'Fast-Track' Drug to Treat Diabetes Tied to 33 Deaths

By DAVID WILLMAN

Dec. 6, 1998 12 AM PT

TIMES STAFF WRITER

WASHINGTON —

The Food and Drug Administration dismissed explicit warnings of danger as the agency raced to approve a new diabetes drug that has been linked to at least 33 deaths due to liver injuries, records and interviews show.

Senior FDA officials reviewed the drug on a “fast track” while downplaying harmful potential side effects. The drug, a pill called Rezulin, has become a sales sensation since it was launched in March of 1997 by the Warner-Lambert Co., a major U.S. pharmaceutical manufacturer and maker of consumer products such as Dentyne chewing gum.

The first reported deaths due to liver failure prompted the withdrawal of Rezulin one year ago in Britain. The FDA and Warner-Lambert have kept the drug on the U.S. market while instructing doctors on three separate occasions to take additional steps to protect patients with adult-onset diabetes.

But previously undisclosed cases acknowledged by FDA officials Friday show that these precautions have not slowed the pace of patient deaths. The new total of 33 deaths related to use of Rezulin in the United States and Japan is up from the 21 fatalities reported by the FDA as of June.

The FDA’s handling of Rezulin is shaping up as a nightmare: One medical officer who opposed the approval of Rezulin was removed as the chief reviewer of the drug.

Two other FDA physicians who recommended approving the drug conceded in interviews that the agency initially overlooked compelling evidence of Rezulin’s danger to the liver.

The FDA decision to approve Rezulin without at least recommending that patients undergo precautionary liver testing “was an enormous blunder,” said Dr. Curt D. Furberg, a drug testing specialist and head of public health sciences at Wake Forest University.

“The agency failed,” said Furberg, who is familiar with the FDA’s review and oversight of the drug. “It’s amazing that Rezulin is still on the market.”

The FDA and Warner-Lambert say that Rezulin is safe for the 1 million or more reported users of the drug when prescribed and used properly.

“We believe this drug brings a unique and significant benefit for patients,” said Dr. Randall W. Whitcomb, Warner-Lambert’s vice president for diabetes research. “And while it has a risk, [this] is true of all medications.”

Adult-onset diabetes affects 15 million Americans and is characterized by high blood-sugar levels that can increase the risk of heart disease and cause other complications. It is distinct from juvenile-onset diabetes, whose victims would die without daily injections of insulin.

The story of Rezulin is a window on the new era of accelerated approval for newly proposed medications. This shift has come amid complaints from pharmaceutical companies and patient activists that the FDA had taken too long to approve medications that could save lives.

The regulation of prescription drugs involves both science and art--the weighing of risk versus benefit. Some patients with AIDS or advanced cancer, for instance, are willing to accept extreme risk for new, experimental treatments.

But for patients with adult-onset diabetes, nine drugs other than Rezulin are available--in addition to diet and exercise--to reduce their blood sugar.

“This drug? Nobody’s going to suffer if it’s taken away,” said Dr. David S.H. Bell, an endocrinologist and professor at the University of Alabama at Birmingham School of Medicine.

Liver injuries caused by Rezulin typically have occurred in about 2% of patients, according to FDA records. Because of the liver’s natural regrowth, a majority of patients recover, usually without experiencing symptoms. However, in the worst cases, victims suffered nausea, fatigue and jaundice before suddenly cascading into irreversible liver failure.

The FDA and Warner-Lambert recommend regular testing so that if signs of liver injury are detected, patients can stop taking the drug before the injuries become more serious.

“We have been evaluating this drug very carefully since we became aware that liver disease was a significant problem,” said Dr. James M. Bilstad, the senior FDA official who gave final approval to Rezulin. “We have in the past and continue up to this time to conclude that we still believe the benefits outweigh the risks.”

A Los Angeles Times investigation reveals how the government agency responsible for ensuring the safety of prescription drugs allowed Rezulin to become a best-selling medicine. Interviews and previously undisclosed government records show that:

* A veteran FDA medical officer assigned to evaluate Rezulin, Dr. John L. Gueriguian, recommended rejecting the drug after he documented its potential danger to the liver. Senior FDA officials took the extraordinary step of removing him from the review.

