gotten vexing news from two Warner-Lambert executives: Patients taking Rezulin were beginning to die of liver failure.
When he hung up the phone at his government desk, Misbin felt a singular anguish. As an FDA diabetes specialist who advocated the approval of Rezulin, he had failed to confront the danger posed by the drug.
After relaying word to his supervisor, Misbin was alone with a central question:
How could this have happened?
Standing 5 feet, 11 inches, with prominent cheekbones, a graying beard and dark features, Misbin is not easily pigeonholed. His mien at first impression is one of unflinching seriousness.
Next to an affinity for opera (he attends regularly and keeps a black-and-white picture of the late soprano Maria Callas framed in his living room), Misbin's passion is medical ethics. He has fundamental concerns about how patients are treated in clinical trials.