March 11, 2000, Saturday, FIVE STAR LIFT EDITION

SECTION: NEWS, Pg. 11

LENGTH: 439 words

HEADLINE: MAKER OF DIABETES PILL ASKS FOR INQUIRY INTO ALLEGATIONS BY WU RESEARCHER

BYLINE: Andrew A. Skolnick

Special To The Post-Dispatch

BODY:

The maker of a diabetes pill associated with a mounting number of liver failures and deaths asked the U.S. Food and Drug Administration Friday to investigate allegations made against the company by a researcher at the Washington University School of Medicine.

Warner-Lambert Co. - the New Jersey-based drug company that markets the widely selling diabetes drug troglitazone under the name Rezulin - is asking the food and drug agency to review allegations that the company did not inform the agency about liver damage in two patients during a clinical trial that the company sponsored at Washington University in 1994.

Calling the allegations "inaccurate," the company asks that the findings be made public as soon as possible. Warner-Lambert's action was a response to reports on the allegations by the Los Angeles Times and CBS News.

The allegations were made in a letter sent on March 1 to Dr. Robert Misbin of the food and drug agency by Dr. Janet McGill, associate professor of medicine at Washington University.

In the letter, McGill said she was coerced by two Warner-Lambert employees into changing how she described adverse effects in one of the patients in the trial.

The agency says it will respond to McGill after evaluating the specific points made and the issues raised in her correspondence. "Dr. McGill's allegations are serious and must not be ignored," an agency spokesman said.

Rezulin is one of a new class of medications for controlling blood sugar levels in patients with type 2 diabetes, the most common form of the disease. Warner-Lambert says more than 2 million people have been treated with the drug.

As of Friday, the food and drug agency said it had received 88 reports of liver failure it considered "possibly or probably related" to the use of Rezulin. Of those patients, 61 died and 10 required liver transplants.

Warner-Lambert spokesman Jason Ford said the company is preparing a detailed report to the food and drug agency addressing the issues raised in McGill's letter.

"Warner-Lambert's actions in connection with Rezulin have been guided by a single consideration - the health and safety of people with type 2 diabetes," the company said.

Also, Warner-Lambert will formally ask the food and drug agency to schedule a public meeting of its Endocrinologic and Metabolic Drugs Advisory Committee in July to discuss the facts regarding the safety of Rezulin and the two other Rezulin-like drugs now on the market.

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March 19, 2000, Sunday, FIVE STAR LIFT EDITION

SECTION: NEWS, Pg. A6

LENGTH: 1707 words

HEADLINE: A PROFESSOR AT WU WARNS THAT A POPULAR DIABETES DRUG COULD CAUSE LIVER;
PROBLEMS

BYLINE: Andrew A. Skolnick; Special To The Post-Dispatch

BODY:

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."

==================

Fighting diabetes with drugs

More than 13 million people in the United States suffer from adult-onset diabetes, known as type 2 diabetes.

The body needs the hormone insulin to metabolize sugar. However, people with type 2 diabetes do not have enough or have become resistant to insulin.

As a result, blood sugar levels often climb high enough to damage their eyes, kidneys, heart and other organs.

There now are five types of oral drugs approved by the Food and Drug Administration for treating type 2 diabetes. They may be used alone or in addition to insulin injections to control the patient's blood sugar levels:

Hypoglycemic agents

These drugs, also called sulfonylureas, include names such as glipizide, glimepiride and glyburide. They lower blood sugar by stimulating the pancreas to secrete more insulin.

Meglitinides

Repaglinide (Prandin) is a newer class of drug that also stimulates the pancreas to secrete more insulin. It is absorbed and cleared from the blood more quickly than sulfonylureas.

Starch blockers

These drugs, also called alpha-glucosidase inhibitors, include acarbose (Precose) and miglitol (Glyset). They reduce the digestion of starches to prevent harmfully high peaks in blood sugar levels.