* After the first patient deaths surfaced in fall 1997, another FDA medical officer, Dr. Robert I. Misbin, estimated that more than 12,000 Rezulin users would experience some liver injury. Misbin also advised his superiors that 2,000 of those patients might die unless their liver functions were closely monitored.

“I said to myself, ‘At this very moment as I am writing this, there are 2,000 patients that are going to die of this drug unless we do something,’ ” Misbin told The Times. “. . . I mean, people were being treated with this drug and had no idea what was going on.” While the FDA did urge doctors to monitor Rezulin patients closely, it did not reveal how many lives might be at stake.

* A third FDA official, Dr. G. Alexander Fleming, suggested restricting the recommended use of Rezulin but said he relented after encountering resistance from Warner-Lambert.

* In May, a 55-year-old high school teacher from East St. Louis, Ill., suffered sudden liver failure and died after volunteering to take Rezulin as part of a government study. The woman, who did not have diabetes, adhered to the strict precautionary liver tests that the FDA says should prevent such deaths.

Many adults now taking Rezulin are satisfied that the drug is helping control their high blood sugar. Some physicians who prescribe Rezulin said they find the drug particularly effective for extremely obese patients whose blood-sugar levels remain uncontrolled despite increased insulin dosages.

But doctors and survivors of Rezulin patients who have died are left to wonder why they were not alerted, up front, to the dangers.

“Stop using people as guinea pigs,” said Elmer D. Jones, widower of the East St. Louis teacher who died after taking Rezulin. “If you’re going to do that to people, you should warn them.”

The FDA has enjoyed respect internationally for its thoroughness and expertise in reviewing drugs. For decades, the agency’s physicians have favored caution over speed as they evaluated the safety and effectiveness of new drugs.

Beginning in the mid-1990s, however, an alliance of Republicans, Democrats and pharmaceutical industry lobbyists pressed for legislation aimed at forcing the FDA to act faster, threatening to sharply limit the agency’s drug-review powers.

This threat, government doctors said, resonated at FDA headquarters in Rockville, Md., outside Washington, and has served to hasten the agency’s review of new drugs. FDA senior officials now boast about the speed and large number of drugs they are approving.

During the last 15 months, the FDA has been forced to withdraw five drugs because of safety concerns--exceeding the total pulled in the preceding decade. In July, a painkiller called Duract was removed from the U.S. market after its use was linked to four liver failure deaths--29 fewer than Rezulin.

There are no hard and fast rules about when a drug should be withdrawn. It is a complex, case-by-case judgment involving the drug’s risks and benefits, the severity of the illness and the availability of other treatments.

The FDA approved Rezulin in January 1997, which then made it the most quickly endorsed diabetes pill in the agency’s 60-year history. The “fast-track” review of six months amounted to less than half the time the agency normally takes to scrutinize new drugs.

Warner-Lambert spokesman Stephen J. Mock said the drug’s risks should be weighed against the serious complications that can arise from adult-onset diabetes.

“There is no drug in this therapeutic category that is benign,” Mock said. “It’s a very serious disease.”

Mock said that Rezulin is safe when used with regular liver-function monitoring. He estimated that with proper monitoring, “at most, one in several hundred thousand” patients would die or require a successful liver transplant to survive. Company executives said they do not know what percentage of current patients are being monitored.

This testing of the liver entails taking regular blood samples. Such monitoring reduces but does not eliminate the risk of liver injury, said Dr. Hyman Zimmerman, a diabetes specialist hired by the FDA to review Rezulin. “Even if you tell people to monitor, and you tell them the cost of not monitoring, you go out in the field and you see how often it’s ignored.”

Zimmerman said he supports the use of Rezulin. But eventually, he said, “I suspect that it’s going to be displaced by another [similar drug] that doesn’t have as much liver toxicity.”

FDA officials said the majority of Rezulin-related deaths have occurred among patients who were not properly monitored.

British Agency Finds Drug Unsafe

Officials in Britain responsible for overseeing use of Rezulin have viewed the drug differently. The British Medicines Control Agency concluded that Rezulin is unsafe because of the risk of liver failure for any patient taking it.

