Rezulin’s Swift Approval, Slow Removal Raise Issues
In December 1997, the diabetes pill Rezulin was taken off pharmacy shelves in Britain because of concern about liver damage to patients in the United States.
Within a year, the Food and Drug Administration had learned of a torrent of additional cases. And by March 1999, agency specialists found the problem had grown far larger: More than 400 Rezulin patients, they estimated, had suffered liver failure.
Yet it was not until Tuesday evening that the FDA moved to withdraw the diabetes medication from the American market, in the process raising a simple question:
Why so long?
The once-high promise of Rezulin and the drug’s collapse--amid possibly thousands of injuries and liver-failure deaths--has provided some private-practice physicians with a bitter lesson in entrusting the FDA to keep dangerous drugs off the market.
The delay also focuses a new spotlight on the government’s policy of swiftly accelerating the approvals of newly proposed medicines, particularly drugs like Rezulin that do not promise lifesaving benefits.
With Rezulin, top FDA officials responsible for protecting the public health chose--from mid-1996 to as recently as last week--to accept the word of the drug’s manufacturer over the blunt misgivings of the agency’s own physicians, interviews and records show.
“The drug never should have gotten on the market,” said Dr. William L. Isley, a Kansas City, Mo., endocrinologist who helped Rezulin’s manufacturer, Warner-Lambert Co., develop the pill. “The whole thing is a travesty.”
Rezulin has been linked by the FDA to at least 90 liver failures, including 63 deaths and seven nonfatal organ transplants. The figures are based on voluntary reports filed by doctors, hospitals and others. They represent a fraction of the total number of fatalities and injuries, experts say.
FDA Official Has No Regrets Over Actions
The director of the FDA’s drug-evaluation center, Dr. Janet Woodcock, expressed no regrets over the agency’s handling of Rezulin. Instead of pulling the drug off the market earlier, the FDA oversaw four safety-labeling changes from the fall of 1997 through June 1999.
“They were what we could do to manage the risk, under the circumstances,” Woodcock said in a brief interview. “You can call for withdrawal of a drug, which is sort of the ultimate risk-management decision that the agency can make.
“When you do that, what you say is that no patient or prescriber can, with full information, make that decision for themselves. And we were not prepared to do that . . . unless we felt that people did have [a] safer alternative.”
FDA officials said that, before moving to withdraw Rezulin, they waited to assess the safety of two newer, similar medications that lower blood-sugar levels in people with type 2, or adult-onset, diabetes.
They said that they wanted to see if Avandia and Actos, pills that are similar chemically to Rezulin, were less dangerous to the liver. In clinical trials, neither drug showed liver toxicity close to that seen with Rezulin.
However, at least nine adult-onset diabetes drugs were already on the market when Rezulin was launched in March 1997 after a six-month “fast-track” review at the FDA. It was in mid-1999 that the agency approved Avandia and Actos, also following accelerated reviews.
So far, both drugs have demonstrated less liver toxicity in general medical practice. The most recent available figures show that 463,000 prescriptions of the two drugs were filled last month, compared with 292,000 prescriptions for Rezulin.
Dr. Brian L. Strom, an epidemiologist at the University of Pennsylvania, said that the withdrawal of Rezulin should serve as a lesson to patients.
“It’s critically important that people not rush out and want the newest drug,” Strom said. He added that “the growing pressure on physicians to prescribe these drugs is driven by direct-to-consumer marketing. . . . We can’t just rely on the FDA.”
Early Warning Signs Seen for Rezulin
With many drugs, the FDA and practicing physicians are unable to discern a dangerous side effect until after a medication has been tested in clinical trials and is put into mass circulation. This is because the clinical trials often involve as few as 2,500 patients, as opposed to the 1 million or more patients who use a blockbuster product.
Yet in Rezulin, specialists inside and outside the FDA said that warning signs were there from the beginning.
Dr. Neil Kaplowitz, a former Warner-Lambert consultant who is a liver specialist in Los Angeles, said: “I think as I look back at it retrospectively, there was a problem from the very get-go, in terms of the propensity to cause liver problems.”
The first FDA medical officer to examine Rezulin, Dr. John L. Gueriguian, opposed granting a fast-track review to the drug at an internal meeting in August 1996, minutes of the session show. Gueriguian questioned Warner-Lambert’s claims that Rezulin offered breakthrough benefits to diabetics. In October 1996, he recommended that Rezulin be kept off the market, citing the drug’s potential to harm the liver and the heart.
After a top FDA official stripped Gueriguian of any further involvement with the drug, the agency approved the pill on Jan. 29, 1997.
