Bitter Pill.

• Author: WILLMAN, DAVID

Rezulin may cause acute liver failure, but the FDA still won't take it off the market

THE FIRST SYMPTOMS OF IMPEDING liver failure typically are dark-colored urine, fatigue, nausea, loss of appetite--not unlike a touch of the flu. And that's precisely the initial misdiagnosis made by doctors across the country, doctors who long were clueless about the risks posed by Rezulin, a new drug for people with diabetes. The diagnosis can soon enough get easier--though by then it may be too late to save the patient. The skin or eyes turn yellow with jaundice. Fluid sacs, called ascites, can form in the abdominal cavity.

Within weeks, other organs can start tipping toward failure. The body's own capacities compromised, the patient is left poisoned in her own toxins. And when it comes to Rezulin, gender matters: Approximately 70 percent of those known to have suffered liver failure from this drug are women, according to data studied by the FDA. I have read the all-too-repetitive daily hospital charts of Rezulin patients who lost their lives to the drug. I have spent days interviewing the patients' loved ones and doctors. Ask a hospital RN: Liver failure is a wretched way to die.

By January 1997, the Food and Drug Administration's files were loaded with enough warning signs to have kept Rezulin out of the hands of unsuspecting diabetic patients. Laboratory studies suggested that Rezulin played havoc with the livers and hearts of rodents. In rats, scientists found the livers were enlarged, with areas of dead tissue. And the rat hearts were distended, dilated, and discolored. "These changes were drug-related, and were responsible for the early mortality in both sexes," FDA pharmacologists concluded in a January 1997 internal report.

Clinical studies of Rezulin's effects on humans provided further cause for alarm: About 1 of every 50 people who took this drug in the original clinical studies developed some degree of liver injury. More than one fourth of those patients with liver injuries experienced toxicities that spiked to potentially life-threatening levels. Overall, nearly four times the rate of liver injury was observed in Rezulin patients than in those who took a placebo in the controlled clinical trials. In the parlance of drug-development scientists, this amounts to a "signal" of a dangerous problem. And a clear one at that.

With any drug, the risks have to be weighed against the potential benefits. Rezulin was developed to combat adult-onset, "Type 2" diabetes, which afflicts 15 million Americans, and can result in complications that include blindness and amputations. (The condition is distinguished from juvenile-onset, Type 1 diabetes, in which patients are incapable of producing their own insulin and would die without daily infusions. Although I am aware of doctors who have done so, Rezulin certainly should not be prescribed to Type 1 diabetics.) The question that faced the FDA: All things considered, was Rezulin safe enough?

The call was not a close one for Dr. John L. Gueriguian, the veteran agency medical officer who was assigned to evaluate the drug. In a detailed review dated Oct. 9, 1996, Gueriguian, citing Rezulin's potential to harm the liver and the heart, recommended the compound be rejected. "[I]t is unwise," Gueriguian wrote, "to force the FDA to hastily introduce a drug into the marketplace with such potential for worrisome toxicity."

Initially, Gueriguian was not alone in questioning Rezulin's safety. Another FDA medical officer, Dr. Robert I. Misbin, took specific note of Gueriguian's concerns regarding potential liver and heart toxicities. In an Oct. 18, 1996 agency memorandum Misbin wrote: "My primary concern about troglitazone [the chemical name for Rezulin] is related to its potential for cardiac toxicity.... [I] do not believe that the sponsor has made a convincing argument that failure to make troglitazone rapidly available would put a significant number of diabetic patients at risk. I believe the greater danger may be to make troglitazone available to patients who do not really need it before we have been convinced of its safety." Newly obtained records show that a study of Rezulin's effect on human hearts ended without definitive results.

No matter. On Jan. 29, 1997 the FDA (with Dr. Misbin's assent) pronounced Rezulin fit for sale, a safe and effective prescription drug. It was the FDA's fastest-ever approval of a diabetes pill.

There was, however, at least one subtext of considerable intrigue: In November 1996, senior FDA officials had stripped Gueriguian of any further involvement with the review of Rezulin, following his use of intemperate language in a meeting with a drug company executive. According to Gueriguian, he tired of the sponsoring company's tactics and told the executive: "You can't shine shit with words." His forced removal robbed the FDA of its best source of institutional memory at a time when the agency was racing to complete a six-month, "fast-track" review of the drug.

Fast forward just over two years, to March 26, 1999, to a Holiday Inn in Bethesda, Md., its upstairs conference room brimming with cell-phone-toting surrogates of Wall Street. The FDA by this time was in the midst of an extraordinary re-evaluation of...