FDA Urged to Heed Warnings on Rezulin
Dr. David J. Graham is regarded as the Food and Drug Administration’s top expert in assessing and preventing deaths related to the use of prescription drugs.
Drawing from the most up-to-date scientific data available, Graham concluded that the diabetes pill Rezulin, which has led to dozens of deaths, is among the most dangerous drugs on the U.S. market. But members of an FDA advisory committee largely rejected Graham’s findings two months ago when they voted overwhelmingly to support keeping Rezulin on the market while recommending that its use be narrowed.
Now, as FDA Commissioner Jane E. Henney and senior agency officials are preparing to announce--perhaps as soon as this week--that they will follow the committee’s lead, an unlikely chorus of voices is encouraging the FDA to heed Graham’s warnings.
“If the FDA believes Dr. Graham is right, the drug should not be on the market,” said Dr. William L. Isley, a diabetes specialist in Kansas City, Mo. Isley, who has served as a paid consultant to the manufacturer of Rezulin, added that he has come to fear the damage the drug can cause to the liver.
Congressman Urges FDA to Listen
Rep. Henry A. Waxman (D-Los Angeles), often a friend of the FDA, referred specifically to Graham’s presentation when he wrote Henney on April 12: “I strongly urge you to take notice of your agency’s own data.”
In effect, the common message from Isley and Waxman is this: FDA leaders no longer can afford to overlook the scientific record.
At the same time the FDA will decide the fate of Rezulin, the agency also is expected to grant final approval to Avandia, a similar new adult-onset diabetes drug that tests indicate is far less dangerous to the liver, according to people familiar with the matter.
Henney declined to be interviewed.
More than 1 million patients have taken Rezulin, which has generated sales totaling $1.4 billion for the New Jersey-based Warner-Lambert Co. since the drug was introduced two years ago. The company has continued to assure doctors that Rezulin is both safe and effective.
To date, the FDA has acknowledged at least 43 cases of Rezulin-related liver failure.
Early this year, Graham was assigned to review the frequency of deaths and liver injuries associated with Rezulin. He concluded that at least 430 Rezulin patients had suffered liver failure, most resulting in death or organ transplant.
Members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, however, largely rejected Graham’s findings when they met in Bethesda, Md., on March 26. The panel voted, 11 to 1, to recommend keeping Rezulin on the market, while suggesting that it not be used by itself to treat adult-onset diabetes.
Why did the advisory committee decline to embrace Graham’s findings? The best explanation may have been provided by one veteran member of the panel, Dr. Robert A. Kreisberg, an endocrinologist from Birmingham, Ala. Looking to the audience, which included 10 doctors who earlier had implored the committee to stand behind Rezulin, Kreisberg declared:
“I’m going to rely very heavily on valued colleagues who practice and take care of patients with diabetes on a day in and day out basis. I think this information is as valuable or more valuable than the theoretic issues that have been brought up here [by Graham].”
In essence, Kreisberg was siding with the opinions of 10 doctors, who told the committee that Rezulin was safe and effective at lowering blood-sugar levels.
At least nine of the doctors who spoke on behalf of Rezulin, however, were paid consultants to Warner-Lambert or to one of its affiliates, according to records and interviews.
The doctors made a point of saying that they had paid their own ways to the March 26 committee hearing. The amounts of consulting fees they received are unknown, but interviews and standard pharmaceutical industry practice indicate that such physicians usually receive payments of as much as tens of thousands of dollars a year.
The Times reported March 25 that two last-minute appointees to the advisory committee were paid consultants to Warner-Lambert or its affiliate. One of the two decided not to attend.
Graham was paid for his expertise exclusively by the FDA. A wiry man with angular features, Graham is a “master reviewer,” the FDA’s top specialist in epidemiology, the discipline that examines the prevalence and means of controlling drug-related deaths and injuries. Graham, 45, also is trained in neurology and internal medicine.
In his presentation to the committee, Graham said that patients considering taking Rezulin are facing sky-high risk: A patient is at least 1,200 times more likely to suffer liver failure by going on Rezulin than by staying off it. He found that rigorous, monthly “monitoring” of Rezulin patients--recommended by the FDA and Warner-Lambert--does not safeguard them from liver failure.
Graham highlighted the case of Audrey LaRue Jones, a participant in a National Institutes of Health study who, despite being monitored monthly, suffered Rezulin-caused liver failure and died May 17, 1998. NIH officials quickly withdrew Rezulin from the study.
Families Await FDA Action
Yet a full year after Jones’ death, many doctors and their patients say that they are still waiting for the FDA to take definitive action.
“I feel like I’ve been bitten by a rattlesnake and didn’t hear the rattle,” said Marsha J. Bean, a 53-year-old Kansas City, Mo., woman who suffered liver failure and underwent a transplant on Jan. 27 after taking Rezulin.
Bean’s ordeal is especially painful: The physician who prescribed the drug was Dr. John L. Bean, her husband. They filed a product-liability lawsuit against Warner-Lambert on April 15, alleging that Mrs. Bean suffered liver failure within just three weeks of taking Rezulin.
“As a physician, I’m pretty outraged. As a husband, I was just devastated,” Dr. Bean said in an interview. “This drug should be removed from the market.”
The FDA, however, has long supported the drug. The agency two years ago ignored Rezulin’s liver danger and granted it “fast-track” approval. The approval came despite the warnings of a veteran FDA medical officer, Dr. John L. Gueriguian, who cited Rezulin’s potential to harm the liver.
On three occasions since Rezulin went on the market in March 1997, the FDA has responded to escalating safety concerns by agreeing with Warner-Lambert to alter the product’s recommended use or labeling.
Rezulin is one of 10 or more drugs available to treat adult-onset, or Type 2, diabetes, a condition characterized by elevated blood-sugar levels. Patients with juvenile-onset, or Type 1, diabetes must take daily injections of insulin to survive.
Warner-Lambert executives met privately May 12 with officials at FDA headquarters in Rockville, Md., to discuss Rezulin’s future. FDA officials in recent weeks have circulated several regulatory options publicly and within the agency.
Among them:
* Declare Rezulin unsafe and order Warner-Lambert to pull the drug from the U.S. market. This would resemble action taken in Britain, where Rezulin was withdrawn in December 1997.
* Withdraw the FDA’s approval of Rezulin use as a stand-alone treatment for adult-onset diabetes. This “monotherapy” accounts for 20% of the drug’s sales.
* Leave Rezulin on the market but recommend that patients submit to monitoring of their liver functions every week or every two weeks, instead of once a month.
* Restrict the prescribed use of Rezulin to one-month increments. Under this scenario, patients might have to establish that they had submitted to liver-function monitoring before getting a refill.
While the FDA has remained reluctant to banish Rezulin, a diverse cadre of physicians says it now is convinced that it is far more dangerous to the liver than two similar diabetes drugs nearing approval.
Dr. Neil Kaplowitz, a liver specialist at the USC School of Medicine, has worked as a paid consultant to both Warner-Lambert and Japan’s Takeda Industries, maker of Actos, one of the two new drugs.
In an interview, Kaplowitz said: “If these [two new] drugs really hold up in terms of being safe in larger populations, which I predict will be the case, then I think there will be no reason to have [Rezulin]. It should be taken away.”
Times researcher Janet Lundblad in Los Angeles contributed to this story.
