FDA Orders Reassessment of Diabetes Drug’s Safety
Citing worrisome new deaths associated with the diabetes pill Rezulin, the Food and Drug Administration is directing an advisory panel of experts to reassess whether the drug is safe enough to remain on the market, officials said Friday.
The FDA action, which comes more than two years after the same experts unanimously endorsed the approval of Rezulin, is an unusual move, according to pharmaceutical industry observers. They said that such a measure is only taken on rare occasions, such as when the agency learns of significant safety concerns.
Until Friday, both the FDA and Rezulin’s maker, the New Jersey-based Warner-Lambert Co., have maintained that the drug is safe as long as patients submit to monthly monitoring of their liver functions. Now, FDA officials are raising new questions about whether patients are adequately protected by such regular testing.
Friday’s announcement marks the first public step that could lead to the narrowed use or withdrawal of Rezulin, which has been taken by more than 1 million people who have adult-onset diabetes.
FDA officials said the advisory committee is being consulted a second time because of heightened concerns about liver-failure deaths and transplants that have occurred among Rezulin users.
In particular, officials said, they are troubled by the sudden liver-failure deaths in November of two patients who had been properly monitored and were believed to have been in no imminent danger. In each case, the patients suffered liver failure within two weeks of undergoing the liver-function tests and died.
In a related development on Friday, Warner-Lambert announced that it would halt two major studies intended to find new uses for Rezulin. The announcement followed negotiations with FDA officials.
According to Warner-Lambert, the future of the two studies will be decided following the FDA advisory committee meeting, scheduled for March 26.
The Times reported in a Dec. 6-7 series that the agency dismissed explicit warnings of danger when it raced to approve Rezulin in January 1997. The articles disclosed that the FDA medical officer assigned to examine Rezulin was stripped of the assignment after he recommended rejection of the drug, citing its potential to damage the liver.
33 Users Died in 21 Months
As of the first week of December, senior FDA officials acknowledged that at least 33 Rezulin users died during the drug’s first 21 months on the market in the U.S. and Japan. The drug has generated sales of nearly $1 billion, according to the company.
It is difficult to determine the total number of patients who have been harmed by Rezulin because the reporting by health-care providers of all adverse events involving prescription drugs--including deaths--is voluntary.
FDA executive Dr. Murray M. Lumpkin, referring to the two recent deaths of Rezulin patients, told the Associated Press on Friday: “Within two weeks, they got into serious problems and died.”
Lumpkin, deputy director of the FDA’s center for drug evaluation and research, said the agency will ask the advisory committee whether more frequent monitoring is needed. “Or are there other things one could do to make the use of this drug even safer,” he said.
Lumpkin--who was among the FDA officials involved in stripping the agency medical officer of his Rezulin duty after his original examination of the drug in the fall of 1996--did not return calls placed by The Times.
When the FDA advisory committee first considered Rezulin on Dec. 11, 1996, agency officials failed to inform the panel members that the medical officer, Dr. John L. Gueriguian, had opposed approval of the drug. FDA officials also did not tell the panel that 11 patients in Warner-Lambert’s research studies had been taken off Rezulin after they developed potentially life-threatening levels of liver toxicity.
Warner-Lambert spokesman Stephen J. Mock said the company “welcomes the opportunity for a rational review of Rezulin” by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. Warner-Lambert announced that it also will ask the advisory committee at the same meeting to consider endorsing the expanded use of Rezulin in combination with a popular competitor, Glucophage.
Firm Critical of News Accounts
Warner-Lambert has criticized The Times series and other media accounts, saying that all prescription drugs pose risks and that hundreds of thousands of diabetics benefit from Rezulin.
The FDA and Warner-Lambert first recommended that Rezulin patients be monitored for liver damage in November 1997--eight months after the drug went on the market. In December 1997 and again in July 1998, officials revised the liver-monitoring recommendations.
The last revision followed the liver failure and death of a 55-year-old high school teacher from East St. Louis, Ill., who had appeared healthy while being monitored in a major research study sponsored by the National Institutes of Health.
Officials leading the NIH study decided to withdraw Rezulin from the $150 million clinical trial last June. On Dec. 1, 1997, the drug was banned in Great Britain following the first reported deaths associated with Rezulin.
The FDA, however, has stood firm and kept the drug on the U.S. market.
Dr. Sidney M. Wolfe, director of the Ralph Nader-founded Public Citizen Health Research Group, said the acknowledged cases of liver failure among patients who were monitored underscore that Rezulin is dangerous.
“Now we see that, with monitoring, people are dying,” Wolfe said, adding that no amount of revising of the monitoring procedures will, in his view, make the drug safe.
Some 15 million Americans have adult-onset or “Type-2” diabetes, a condition characterized by elevated blood-sugar levels. Experts estimate that roughly half of all Type-2 diabetics are not diagnosed or have no symptoms.
The condition can be treated with improved diet and exercise or through the use of 10 or more drugs, including Rezulin. If blood-sugar levels are allowed to remain excessively high, patients may suffer complications including blindness or kidney failure.
Handling Draws Lawmakers’ Questions
The FDA’s handling of Rezulin was sharply questioned last month by three leading House Democrats in a letter to Dr. Jane E. Henney, the new commissioner of the agency. The lawmakers also asked Henney to explain or defend the reliability of the liver-function monitoring.
“In light of the rising number of patient deaths and cases of liver damage, does the agency continue to believe that testing of liver function is an adequate means of preventing future fatalities and serious adverse reactions?” asked Reps. Henry A. Waxman of Los Angeles, John D. Dingell of Michigan and Sherrod Brown of Ohio.
