By Andrew A. Skolnick
Special To The Post-Dispatch

March 19, 2000
Edited by Virginia Baldwin Gilbert

Six years ago, Dr. Janet B. McGill was optimistic that a new drug she was testing at Washington University would protect the health of many patients with diabetes.

Now McGill thinks the widely sold drug -- Rezulin -- is too dangerous. She wants the Food and Drug Administration to take it off the market.

McGill also is calling on Congress to investigate whether one of the nation's largest drug companies failed to properly report liver problems in patients who took that medication.

McGill's allegations -- coupled with safety concerns voiced by doctors inside and outside the FDA -- are bringing additional pressure on the agency to withdraw its approval of Rezulin. The drug has been used by about 2 million people.

In the United States, Rezulin's labeling has been revised four times to reflect medical experts' increasing concern over its safety. Although the drug was withdrawn in Britain, the FDA still considers Rezulin to have more benefits than risks when used as directed.

McGill is an endocrinologist and associate professor of medicine at Washington University. In 1994, she led a clinical trial of Rezulin, which is the trade name for a drug called troglitazone.

The pill is made by Parke-Davis, a division of Warner-Lambert Co. of Morris Plains, N.J.

Warner-Lambert, once based in St. Louis, makes a wide range of pharmaceutical and consumer products, including the Lipitor cholesterol-reducing drug; Zantac 75 heartburn treatment; Sudafed cold medicine; Listerine antiseptic mouthwash; Schick and Wilkinson shaving products; and Dentyne, Trident and Chiclet gums.

Rezulin, with sales of $748 million in 1998, represents more than 7 percent of Warner-Lambert's total annual sales.

Rezulin was the first of a new class of oral drugs to be approved by the FDA to help patients with diabetes control their blood sugar level.

However, the drug has been linked to 89 reports of liver failure, including 61 deaths, since it was marketed in 1997 after "fast-track" approval by the FDA.

One of the patients who died was Audrey La Rue Jones, a teacher from East St. Louis. Jones volunteered for a study in 1998 to see if Rezulin could prevent people at risk from developing type 2 or adult diabetes, the more common form of the disease.

Taking a second look

Although McGill had only minor involvement with that study, she said Jones' death and the rising number of liver failures, liver transplants and deaths linked to Rezulin caused her to take another look at the company's final report of her 1994 study.

What she noticed, she says, greatly troubled her and led her to write the FDA and five members of Congress earlier this month.

In letters to the FDA and to Sen. Edward Kennedy, D-Mass., McGill complained of discrepancies that she says she found in the drug company's final report of her study.

The report says that none of her patients had abnormal liver function test results. However, two of her patients taking Rezulin did develop seriously abnormal liver enzymes.

While that number may appear small, omission of data from only a few patients could affect the FDA's ruling whether a drug is safe enough to market or how the drug's warning label should read.

"Parke-Davis deliberately omitted reports of liver toxicity and misrep resented serious adverse events experienced by patients in their clinical studies," McGill wrote in the letter to Kennedy.

Warner-Lambert insists McGill's allegations are false.

In a letter sent to the FDA Tuesday, Mary E. Taylor, Parke-Davis' senior director of worldwide regulatory affairs, denied that the company failed to report liver toxicity data to the FDA.

She blamed any omission on McGill: "All information provided to Parke-Davis by Dr. McGill concerning the two patients . . . including any liver enzyme abnormalities, was reported to the FDA."

One of the patients in McGill's study developed malaise, fatigue and a skin rash after about six weeks on the drug.

Although the patient's tests showed abnormally high liver enzymes, McGill had reported the case as what she judged was his most serious problem, "hypersensitivity vasculitis," a potentially lethal inflammation of blood vessels. "In retrospect, I should have labeled this a case of liver toxicity with skin rash," she wrote.

A second case involved John D. Slater Jr., a man from Richmond Heights who suffered liver and kidney damage after four weeks on the drug.

At the time, McGill had diagnosed the illness as hemolytic-uremic syndrome, in which something damages the patient's red blood cells and kidneys.

Noting Slater's case "is far from clear-cut," McGill said last week that her patient's troubles may have been a drug-induced form of a liver illness called cholestasis. The results of Slater's lab tests showed very abnormal liver enzymes, which were not included in company's final report, she said.

Charges of coercion

McGill, who has conducted clinical research for 12 years, also told the FDA that a Parke-Davis representative had "coerced" her into changing the way she described the patients' problems.

"With more studies and years of clinical trials experience behind me, I would not acquiesce to such a request under similar circumstances today," she wrote.

Warner-Lambert disputes that charge, too.

"First, Dr. McGill was not coerced in any way to change her causality assessment," Taylor wrote the FDA. "Second, Dr. McGill's voluntary change in the causality designation had no impact on the way that the data were reported by Parke-Davis to the FDA."

Some of McGill's concerns were echoed in another letter sent to the FDA Tuesday by Dr. Sidney M. Wolfe, director of Public Citizen's Health Research Group, a Washington-based consumer advocacy organization. The letter asks the FDA to open a criminal investigation of Warner-Lambert for what Wolfe says appears to be the illegal delay of reporting other evidence of liver toxicity linked to Rezulin.

Wolfe alleges that the company delayed reporting the data until six months after Rezulin was on the market.

Had the information been reported promptly as required by law, he said, the drug's label could have warned physicians and patients to watch for signs of liver damage, and lives may have been saved.

Warner-Lambert officials deny Wolfe's charges. "Public Citizen's allegations of misconduct regarding Warner-Lambert's disclosure of clinical study data are baseless," said Warner-Lambert spokeswoman Carol Goodrich.

With all the allegations and counterallegations, the Rezulin controversy is getting noticed.

On Wednesday, the American Diabetes Association, which considered Rezulin to be safe enough in the past, indicated that its confidence may be waning.

The group issued a statement that sought to differentiate Rezulin from two similar drugs: rosiglitazone (Avandia, marketed by SmithKline Beecham Pharmaceuticals) and pioglitazone (Actos, made by Takeda Pharmaceuticals America Inc. and marketed by Eli Lilly & Co.).

"At this time, the American Diabetes Association does not believe . . . that the safety concerns regarding Rezulin extend to the other two medications which are in the same class of diabetes drugs as Rezulin," it said.

Respected by colleagues

Back in St. Louis, McGill is uncomfortable with the sudden attention her accusations against Warner-Lambert have brought.

The physician and researcher joined Washington University's medical faculty in 1987.

Widowed, McGill, 49, lives in University City. She has two daughters, ages 16 and 19, and a son age 20. "Her buddies," she calls them.

McGill is well-respected by her colleagues. Even one who strongly disagrees with her opinion of Rezulin speaks well of her: Dr. Charles Kilo.

Kilo is a professor of medicine at the Washington University School of Medicine and chairman of the Kilo Diabetes and Vascular Research Foundation in St. Louis. He has authored several studies with McGill and says he admires her.

But he remains convinced that Rezulin and similar drugs "are excellent drugs and that they are safe when used as directed."

Despite the attention, McGill says she has nothing to gain from coming forward.

"I knew it would provoke a lot of controversy," she said. "But I felt I had no choice. The problem needs to be addressed."