The FDA’s senior epidemiologist, Dr. David J. Graham, told an advisory committee meeting on March 26, 1999, that Rezulin was one of the most dangerous drugs on the market. Citing data culled from a major health maintenance organization, Graham said that no reliable way existed to protect patients using Rezulin from liver failure.
His presentation was attacked by Warner-Lambert, and it was rejected by Woodcock. When Graham and at least four other FDA physicians concluded at an internal agency meeting on Jan. 6 that Rezulin should be promptly withdrawn, Woodcock and her deputy, Dr. Murray M. Lumpkin, again held firm in their support of Rezulin.
Now, the questions surrounding both the FDA’s approval and supervision of Rezulin must be addressed, according to Rep. Henry A. Waxman (D-Los Angeles).
“I am pleased that the FDA took this drug off the market,” Waxman said. “But this whole experience leaves a lot of questions about how FDA conducts [its] whole drug-approval process.
“I think the underlying problem is that FDA may feel too pressured by industry and Congress to approve drugs quickly. . . . Rezulin may be a perfect example of when the fast track was just too fast.”
Waxman called on Congress to investigate the circumstances surrounding the FDA’s handling of Rezulin. Among other things, Waxman said that he wants to find out why the FDA decided, as far back as the fall of 1997, to leave Rezulin on the market in the hope that monthly blood tests would protect patients from liver failure.
Each of the four safety-label changes overseen by the FDA recommended more vigorous “monitoring” of patients’ liver functions.
FDA officials, “after they heard all these problems, became convinced that if they called for liver testing and labeling changes, that patients would be protected,” Waxman said. “I want to find out what data they had that led them to the conclusion that patients would be protected from these labeling changes.”
Also Wednesday, House Commerce Committee Chairman Thomas J. Bliley Jr. (R-Va.) cautioned the FDA over its pursuit of a recently opened internal-affairs investigation that has focused in part on Dr. Robert I. Misbin, an agency medical officer who in January began pushing for withdrawal of Rezulin.
“I am concerned about the appearance of retaliation against an FDA whistle-blower . . . ,” Bliley wrote in a letter to agency Commissioner Jane E. Henney. “Let me be clear: I take no position on the merits of the Rezulin controversy. Nevertheless, this committee has had a strong interest in safeguarding against FDA retaliation or appearance of retaliation.”
Bliley wrote that former FDA Commissioner David A. Kessler assured him in 1995 that whistle-blowers would be protected. “Based on recent reports, I am concerned that the appearance of the internal investigation of Dr. Misbin may have violated this assurance made to this committee.”
According to people familiar with the matter, the inquiry stems from The Times’ publication of internal e-mail excerpts. The e-mail messages documented that Misbin, Graham and other FDA physicians favored withdrawing Rezulin and that they were resisted by their superiors.
The FDA last week threatened Misbin with dismissal if he did not cooperate with the investigation. Misbin, who has been on the job this week, said Wednesday: “Congress has oversight of the FDA and the problems at the FDA can largely be laid at the feet of a reticent Congress.”
Prison Term Threatened
Another FDA medical officer, Dr. Leo Lutwak, said he was told by agency investigators last week that he could face five years in prison if the inquiry determines that he answered questions falsely.
Two other federal investigations related to Rezulin have been initiated:
An inspector general’s inquiry opened in response to The Times’ disclosure in December 1998 that Dr. Richard C. Eastman, a senior researcher at the National Institutes of Health, served as a paid consultant to Warner-Lambert at the same time he oversaw the selection of Rezulin for use in a $150-million government clinical trial. Officials banished Rezulin from the clinical trial in June 1988 after the liver failure and death of a 55-year-old participant.
Last week, two FDA investigators sought to question a St. Louis endocrinologist, Dr. Janet B. McGill, a former Warner-Lambert researcher, after her allegations that the company omitted findings of liver toxicity from a 1994 clinical trial.
Times researchers Janet Lundblad in Los Angeles and Sunny Kaplan in Washington contributed to this story.
A series of investigative reports on Rezulin is on The Times’ Web site: https://www.latimes.com/rezulin
(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)
Drugs Withdrawn From Market
Rezulin is one of eight drugs pulled from the market in the last 2 and 1/2 years.
*
Source: Food and Drug Administration
Compiled by JANET LUNDBLAD/Los Angeles Times
(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)
Rezulin Alternatives
FDA officials say the diabetes pill Rezulin is being withdrawn because its risks outweigh its benefits and after findings that two alternative drugs, Avandia and Actos, are less dangerous to the liver.
Source: IMS Health; compiled by JANET LUNDBLAD / Los Angeles Times
PATIENTS PERPLEXED
Drug’s withdrawal is met with confusion and ambivalence among patients. A17
