FDA Panel Not Told of Drug’s Ill Effects
A Food and Drug Administration advisory committee that recommended approving the diabetes pill Rezulin was never told that 11 research patients had suffered potentially life-threatening liver injuries or that an agency medical officer opposed the drug, according to three experts who served on the panel.
The specialists said in interviews that they would have proposed precautionary liver monitoring for Rezulin users if they had known the full extent of liver problems found during the testing of the drug.
Dr. Jose Francisco Cara of Detroit, a committee member, said that the panel also may have called for further study of the liver risk before Rezulin was allowed on the market in March of last year.
“If we had seen that sort of data, I think we would have been more cautious in terms of giving the drug such a strong voice of approval,” said Cara, a pediatric diabetes specialist.
The failure of the FDA to inform the committee is significant because senior agency officials now emphasize that monitoring is necessary to ensure the safety of those taking Rezulin. More than 1 million patients have been prescribed the drug.
The advisory committee voted, 8 to 0, on Dec. 11, 1996, to recommend that the FDA approve Rezulin, a pill that can lower blood-sugar levels of patients with adult-onset diabetes.
The FDA’s dismissal of explicit warnings of danger while racing to approve Rezulin within a six-month “fast-track” review was disclosed by The Times on Dec. 6. The article also reported that the veteran FDA medical officer assigned to examine Rezulin opposed approval of the drug and was removed from his assignment by senior FDA officials.
It was not until November 1997--eight months after Rezulin went on the market--that the FDA and the manufacturer recommended that patients undergo regular liver-function testing. That recommendation came after the first reported liver-failure death.
The FDA now acknowledges that Rezulin has been linked to at least 33 liver-failure deaths.
The FDA and the drug’s sponsor, Warner-Lambert Co. of New Jersey, continue to advise doctors and patients that Rezulin is safe when prescribed properly and taken with regular liver monitoring.
Officials said that they do not know how many patients are following the liver-monitoring recommendations.
The deaths of Rezulin patients have continued even though recommendations for liver testing have been in effect for more than a year.
Since June, at least 12 patients taking the drug have died, said Dr. James M. Bilstad, the senior FDA official who gave final approval to Rezulin.
“Those are the ones that would have occurred from June until now,” Bilstad said in an interview, adding: “Of those 12 additional deaths since June, three are transplants.”
Stephen J. Mock, a spokesman for Warner-Lambert, said that he is unaware of any deaths or transplants occurring after July 28, when the liver-monitoring recommendations were last changed.
When the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee met in December 1996, to weigh the benefits and risks of Rezulin, the drug’s potential to harm the liver was not explored.
Asked why FDA staff did not inform the committee of the 11 research patients with potentially life-threatening liver injuries, Bilstad said: “I can’t answer that question.”
A Warner-Lambert executive, Dr. Randall W. Whitcomb, has told The Times that the company discussed findings of liver toxicity with at least four FDA officials, including Bilstad.
Bilstad confirmed that Warner-Lambert Co. had notified FDA staff of the cases before the agency approved the drug, on Jan. 29, 1997.
Bilstad indicated that the decisions on what information to present to the advisory committee in December 1996 were not made by him but by a subordinate.
“He didn’t happen to emphasize the liver, the questions about the liver,” Bilstad said.
Would the advisory committee have recommended liver-function monitoring for prospective users of Rezulin if the 11 cases had been brought to the panel’s attention?
“Yes, based on this information, yes,” said one committee member, Dr. D. Roger Illingworth, a metabolism and diabetes specialist at Oregon Health Sciences University in Portland. He termed the FDA’s failure to point out this information to the committee “unusual.”
Two other advisory committee members, Cara and clinical pharmacist Colleen Colley, said that they, too, would have called for monitoring. The three said that they probably still would have been inclined ultimately to recommend approval of Rezulin.
The advisory committee was informed, however, that two additional patients given the drug developed jaundice--often a sign of serious liver injury.
Before the drug was approved, about 2% of the more than 2,000 research patients taking Rezulin was found to have signs of liver injury. None of the patients suffered permanent damage.
According to a Nov. 12, 1997, FDA report, a total of 13 research patients were found to have liver toxicity resulting in blood-enzyme levels greater than 10 times the “upper limit of normal.” Five of the patients were found to have levels of about 30 times over the upper limit.
Such toxicity is potentially life threatening and can indicate significant liver injury, according to experts.
“Certainly, 10 times the upper limit of normal is concerning,” said Colley, who is a pharmacist for the Veterans Affairs Department in Portland, Ore. “There certainly would have been questions about those patients, if it had come up.”
All 13 of the patients were taken off the drug and recovered.
The committee members also said that they had no idea the FDA medical officer, Dr. John L. Gueriguian, was removed or that he had opposed approval of Rezulin, based in part on concern about the drug’s potential to cause liver injury.
