The Rise and Fall of the Killer Drug RezulinSeptember 2000
By David Willman
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 Before it was withdrawn on March 21, the FDA assured doctors and patients that Rezulin’s potential benefits in lowering blood-sugar levels outweighed its grave risks.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.
After graduating from Boston University Medical School, Misbin in 1976 arrived at Ceiba-Geigy, a drug company that then was defending its own lethal diabetes pill, called Phenformin.
Misbin, now 53, said that he found himself unable to accept the company’s basic defense of Phenformin: Patients were dying because of preexisting complications or other factors, but not because of the drug itself.
In July 1977, the government declared Phenformin an “imminent hazard” and ordered its immediate banishment. Two decades later, Misbin would have feelings of deja vu about another flawed diabetes drug.
Firm seeks to make drug a ’Blockbuster’
By May 15, 1995, Misbin’s first day as an FDA medical officer, Warner-Lambert was moving to position Rezulin for heavy sales. The company, a conglomerate that makes products ranging from Chiclets chewing gum to Listerine mouthwash, launched a multitiered strategy for transforming Rezulin into a “billion-dollar blockbuster.”
Early slide-show pitches were made to Wall Street analysts, emphasizing the market of America’s 15 million adult-onset diabetics and touting Rezulin’s “new mechanism of action.”
Warner-Lambert and its affiliates paid speaking or other fees to more than 300 doctors, from endocrinologists to family practitioners. The company flew diabetes specialists to the 1996 Olympic Games in Atlanta and provided accommodations at the Chateau Elan Winery and Resort.
Warner-Lambert also put on its payroll the government’s top diabetes researcher, Dr. Richard C. Eastman, who at the same time oversaw the selection of Rezulin for use in a National Institutes of Health clinical trial.
Much of the excitement surrounding the emergence of Rezulin stemmed from its status as the first of a new class of drugs for treating adult-onset diabetes. Rezulin promised to lower blood sugar much the same as Glucophage, the market’s top-selling diabetes pill, by helping the body better use its own insulin. Most of the eight other diabetes pills worked by stimulating the pancreas to secrete more insulin.
Patients with adult-onset, or Type 2, diabetes do not produce enough of their own insulin at the right moments or their bodies do not make efficient use of this hormone, which regulates the metabolism of blood sugar. Type 2 diabetes also can be treated effectively with changes in diet and exercise. The disease is distinguished from juvenile-onset, Type 1, diabetes, in which patients cannot produce their own insulin and would die without daily injections or infusions.
Soon after Warner-Lambert submitted its new-drug application for Rezulin in July 1996, the FDA for the first time in its history granted a six-month fast-track review to a diabetes pill. The FDA then was taking a year or more to examine standard new-drug applications.
The assignment of vetting Rezulin’s safety and effectiveness initially fell to Dr. John L. Gueriguian, a veteran FDA medical officer. Gueriguian “emphasized that [Rezulin] offered very little significant therapeutic advantage” over existing diabetes medications, according to a summary of an FDA staff meeting on Aug. 22, 1996.
By the fall of 1996, Gueriguian concluded that Rezulin was unfit for approval and warned of its potential to harm both the liver and the heart. But Gueriguian came under fire from Warner-Lambert executives, who contacted the FDA’s Lumpkin to complain about Gueriguian’s use of intemperate language.
Effective Nov. 4, 1996, Lumpkin ordered Gueriguian removed from the evaluation of Rezulin and any further dealings with Warner-Lambert, according to physicians familiar with the matter. Gueriguian’s medical review also was purged from agency files.
These actions sent an early and enduring message within the FDA: Challenging Rezulin was not without risk to one’s career.
More study brings unsettling conclusion
“We have real trouble.”
With this entry in his personal diary in October 1997, Misbin described prophetically the darkening turn of events.
He recalls being startled the afternoon of Friday, Oct. 10, when the two Warner-Lambert executives informed him of the first liver failures.
Before recommending a regulatory response, Misbin studied Warner-Lambert’s original research and the recent cases of liver damage. He reached an unsettling conclusion.
"We knew the essential truth - that Rezulin could cause liver failure," Misbin recalled. "There was a potential for a disaster."
The FDA is obligated under federal law to ensure that new and existing prescription drugs are safe and effective for their intended use. The agency’s quandary of what to do about Rezulin, medical experts say, was framed by this reality.
Compared to the constant risk of liver failure, patients would need to take Rezulin for years to gain potential benefits that could lessen the serious complications of diabetes, such as blindness or amputation. And Rezulin was one of 10 pills available to lower blood-sugar levels for adult-onset diabetics.
On the other hand, many doctors who were prescribing the drug urged the government not to take away a new anti-diabetes treatment. At the FDA, the official who manages the agency’s response to unexpected deaths from a prescription drug is Lumpkin. He also is the official directly responsible for ensuring that new drugs are reviewed and approved faster than ever before.
