Officials Faulted for Not Following Rules in Rezulin Case
Specialists overseeing a clinical trial of the diabetes drug Rezulin did not follow required procedures for monitoring a 55-year-old volunteer who died after taking the pill, interviews and government records show.
A recent e-mail written by a Food and Drug Administration medical officer responsible for evaluating Rezulin’s safety and an interview with a National Institutes of Health panelist provide new details on the death of the clinical-trial participant, Audrey LaRue Jones of East St. Louis, Ill.
The e-mail, sent Friday by Dr. Robert I. Misbin to his superiors at the FDA, reported that Jones was not retested promptly after a blood test first detected evidence of mild liver injury. The follow-up test came about a month later in April 1998. She died May 17, 1998, after suffering liver failure and undergoing an organ transplant.
Dr. James R. Gavin III, who served on a safety monitoring board for the clinical trial at the National Institutes of Health, said in an interview: “The patient was not followed up exactly as would have been required by the protocol.”
The flaw in the clinical trial comes to light as the FDA is considering whether to withdraw Rezulin from sale to the general public. Physicians at the FDA are scheduled to meet today with one of the senior officials in whose hands the decision rests, Dr. Janet Woodcock, director of the agency’s drug-evaluation center.
Jones’ death was of strong interest to the FDA and other officials in mid-1998 because it showed that even a patient monitored within an NIH clinical trial could not be saved from liver failure. Citing concern for the safety of the remaining 580 patients, NIH officials banished Rezulin from the clinical trial in June 1998.
The FDA has linked Rezulin to 89 voluntarily reported liver failures, including 61 deaths, since it went on the market in March 1997.
Dr. David M. Nathan, a Harvard medical professor who as chairman of the NIH study encouraged the selection of Rezulin, did not return calls Monday seeking his comment. Dr. Samuel Dogogo-Jack, the NIH trial’s principal investigator in St. Louis, also did not return calls, nor did his chief assistant. The $150-million clinical study, still ongoing minus Rezulin, was sponsored originally by NIH and Rezulin’s manufacturer, Warner-Lambert Co.
On Monday, Elmer D. Jones, husband of Audrey Jones, said that he was unaware that the required procedure in the trial had not been followed. “At this point,” said Jones, whose wife was a high school English teacher, “you’re never surprised about anything.”
The trial originally administered Rezulin and one other drug to patients to see whether either agent could prevent adult-onset diabetes in patients who had moderately elevated blood-sugar levels.
NIH’s Written Standards Stringent
Newly obtained government records show that the NIH’s written procedures were stringent. When the test in March 1998 found that Jones’ blood showed evidence of mild liver injury, she should have been tested again within two weeks, according to the clinical-trial protocol. But Jones was not tested again at Barnes Jewish Hospital in St. Louis for 33 days, at which time the blood test showed liver-related toxicity more than 20 times the “upper limit of normal.” Members of the Jones family told The Times in fall 1998 that Audrey Jones was fatigued and nauseated for a week or longer before this follow-up blood test.
Gavin and another physician who was involved with the NIH-sponsored clinical trial said that it would be difficult to speculate whether earlier testing might have saved Jones. Gavin said, however, that the episode provided a “sobering kind of epiphany” of how dangerous Rezulin could be. He said he faults the FDA for not acting sooner to withdraw the drug.
“There’s no point in equivocating about this,” said Gavin, who served as president of the American Diabetes Assn. from 1993 to 1994. “It needs to be declared null and void.”
Misbin, the FDA medical officer, was consulted by the NIH at the outset of the nationwide clinical trial. He supported the FDA’s original approval of Rezulin but now is urging its withdrawal.
In his recent e-mail, a copy of which was obtained by The Times, Misbin said: “According to the protocol, the patient, who went on to die following a liver transplant, should have had her [liver-function test] repeated within two weeks after the first elevation. In fact, it took five weeks to recheck her values. By that time her liver had been irrevocably damaged.” Misbin addressed the e-mail to his boss and to 10 other FDA officials, including Commissioner Jane E. Henney.
Safety Concerns Raised in Documents
Documents show that Misbin had earlier raised concern about NIH’s selection of the drug because it would be given, not to diabetics, but to relatively healthy volunteers who did not stand to gain tangible benefits from treatment. Officials at NIH acknowledged that this same ethical concern prompted them to agree to exempt Arizona’s Pima Indians from any use of Rezulin during the clinical trial.
A series of investigative reports on FDA’s “fast-track” approval of Rezulin is available on The Times’ Web site: https://www.latimes.com/rezulin.
