Health: Five FDA physicians say the lives of diabetes patients are at stake. Company's conduct in development of the drug also comes under fire.
WASHINGTON--Amid mounting pressure to remove the popular pill Rezulin from the U.S. market, a growing number of physicians at the Food and Drug Administration have expressed concern that further delay will claim the lives of diabetes patients.
Five agency physicians, all specialists who have studied Rezulin's propensity to cause liver failure, stand apart from top FDA administrators, who have renewed public endorsements of the drug.
The dispute comes as new allegations have been lodged with the FDA and Congress about the conduct of the New Jersey-based Warner-Lambert Co. in developing Rezulin. Dr. Janet B. McGill, a St. Louis endocrinologist who assisted in the company's early clinical testing of Rezulin, claimed that Warner-Lambert "clearly places profits before the lives of patients with diabetes..
Rezulin has produced $1.8 billion in sales for Warner-Lambert since 1997, but the FDA has linked the drug to 89 liver failures, including 61 deaths.
The FDA said Thursday in a prepared statement that "Dr. McGill's allegations are serious and must not be ignored..
A spokeswoman for Warner-Lambert, Carol Goodrich, said that McGill had made "a number of inaccurate allegations." Goodrich declined to provide a more specific response.
Warner-Lambert continues to maintain that Rezulin is safe, if used as recommended. At a private meeting last week with FDA officials to discuss the drug's fate, company executives cited the absence of reported liver-failure deaths among patients who have started the drug in recent months.
After the March 1 meeting, a company representative disclosed that the FDA had reaffirmed its confidence in Rezulin.
Inside the FDA, however, a contrary stance toward the drug has emerged, according to internal e-mail correspondence obtained by The Times.
"My question is: How many fatal cases will suffice, to put to rest [Warner-Lambert's] argument?" wrote Dr. Saul N. Malozowski in a March 2 e-mail to colleagues. "I believe that one case will be too many..
Malozowski, a team leader in the agency's diabetes drug division with supervisory responsibility, added:
"The number of [liver] associated deaths with Rezulin . . . is in excess of anything previously seen with any of the approved [diabetes] drugs. . . . We know now what has happened with Rezulin and there is not a single piece of information to believe that either new or old patients will not develop severe or fatal complications with it..
Statements Are in Conflict
The statements by Malozowski and other FDA experts conflict with the position to date of Dr. Murray M. Lumpkin, the deputy director of the agency's Center for Drug Evaluation and Research. Lumpkin and his superior, Dr. Janet Woodcock, director of the drug center, continue to support Rezulin.
Lumpkin, who presided at the March 1 meeting with Warner-Lambert, did not return telephone and e-mail messages seeking his comment. He is attending a drug-industry trade group's conference this week on the French Riviera.
Lumpkin and other colleagues also were warned in a March 2 e-mail of an FDA medical officer's "conservative estimate" that 35 of 70,000 patients who started taking Rezulin since last July will suffer liver failure.
"I do not think we have the luxury of debating the fine points of [scientific] methods as if this were just an academic exercise," wrote FDA medical officer Robert I. Misbin, a diabetes specialist who in 1997 recommended "fast-track" approval of Rezulin.
The Times reported on Feb. 19 that Misbin had abandoned his long-standing support of Rezulin, concluding that the drug's benefits no longer outweighed its risks.
According to those familiar with the matter and internal FDA correspondence, at least four other veteran agency physicians have voiced similar concerns, including Dr. Solomon Sobel, who as director of the diabetes-drug division oversaw with Lumpkin the approval of Rezulin; Dr. Robert J. Temple, director of one of the agency's five drug-evaluation offices; Dr. David J. Graham, a senior epidemiologist who publicly warned a year ago that no reliable way exists to protect Rezulin patients from liver failure; and Malozowski, the diabetes team leader.
For the last two months, Lumpkin has rebuffed the increasingly pointed sentiments of his subordinates. Lumpkin oversaw the FDA's decisions to revise the safety labeling of Rezulin on four occasions over the last 2½ years, rather than withdraw the drug.
"I think our colleagues here are very, very good but we are not clairvoyent [sic] yet!" Lumpkin wrote in a Feb. 28 e-mail to Misbin. He added: "This is not a game of GOTCHA..