“Based on present information, the risks of [Rezulin] therapy outweigh the potential benefits,” the British agency said last December.

Nearly eight months after Rezulin was pulled off pharmacy shelves in Britain, the FDA was urged to ban the drug by Public Citizen, a consumer advocacy group founded by Ralph Nader.

“How many more Americans will have to die or require liver transplants before [Warner-Lambert] and the FDA take action to protect people in this country by banning the drug?” wrote Public Citizen’s Dr. Sidney Wolfe in a July 27 petition filed with the FDA.

The precise number of Rezulin-related deaths and serious injuries remains unclear.

Experts say as few as 1% of harmful side effects from prescription drugs are voluntarily reported by hospitals, doctors and pharmacists to the FDA or manufacturers. In addition, it is often difficult to establish proof that the use of any drug caused a death by itself. Because of this, FDA officials said, their practice is to say that a drug is “associated” with a death.

Because of the voluntary reporting system, officials acknowledged that they do not know the true number of casualties among Rezulin users.

“I think we really can’t say,” said the FDA’s Bilstad.

For Americans with adult-onset diabetes, Warner-Lambert originally heralded Rezulin, a tan-tinted oval pill, as a breakthrough: potent enough to lower blood-sugar levels and virtually free of harmful side effects.

Progress in the treatment of diabetes is important because the disease is the seventh-leading cause of death in the United States; each year it claims the lives of close to 200,000 Americans.

For the estimated 800,000 people afflicted with Type 1, or juvenile-onset, diabetes, the pancreas fails to produce insulin, the hormone that influences how cells use sugar from blood. Without daily insulin, these patients will die.

With Type 2, or adult-onset, diabetes, blood-sugar levels are higher than normal, but the body still produces insulin. About half of the nation’s cases of Type 2 diabetes show no symptoms or are not diagnosed, experts say.

Although Type 1 diabetes poses a more imminent threat of death if left untreated, Type 2 diabetes is where most of the treatment money is to be made because of the higher number of patients.

Since its introduction, Rezulin has climbed quickly toward the “billion-dollar blockbuster” status envisioned by Warner-Lambert. Rezulin has won a following among patients who say they prefer the convenience of a once-a-day pill to some competing medications.

Rezulin is one of 10 competing medications that can lower patients’ blood sugar. And, for the limited number of adult-onset diabetics who take insulin, Rezulin has allowed some to halt their injections and many others to reduce their dosages.

Patricia J. Holland, a technical writer at Cornell University, was found to have Type 2 diabetes two years ago. The first year, she said, was “a nightmare” as she tried one oral drug after another that caused her considerable pain, including severe gastric distress. She said this changed when she switched to Rezulin more than a year ago.

“It’s been great,” Holland said. “It’s the only medication for diabetes I take, and it has no side effects. My blood sugar is near normal all the time, and I can eat pretty normally, within reason.”

Several diabetes specialists said they prescribe Rezulin in limited circumstances. They cited the risk of sudden liver failure and the expense: About $5 per pill, more than twice as much as the other drugs available for Type 2 diabetics.

“There are other viable treatment options for most Type 2 diabetic patients,” said Dr. Bruce Zimmerman, an endocrinologist at the Mayo Clinic and president-elect of the American Diabetes Assn.

Zimmerman noted that doctors at the Mayo Clinic suspect that liver complications caused by Rezulin led to the death of a man treated there last spring.

“I’ve probably discontinued [Rezulin] more than I’ve started patients on it,” he said.

FDA Role Illustrated by Thalidomide Case

A central responsibility of the FDA is to ensure that prescription drugs are both safe and effective.

The gravity of this role was starkly illustrated in the early 1960s when an agency doctor, Frances O. Kelsey, detected worrisome problems with a sedative called thalidomide. On the strength of her recommendation, FDA officials kept it off the U.S. market.

Kelsey was recognized as a hero after the drug’s use by expectant European and Canadian mothers was linked to severe birth defects in at least 10,000 babies. She was saluted by members of Congress and President Kennedy, who presented her the Award of Distinguished Federal Service.