Biguanides

Metformin (Glucophage) increases the liver's sensitivity to insulin, causing it to reduce the release of blood sugar into the blood.

Insulin sensitizers

This newest class of diabetes drugs, also called glitazones or thiazolidinediones, includes troglitazone (Rezulin), rosiglitazone (Avandia) and pioglitazone (Actos). They work primarily by making the patient's body more sensitive to insulin.

GRAPHIC: PHOTO PHOTO by KEVIN MANNING / POST-DISPATCH - Dr. Janet B. McGill, an endocrinologist and associate professor of medicine at Washington University, interviews a man last week who was volunteering for a new research project on diabetes.

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March 19, 2000, Sunday, FIVE STAR LIFT EDITION

SECTION: NEWS, Pg. A6

LENGTH: 418 words

HEADLINE: BAD EXPERIENCE DIDN'T DETER DRUG STUDY PARTICIPANT;
MAN STILL VOLUNTEERS IN MEDICAL PROGRAMS

BYLINE: Andrew A. Skolnick

Special To The Post-Dispatch

BODY:

John D. Slater Jr. has had three major callings in his 73 years.

Until he retired 16 years ago, Slater, of Richmond Heights, ran a parking lot near the Fox Theatre in St. Louis.

Then he was a limousine chauffeur -- until he slipped on ice and suffered a head injury last year.

For the past decade, he also has been a volunteer human guinea pig -- helping researchers look for better treatments for some of his illnesses.

Slater, whose fiancée works as an editorial writer at the Post-Dispatch, has type 2 diabetes.

In 1994, he volunteered for a study of Warner-Lambert Co.'s diabetes drug Rezulin. The study was headed by Dr. Janet B. McGill, associate professor of medicine at Washington University.

While on vacation in Hawaii -- just days after he was seen by the researcher -- he suddenly fell ill.

Slater's urine turned brown and he became jaundiced. He was so ill that the airline moved him into a first-class seat on a nonstop flight home and had a doctor waiting at the airport for his arrival.

After two days in an intensive-care unit and another week in the hospital, he had recovered enough to go home.

While the exact diagnosis is still uncertain, it is clear that the Rezulin was toxic to Slater's kidneys and liver, McGill said. Without the proper hospital care, he would have died, she said.

Abnormal results of Slater's liver tests are at the heart of the allegations in the Rezulin controversy at the Food and Drug Administration. McGill says Warner-Lambert failed to report the data in its final study report. The company says it never got that data.

Slater has nothing but praise for the care he received from his physician and from McGill. He has become a staunch supporter and friend of the researcher.

"I trust her implicitly," he said. "If she says it's not going to hurt me, then I'm willing to do it."

What's more, he has continued to volunteer for medical studies.

He is now a patient in a study to prevent the progression of macular degeneration -- the leading cause of blindness in adults. He already has shown early symptoms of the disease.

Why does Slater keep volunteering for studies?

"I'm 73 years old," he explained. "If I can help somebody else along the way, I'd be happy."

When he comes to the hospital for one of the studies, Slater usually pays McGill a visit.

Said McGill: "The world owes a lot to people like Jack, who, out of altruism, contribute so much to our understanding of diseases and how to treat them."

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March 19, 2000, Sunday, FIVE STAR LIFT EDITION

SECTION: NEWS, Pg. A6

LENGTH: 395 words

HEADLINE: WHEN ADVERSE REACTIONS GO UNREPORTED, OTHER PATIENTS ARE PUT AT RISK

BYLINE: Andrew A. Skolnick

Special To The Post-Dispatch

BODY:
If one or two adverse drug reactions slip through the Food and Drug Administration's reporting process, the results can be tragic for some patients.

That is especially true when the adverse reactions are rare but serious -- such as in the case of liver failure caused by medication.

All drugs have the potential to harm or kill the people they're supposed to help. A shot of penicillin can kill in minutes if the recipient is allergic to the life-saving drug. Even common aspirin can be deadly.

