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SUNDAY REPORT

Hidden Risks, Lethal Truths

Warner-Lambert won approval for Rezulin after masking the scope of liver injuries in clinical studies

June 30, 2002|DAVID WILLMAN | TIMES STAFF WRITER

Dr. Robert I. Misbin, an FDA medical officer who for years supported Rezulin but who ultimately fought for its withdrawal, testified recently that Warner-Lambert "never" informed him of the higher number of cases.

Misbin testified that if the company had conveyed more accurate and complete information about the severity of liver injuries in the clinical studies, he would have opposed approving the drug, in August 1997, as a stand-alone pill for adult-onset diabetes.

According to company documents and sworn testimony this year, even specialists within Warner-Lambert were unable to discern Whitcomb's rationale for reporting 48 cases rather than 78.

Beth Ann Baron, a manager on Warner-Lambert's diabetes team in Ann Arbor, was one of the specialists who tried to obtain documentation for Whitcomb's rationale, starting in October 1997. "I think it's fair to say that everyone that was involved ... would have liked to have seen that," Baron testified in a deposition on March 12. Her colleague, Donald Sizemore, testified in January that he also raised the issue with Warner-Lambert's director of worldwide regulatory affairs, who, he said, "never got back to me on that." Sizemore testified that he was unaware of any other instance when Warner-Lambert did not internally "validate" safety data submitted to the FDA.

A request by The Times to interview Whitcomb last week was declined by Pfizer. In recent trials of civil lawsuits, company lawyers have defended as proper his handling of the liver-injury cases .

Whitcomb remains active in the pharmaceutical industry. In November, he joined the board of directors of Insmed Inc., a publicly traded firm that is developing another drug for adult-onset diabetes. In January, Whitcomb, 48, was one of four former Warner-Lambert executives who launched a privately held drug-development company based in Ann Arbor called QUATRx.

Striving for Clinical Studies Free of Bias

Controlled clinical studies are the gold standard of pharmaceutical research. The studies can help measure the effectiveness and the safety of a drug. The goal is to insulate the research from the subjective judgment, or bias, of the people conducting the experiment.

For this reason, the ground rules for clinical studies are written and discussed in advance, typically in painstaking detail.

This scientific approach helps the FDA and prescribing physicians sort viable therapies from unproved hype. Companies also conduct clinical studies of medicines that have already won government approval, often in an effort to find expanded uses for them.

Dr. Curt D. Furberg, a clinical studies expert who is a professor of public health at Wake Forest University, said that in his view Warner-Lambert may have inappropriately reduced the count of liver injuries from its clinical studies of Rezulin. "It appears that they made up rules as they went along," said Furberg, who also serves on an FDA drug-safety advisory committee.

Whitcomb, in sworn testimony given March 6 to 8, said he did not count cases if he concluded that a study patient's liver injury resulted from what he suspected was a cause other than Rezulin. Yet, according to clinical studies experts, all cases of injury should have been counted and reported. Theorizing about the cause of the events, they say, improperly infused Whitcomb's opinion into the research.

John W. Hornbeck, a Los Angeles-based lawyer for plaintiffs suing the manufacturer, asked Whitcomb in March whether the rejection of a liver-injury case on the basis of what Whitcomb suspected was a "clear alternative cause" could introduce bias into the study.

Whitcomb responded: "It is a possibility, yes."

Hornbeck then asked Whitcomb whether placebo patients showing liver injury were counted, regardless of his opinion about the cause.

Whitcomb responded: "Right."

When Hornbeck asked whether he applied all of the same rules for counting liver injury to placebo and Rezulin patients alike, Whitcomb responded: "I would need to go back and look at each of the placebo patients. Again, I don't recall exactly."

Whitcomb testified that he conferred with a liver specialist retained by Warner-Lambert about shrinking the total of liver-injury patients from the clinical studies from 78 to 48. Whitcomb said he could not remember whether the rules for excluding cases were in writing when he met with the liver specialist, Dr. Paul Watkins, in the fall of 1997.

"There may have been some handwritten things that were put together in the fall of 1997 as we were working on this," Whitcomb said. " ... I can't tell you for sure."

Whitcomb said he was unable to specify exactly how he went about reducing the 78 cases to 48. "I don't have a specific recollection of how we got down to the 48," Whitcomb testified.

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