Yet for years, critics also have contended that the FDA took too long to evaluate proposed drugs. These complaints crested with the AIDS epidemic, when activists persuaded the FDA to allow experimental use of certain non-approved drugs.

But the push for faster approval of more drugs did not stop with AIDS. On Nov. 15, 1994, incoming House Speaker Newt Gingrich (R-Ga.) weighed in, calling the then-commissioner of the FDA, Dr. David A. Kessler, “a bully and a thug.”

With Republicans in control of Congress, the critics converted rhetoric to action: Legislation with bipartisan support began moving in the House and the Senate, threatening to severely limit the agency’s drug review powers. Ultimately, the legislation stalled in 1996 at the end of the 104th Congress.

But the seed of fear was sown at the FDA, undermining vigorous scrutiny of newly proposed drugs, current and former agency officials said.

“They’re trying to please everyone at the same time, and you can’t do that when you’re dealing with public health,” said Dr. Laurence Landow, a former FDA reviewer of new drug applications who now teaches at Harvard Medical School.

This pressure came as Warner-Lambert and its drug unit, Parke-Davis, were seeking to mine more deeply the field of Type 2 diabetes treatment. At stake were millions of potential customers in one of the nation’s most lucrative prescription drug markets.

“In the long history of Parke-Davis, few drugs have generated the interest that now surrounds” Rezulin, Warner-Lambert said in its annual report published in the spring of 1996. “. . . Parke-Davis is working aggressively to accelerate [Rezulin’s] evaluation” by the FDA.

The company got its wish.

Within a month after Warner-Lambert submitted a new drug application on July 31, 1996, FDA officials agreed to a six-month “priority” review.

Unlike Kelsey’s recognized heroism with thalidomide, there would be no kudos for the FDA medical officer assigned to examine Rezulin.

Gueriguian had worked at the FDA for nearly two decades, often specializing in reviewing proposed diabetes drugs.

By the time Gueriguian received the Rezulin application in mid-1996, he had already reviewed about 30 formal new drug submissions, including the popular Type 2 diabetes pill Glucophage, which he recommended for approval in 1995.

Gueriguian found what he regarded as troubling signs in Rezulin. He documented and alerted the agency to Rezulin’s potential dangers, records and interviews show.

Gueriguian recommended rejecting Warner-Lambert’s application.

“I said the [new drug application] should not be approved,” Gueriguian said in an interview. “I cited several reasons. One of them was a telltale sign of very worrisome liver toxicity. I stand behind my review, absolutely.”

The Times obtained a copy of Gueriguian’s medical review of Rezulin. In the evaluation, dated Oct. 9, 1996, Gueriguian detailed his concerns to his superiors and colleagues.

Gueriguian detected “worrisome” incidences of liver injury among patients given Rezulin in two pivotal clinical trials conducted by Warner-Lambert. The FDA typically requires companies to present results of such trials to prove the safety and effectiveness of a proposed drug.

Gueriguian found that Warner-Lambert’s own research of Rezulin patients included instances of jaundice, a sign of severe liver injury. These patients nonetheless recovered without permanent injury.

Gueriguian also expressed concern at what Rezulin might do to the heart.

He pointed out that 23 of 140 patients, or 16%, treated with Rezulin in one of the company’s clinical trials experienced heart troubles, compared with 7% of those treated with a dummy, or placebo, pill.

“When one realizes that the greatest killer of diabetics is cardiovascular disease,” Gueriguian wrote, “. . . one realizes the potential for some deadly effects by [Rezulin] in such brittle patients, particularly since treatment of diabetes is a long-term, if not lifelong, therapeutic proposition.”

Gueriguian termed the heart data potentially worrisome but inconclusive. At the FDA’s request, Warner-Lambert is conducting a study of how Rezulin affects diabetic patients with preexisting heart disease.

The issues raised by Gueriguian seemingly went to the core of whether Rezulin could clear the FDA’s standard for approving any proposed prescription drug:

Was Rezulin both safe and effective for public use based on the research submitted by the company?