Clinical trials of a new drug often involve a few hundred patients and therefore may not reveal that a drug can cause serious injury or death in one patient in 10,000 or even 1,000 patients. So it is critical for researchers and drug companies to report to the FDA all suspected adverse reactions among patients in their studies.

Before allowing a drug to be marketed, the FDA requires that it be tested for efficacy and safety in a series of clinical trials.

If these studies find that the potential harm from a drug outweighs its benefits, the FDA probably won't grant approval. While that decision depends on science, the decision-making process does not take place in a vacuum.

For drugs used to treat diseases such as diabetes, which affects so many people and is difficult to treat, FDA officials often face tremendous pressure to speed up their approval process.

Often, in this "fast-track" process, cases of adverse drug effects may slip through reporting cracks, consumer advocates say.

An even bigger challenge to the FDA is tracking adverse drug reactions after the drug is on the market.

Physicians are not required by law to monitor and report adverse drug effects associated with approved drugs. Some physicians, fearing a malpractice suit, may even be reluctant to report an adverse reaction.

Prompt reporting of suspected adverse drug effects is necessary to rapidly identify health hazards associated with drugs or other medical products, the FDA says.

To encourage the monitoring and reporting of all adverse drug reactions, the FDA established a medical product reporting program called MedWatch. It does not require the reporting of the patient's identity.

Information about drug problems can be found through the FDA's MedWatch Web site:

www.fda.gov/medwatch/index.html. To report adverse drug events, call 800-332-1088.

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March 23, 2000, Thursday, FIVE STAR LIFT EDITION

SECTION: NEWS, Pg. A9

LENGTH: 466 words

HEADLINE: NEWS OF DIABETES DRUG'S WITHDRAWAL IS HAILED IN THE ST. LOUIS AREA - BUT NOT; BY EVERYONE;

TWO DOCTORS DIFFER IN OPINION OF REZULIN

BYLINE: Andrew A. Skolnick

Special To The Post-Dispatch

BODY:

In May 1998, Audrey La Rue Jones, 55, developed liver failure while taking Rezulin as part of a study to see whether the drug could prevent diabetes. She received a liver transplant but did not survive.

Rezulin, also called troglitazone, has been linked to 89 reports of liver failure, including 61 deaths, since it was first marketed in 1997 by Parke-Davis, a division of Warner-Lambert Co. of Morris Plains, N.J.

After mounting complaints about the drug's safety, the Food and Drug Administration late Tuesday asked the company to stop selling the drug. The company agreed.

"It is a great relief to know that the same thing that happened to my wife will not happen to any more people," said Jones, 59.

Dr. Janet McGill, associate professor of medicine at the Washington University School of Medicine, is also pleased.

McGill, who led a 1994 study of Rezulin, sent letters to the FDA and several members of Congress early this month calling for an investigation of how Warner-Lambert reported cases of liver problems.

"It was a tough decision for the FDA to make, but it was the right decision," McGill said.

Warner-Lambert officials say they continue to believe that the benefits of the drug outweigh its associated risks.

"Repeated media reports sensationalizing the risks associated with Rezulin therapy have created an environment in which patients and physicians are simply unable to make well-informed decisions regarding the safety and efficacy of Rezulin," the company said in a prepared statement. "We have decided it is in the best interests of patients to discontinue marketing Rezulin at this time."

Rezulin still has its supporters - some of whom blame the media attention for the drug's removal.

One of those is Dr. Charles Kilo, a professor of medicine at Washington University and chairman of the Kilo Diabetes and Vascular Research Foundation in St. Louis.

Calling the allegations of the critics "unsubstantiated," Kilo said Wednesday that news reports "created an emotional outcry from consumers, who were presented with only one side of the controversy."

The FDA's decision to pull the drug was based on the agency's review of safety data that showed Rezulin was more toxic to the liver than two similar drugs approved in the past year - rosiglitazone (Avandia) and pioglitazone (Actos), said Dr. Janet Woodcock, director of FDA's Center for Drug Evaluation and Research.