In this and other messages, Lumpkin defended his recent decision to provide Warner-Lambert with the FDA's most up-to-date data on all reported adverse reactions to two drugs that compete with Rezulin. The FDA granted fast-track approval to the drugs, Avandia and Actos, last year. Clinical trials found that the newer agents, while similar chemically to Rezulin, were less toxic to the liver.
Lumpkin has made clear that he believes the FDA must now demonstrate that Avandia and Actos are safer than Rezulin before deciding to withdraw the drug. This could delay the withdrawal of Rezulin for months. Eight drugs other than Rezulin, Avandia and Actos are available to lower blood sugar for the 15 million Americans with adult-onset diabetes.
As the dispute over the status of Rezulin intensifies, the FDA said Thursday that it is reviewing allegations raised by the physician who served as a paid consultant to Warner-Lambert.
McGill, an associate professor of medicine at Washington University in St. Louis, assisted in the company's clinical testing of Rezulin beginning in 1994.
In a March 1 letter to the FDA, she alleged that two instances of possible liver injury of her patients were not properly reported. In addition, McGill acknowledged shortcomings in her supervision of the research.
McGill also wrote on March 1 to Sen. Edward M. Kennedy (D-Mass.): "I believe that the company . . . deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies..
Warner-Lambert spokeswoman Goodrich said in a prepared statement that the company would inform the FDA of its response to McGill's allegations.
McGill's correspondence focuses on Warner-Lambert's handling of adverse events in patients who took Rezulin in two clinical trials. The research studies were important, as Rezulin received accelerated approval from the FDA to market the drug.
The first clinical trial cited by McGill was a 1994 project paid for by Warner-Lambert, known as the "echo study." It assessed Rezulin's effect on heart functions. The second was a $150-million clinical trial sponsored jointly by the company and the National Institutes of Health. It was intended to study whether Rezulin could prevent adult-onset diabetes.
Federal officials banished Rezulin from the prevention study after the May 17, 1998, liver failure and death of Audrey LaRue Jones, a 55-year-old high school teacher whose care was overseen by McGill and her colleagues in St. Louis.
McGill said that what she observed as a clinical investigator "has been reflected numerous times in the [Warner-Lambert] approach to their handling of adverse" reactions among Rezulin patients. She cited the 1998 death of Jones in the diabetes-prevention study, noting that the company had denied to doctors nationally that Rezulin caused the death. McGill served as a deputy principal investigator in that study, according to records maintained by the NIH.
She Faults Her Own Supervision
However, despite her criticisms, McGill also conceded that she could have better supervised aspects of the echo study. McGill told the FDA that she regretted labeling one of the two cases of possible liver injury something other than what in hindsight she believes it was: "A case of liver toxicity with skin rash..
"I take full responsibility for the mislabeled diagnoses and any errors," McGill wrote, noting that she had shared some of her concerns in June 1997 with an FDA auditor. McGill wrote that she did not recall discussing with the auditor that the company's study report reflected zero liver-function abnormalities. She said she noticed this only recently.
The auditor, Robert J. Nesselhauf, wrote in his inspection report that McGill's "accountability records are inadequate. . . . The records have numerous scratch-overs and write-overs and at times it is impossible to tell what the record is intended to show..
Both of the patients whose liver abnormalities are described in McGill's correspondence told The Times that they never had felt so sick.
"It almost killed me," said John D. Slater Jr., who, according to medical records, developed jaundice and was hospitalized after taking Rezulin. "They put me in the ICU for two days. My liver and my kidneys had quit me..
Slater, now 73, said he recovered but had to retire as a limousine driver.
In addition to Sen. Kennedy, McGill sent copies of her correspondence to Rep. Henry A. Waxman (D-Los Angeles), House Minority Leader Richard A. Gephardt (D-Mo.), Sen. John Ashcroft (R-Mo.) and Rep. Dan Burton (R-Ind.), chairman of the House Government Reform and Oversight Committee.
After reviewing McGill's materials, the FDA's Misbin wrote his own letter to Ashcroft, faulting the agency's handling of Rezulin.
"In the absence of the threat of a congressional hearing," Misbin wrote on March 3, "I see little hope of turning this around until many more patients have died.
Times researcher Janet Lundblad in Los Angeles contributed to this story.