Gueriguian said no. “Clearly, the sponsor has not made its case,” he concluded.

Gueriguian also raised concerns that Rezulin, if approved, would be prescribed to far more diabetes patients than the FDA envisioned.

Far from being lauded by FDA superiors for meticulous work, Gueriguian found himself under attack.

Gueriguian’s skepticism toward the drug was no secret to Warner-Lambert. In the course of his medical review, Gueriguian said, he posed questions and relayed concerns to the company’s director of worldwide regulatory affairs.

During one meeting in late September 1996, Gueriguian recalled, the company representative inquired about the drug’s prospects.

Gueriguian voiced doubts about the drug in language that both he and Mock, the Warner-Lambert spokesman, described as intemperate.

After Warner-Lambert executives complained about his “behavior” at the meeting, the FDA removed Gueriguian from the review of Rezulin and any other Warner-Lambert drug.

FDA officials declined to discuss the incident. Mock declined to discuss the episode in detail, beyond calling Gueriguian’s behavior “inappropriate.” Mock said the company objected to Gueriguian’s comments, not his concerns about Rezulin.

Gueriguian, 63, retired in September and has become a drug industry consultant. He said the deaths and serious injuries that emerged have come as no surprise.

“If [Rezulin] hadn’t have been approved, at least 21 people would be alive now,” he said. “In all probability, many more than that.”

Safety Issues Fail to Block Approval

With Gueriguian gone, Rezulin was squarely on track.

Each of four FDA officials who examined the drug after his removal viewed Rezulin’s benefits more positively and its risks more modestly.

But Gueriguian’s explicit warnings posed choices for senior FDA officials: Should they reject Rezulin? Should they slow down, scrap the “fast-track” schedule and order more extensive testing of the drug? Or should they continue to push for its speedy approval?

They stayed on the accelerator.

FDA documents and interviews show that, at several critical stages throughout the review process, senior agency officials championed the benefits of Rezulin while downplaying the dangerous effects noted in Gueriguian’s evaluation.

After Gueriguian’s removal from the case, the examination of Rezulin was assumed by his immediate boss, Fleming, a team leader in one of the FDA’s drug review divisions.

Fleming advocated that the FDA approve Rezulin.

In his written medical review, Fleming noted that Warner-Lambert’s clinical trials had identified “significant safety issues” and that instances of liver injury “suggested” unpredictable damage associated with Rezulin.

One of Fleming’s first tasks was to present the agency’s scientific evaluation of Rezulin to an FDA advisory committee on Dec. 11, 1996. The panel, composed of academics and practicing doctors from around the country, makes recommendations concerning newly proposed drugs.

Fleming touched lightly on Rezulin’s threat to the liver, according to a transcript of the session. The panel was not informed about Gueriguian’s many concerns.

After Fleming’s presentation, the FDA committee voted unanimously to recommend approval of the drug.

Fleming, however, alerted the committee that the hurried consideration of Rezulin was unusual.

“It is clear that this is not the typical approach to developing [a] drug for a chronic disorder,” Fleming said. “. . . But there is nothing wrong with this. In fact, I think it shows flexibility on the part of the agency and earnestness in working with industry to get drugs that are desperately needed to those who need them.”

Fleming, 49, who left the FDA in September to work in the drug industry, said in an interview that he now wishes he had responded differently to the warnings of liver trouble. Specifically, Fleming acknowledged two misgivings: First, that he did not call for liver tests as a condition of approving Rezulin. And second, that he did not rebuff Warner-Lambert after the initial deaths and seek to persuade FDA to restrict the drug’s recommended use.

Assisting Fleming was Misbin, a diabetes specialist assigned in the fall of 1996 to review the small-print language that would appear on Rezulin labels.

Misbin, like Gueriguian, expressed skepticism about the drug. In an Oct. 18, 1996, agency memorandum to Gueriguian, Misbin wrote:

“I do not believe that [Warner-Lambert] has made a convincing argument that failure to make [Rezulin] rapidly available would put a significant number of diabetic patients at risk. I believe the greater danger may be to make [Rezulin] available to patients who do not really need it before we have been convinced of its safety.”