The FDA is advising patients not to make any decisions about stopping medication without consulting their physicians.

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March 8, 2000, Wednesday, FIVE STAR LIFT EDITION

SECTION: NEWS, Pg. A7

LENGTH: 675 words

HEADLINE: GROUP IS ASKING FDA TO CHANGE WARNING LABELS ON THREE DIABETES DRUGS;
SOME EXPERTS ON THE DISEASE SAY THE CHANGES AREN'T NEEDED

BYLINE: Andrew A. Skolnick

Special To The Post-Dispatch

BODY:
A national consumer organization is asking the U.S. Food and Drug Administration to change the labeling requirements for three diabetes drugs that the group says may cause serious illness or death.

Current labeling requirements "are inadequate, misleading, and potentially dangerous," says a petition submitted Tuesday to the FDA by the Washington-based Public Citizen's Health Research Group.

"The labeling omits important safety and efficacy information to such an extent that physicians are likely to prescribe these drugs inappropriately," the petition says.

However, some diabetes experts strongly disagree. "These labeling changes are totally uncalled for," says Dr. Charles Kilo, professor of medicine at Washington University School of Medicine and chairman of the Kilo Diabetes and Vascular Research Foundation in St. Louis. "I am convinced that these are excellent drugs and that they are safe when used as directed."

The drugs in question are a relatively new class of medication for controlling blood sugar levels in patients with type 2 diabetes, the most common form of the disease. Troglitazone, marketed by Warner-Lambert under the name Rezulin, has been linked to liver damage and deaths since it was approved for marketing in 1997.

Warner-Lambert says nearly 2 million patients have been treated with Rezulin, the most widely used of the drugs.

Although serious side effects from these drugs appear to be rare, the consequences of liver damage are often severe. As of Feb. 19, the FDA received 85 reports of liver failure that it considers "possibly or probably related" to the use of Rezulin, said Dr. David Orloff of the FDA. Of those, 10 required liver transplants with a total of 58 deaths.

The other drugs, rosiglitazone, marketed by SmithKline Beecham under the name Avandia, and pioglitazone, marketed by Takeda Pharmaceuticals America Inc. and Eli Lilly and Co. under the name Actos, were approved for marketing last year.

Orloff said the FDA considers only one of the reported cases of liver fa ilure to have been "possibly or probably related to use of Avandia." And the FDA has received no reported cases of liver failure that appear related to Actos use.

In July 1998, the same consumer group petitioned the FDA to ban the sale of Rezulin following earlier reports of fatal liver failures - including the death of a woman from East St. Louis who had been a patient in a clinical trial at Washington University School of Medicine.

"Omission of facts"

Tuesday's petition calls for further changes in drug labeling to increase the awareness of physicians and patients to the risk of liver damage, as well as heart damage, weight gain and other adverse effects.

"We are concerned that this petition contains some inaccuracies as well as omission of facts," said Dr. Wayman Wendell Cheatham, medical director of Takeda Pharmaceuticals. "As of Feb. 29, over 500,000 prescriptions for Actos have been written for more than 300,000 patients. ... To date, our monitoring system has seen no evidence for the concerns raised in this petition."

SmithKline Beecham spokesman Brian Jones said the drug company "stands behind the safety and efficacy of Avandia and continues to work closely with the FDA."

Carol Goodrich, spokeswoman for Warner-Lambert, said Tuesday that there have been no additional cases of liver failure deaths or transplantation among patients who began Rezulin after stricter warning labels were adopted in June. This labeling warned health professionals and patients to watch closely for liver problems.

Type 2, or adult-onset diabetes, is caused by the body's inability to make enough, or properly use, insulin.

Unlike other medications to control type 2 diabetes, the newer class of drugs work by decreasing the patient's resistance to insulin. Patients with uncontrolled diabetes are at high risk for blindness, heart disease, strokes, kidney failure, limb amputations and early death. More than 13 million people in the United States have type 2 diabetes.

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