Bad FDA: Part 2 Dr. Fleming and Dr. Lumpkin are

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The FDA initially approved troglitazone, marketed as Rezulin, in January 1997 for treatment of type 2 diabetes. The drug was pulled from the market in March 2000 because of the number of reports of liver failure associated with its use. At an FDA advisory committee meeting last year, regulators reported that there had been 90 cases of liver failure among patients taking the drug since its launch.

As portrayed in the records, FDA officials provided Warner-Lambert with inside information and favours at critical moments throughout the development and marketing of troglitazone, according to the Los Angeles Times. At least one senior manager believed that if an FDA medical officer who had questioned the drug's safety and effectiveness did not please the company, he would be “out.” Soon enough, he was, prompting another executive to report internally that a “hurdle” had been cleared for troglitazone.

Dr John Gueriguian, an FDA medical officer assigned to examine troglitazone, told the company as early as 1994 that he was concerned about “potential toxicities.” But Dr Gueriguian's boss, Dr G Alexander Fleming, told a Warner-Lambert executive in 1995 that he would “ease Dr Gueriguian out” if the executive was displeased with him, according to a memorandum from the executive.

Dr Gueriguian was removed from the case in 1996. Dr Fleming emailed a copy of Dr Gueriguian's unflattering medical review to the company, but it was withheld from the advisory committee that examined the drug, the newspaper said.

Two days before the advisory committee meeting, Dr Fleming emailed Warner-Lambert's executive vice president for regulatory affairs, Irwin Martin, saying, “the drug looks like it ought to be on the market. Loosen up and put on a good presentation. Call if you need help.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1119902/

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By the fall of 1996, Gueriguian concluded that Rezulin was unfit for approval and warned of its potential to harm both the liver and the heart. But Gueriguian came under fire from Warner-Lambert executives, who contacted the FDA’s Lumpkin to complain about Gueriguian’s use of intemperate language.

Effective Nov. 4, 1996, Lumpkin ordered Gueriguian removed from the evaluation of Rezulin and any further dealings with Warner-Lambert, according to physicians familiar with the matter. Gueriguian’s medical review also was purged from agency files.

These actions sent an early and enduring message within the FDA: Challenging Rezulin was not without risk to one’s career.

Newly appointed FDA Commissioner Jane E. Henney ordered a reevaluation of Rezulin in January 1999, in response to a Los Angeles Times investigative series that disclosed at least 33 liver failure deaths attributable to Rezulin.

Trained at Yale and Johns Hopkins medical schools, Graham’s straight-arrow approach was unaffected by the rough-and-tumble of 15 years inside the FDA: Delivering bad news about a hot-selling drug could stymie a career. Senior FDA officials could not be counted on to provide support. Full-throated opposition often would come from the product’s manufacturer.

Warner-Lambert’s representatives told the advisory committee that Rezulin could not be held responsible for many of the liver failures. They cited factors such as preexisting medical conditions.

The committee was unpersuaded by Graham and voted, 11 to 1, to recommend keeping Rezulin on the market. Three of the panelists had received compensation from Warner-Lambert or an affiliate; they were granted conflict-of-interest waivers by the FDA.

After the meeting, the FDA’s Woodcock promptly distanced herself from Graham’s presentation. She said that it was based on “a very broad range . . . of best guesses.”

Graham also was admonished by his immediate boss for the breadth of his report to the committee, he told acquaintances. The FDA declined to allow Graham to comment for this article.

As the advisory committee members dispersed from the March 26 meeting, tragedy again was unfolding. Another Rezulin patient, despite undergoing monthly monitoring in a Warner-Lambert clinical trial, lay near death.
https://www.latimes.com/archives/la-xpm-2000-...story.html

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