The FDA’s newfound emphasis on speed—as well as less-adversarial dealings with industry—has been pushed by lawmakers from both political parties. Pharmaceutical companies in the past have criticized the FDA for taking longer than European authorities to approve new drugs. Lumpkin and his boss, Dr. Janet Woodcock, are the two FDA officials directly responsible for meeting the agency’s new objectives.
Stocky and hard-driving, Lumpkin, 46, graduated from Wake Forest University School of Medicine. He specialized in pediatric infectious disease at the Mayo Clinic and directed international research for Abbott Laboratories, a major pharmaceutical firm, before coming to the FDA in 1989. As deputy director of the FDA’s Center for Drug Evaluation and Research, Lumpkin was the chief firefighter for Rezulin’s wildfires.
And by the fall of 1997—seven months after its arrival on the U.S. market in March—Rezulin had become a difficult-to-contain blaze.
Patient monitoring seen as a remedy
Within three weeks of the first acknowledged liver failure cases on Oct. 10, 1997, the FDA and Warner-Lambert jointly devised a remedy: Rezulin patients should have their liver functions monitored by blood test every two to three months during the first year of use.
The FDA and the company hoped that blood testing would detect liver injury early enough to alert patients to stop taking Rezulin and avert the catastrophe of organ failure. The FDA predicted in a statement on Nov. 3, 1997, that “few, if any of these patients will go on to develop permanent liver damage if the drug is stopped.” At this point, the agency confirmed four liver failure deaths.
But less than a month after announcing this remedy, officials at the FDA learned of a disturbing development. Authorities in Britain were planning to announce Rezulin’s withdrawal from the British market on Dec. 1, 1997. British officials, informed of six fatalities linked to Rezulin, had concluded that the drug’s risks outweighed its benefits.
The mind-set of British authorities was detailed in a Nov. 26, 1997, e-mail message from Lumpkin to Woodcock, his superior and director of the FDA’s drug review center.
“They believe that the deaths and serious toxicities are primarily seen after greater than 3 months exposure,” Lumpkin wrote in his e-mail. This analysis made “the apparent incidence of serious toxicity much greater than originally thought.”
Lumpkin told Woodcock that “unless there is some leak,” the revelation from Britain would stay sealed five more days.
The FDA, viewed for decades as upholding the gold standard for drug safety, was about to be upstaged by its counterpart, the British Medicines Control Agency. But the FDA, together with Warner-Lambert, raced to offset the pending news out of London.
Warner-Lambert maintained that the frequency of liver failure was extremely rare and insisted that the drug should remain on the U.S. market. In a Nov. 27 e-mail to the FDA, a Warner-Lambert vice president wrote:
“We are concerned about misleading physicians and patients as to the relative risk of Rezulin therapy.”
The company’s position was embraced at the FDA by Lumpkin. Instead of withdrawing Rezulin, the FDA and Warner-Lambert announced a second change in the drug’s labeling.
Rezulin patients were now advised to have their liver functions monitored monthly, instead of every two to three months, for the first half-year of use.
In a statement on Dec. 1, the same day that Rezulin’s withdrawal was announced in Britain, the FDA said: “The increased monitoring of patients taking Rezulin is designed to detect those few patients in whom use of the drug can lead to serious liver damage.”
Five months later, tragedy struck in St. Louis with the liver failure and death of Audrey LaRue Jones, a vivacious 55-year-old high school teacher.
Jones had been monitored closely as a volunteer participant in testing of Rezulin by the prestigious National Institutes of Health. Her death on May 17, 1998, challenged the usefulness of monthly liver monitoring.
“It had terrible implications for the drug itself,” the FDA’s Misbin said. “Because if the NIH couldn’t protect a patient, then who could?”
Since the nationwide clinical trial explored whether Rezulin could prevent diabetes, none of the 580 participants taking the drug had the disease.
Within three weeks of Jones’ death, officials at the NIH banished Rezulin from the clinical trial, citing safety concerns.
At the FDA, however, regulators did not broach even the possibility of withdrawing Rezulin, said several physicians familiar with the matter.
On July 28, Warner-Lambert announced that the company and the FDA had agreed to a third labeling change: Instead of monthly monitoring for half a year, patients were advised to submit to testing for the first eight months of use.
By now, 21 patients had died of Rezulin-related liver failure.
In Britain, meanwhile, authorities were considering whether to allow reintroduction of Rezulin. A doctor at the British Medicines Control Agency wrote Lumpkin on Sept. 4 requesting any “new data” showing “additional benefits” of Rezulin over other diabetes pills. A subordinate to Lumpkin responded on Oct. 16: “We do not have any recent . . . data regarding additional benefits of” Rezulin.
The British, again citing safety concerns, later refused to allow reintroduction of Rezulin. British authorities explained their position during a video conference with their FDA counterparts. According to an FDA participant, one British official said that the benefits offered by Rezulin were “nothing that isn’t already there with other drugs.”