Misbin, 51, added: “In particular, careful attention should be paid to the [events] you have already identified,” including liver toxicity and potential heart problems.

Yet Misbin backed Rezulin’s approval and he did not urge that patients undergo testing to guard against liver injury.

Such monitoring has been negotiated or required in recent years by the FDA while approving three cholesterol drugs with lower incidences of liver injury than Rezulin, records show. One of them, Lipitor, is made by Warner-Lambert.

Fleming’s supervisor, Dr. Solomon Sobel, also played a central role in the review. As chief of the agency’s diabetes drug division, Sobel is the official who directly ordered Gueriguian’s recusal.

Sobel hailed Rezulin as “this very exciting new drug” and made no mention of liver problems in his written assessment.

On Jan. 23, 1997, Sobel recommended approving Rezulin. Six days later, his boss, Bilstad, informed Warner-Lambert that Rezulin was approved as a prescription drug.

Both officials told The Times that it was unclear to the agency whether Rezulin or some other factor had caused the liver injuries during the company’s clinical research.

However, patients in the two pivotal clinical trials who took Rezulin developed liver injuries at nearly four times the rate of those given a placebo, FDA records show. This comparison of how a drug and a placebo affect similar patients typically provides the scientific basis for determining if a drug is safe and effective.

“What’s the point to insist on placebo-controlled trials if they ignore the results?” asked Furberg, an expert in clinical testing who reviewed the data. “They blew it.”

Referring specifically to the higher rate of liver injury found among patients who took Rezulin, compared with the placebo, Furberg said: “That is extremely strong evidence. It is highly significant.” Furberg formerly oversaw clinical trial research at the National Heart, Lung and Blood Institute.

In an interview, Fleming conceded that the FDA should have exercised more caution in approving Rezulin.

“You do the best you can, and sometimes you’re right and sometimes you’re wrong,” Fleming said. “I will admit that we were not conservative enough.”

Warner-Lambert executives expressed no misgivings.

“Everybody looks at situations and says something could have been done different,” said Dr. Robert L. Zerbe, senior vice president for worldwide clinical research. “But based on the information that we had, and the FDA had at the time, I don’t have any apologies for the actions that have been taken.”

The FDA approved Rezulin on Jan. 29, 1997, for use in combination with insulin only. The drug appeared on pharmacy shelves two months later.

On Aug. 4, 1997, the FDA approved broader uses of Rezulin--in combination with other Type 2 diabetes pills and as a stand-alone therapy. Again, despite the earlier warnings that Rezulin could lead to serious liver injury, no precautionary monitoring was recommended.

Response to Reports of Death, Injuries

Just two months later, the first death and liver injuries among Rezulin patients surfaced in reports to the FDA submitted by Warner-Lambert. Inside the FDA, the same officials who had downplayed or overlooked the earlier warnings of liver danger were left scrambling.

The challenge for the FDA was to determine what action, if any, should be taken to protect the public: Should the agency issue urgent warnings to doctors and patients? Restrict the recommended use of the drug? Or order the withdrawal of Rezulin?

Misbin, the diabetes specialist, assumed primary responsibility for overseeing Rezulin’s safety risks. He detailed the death and injuries in a Nov. 12, 1997, internal report to FDA supervisors Fleming, Sobel and Bilstad.

In his report, Misbin underscored for the first time the severity of liver injury that had been documented a year earlier during Warner-Lambert’s clinical trials.

According to his report, 21 patients treated with Rezulin before the FDA granted approval had to stop taking the drug because of serious liver injury. Thirteen of the patients had markers of liver injury 10 to 30 times above normal--a potentially life-threatening concentration. Three patients had “biopsy proven” hepatitis; two had jaundice. He also noted that none “had irreversible liver damage.”

Significantly, none of the 475 patients given a placebo showed liver injury at these levels.

Misbin wrote that it was “reasonable” to estimate that 2%, or 12,350, of the 650,000 patients then using Rezulin would experience some degree of liver injury. He estimated that up to 0.4%, or 2,000, would suffer liver injury of about 30 times above normal.

“Generally, at that level, you’re dealing with a severe injury,” said Dr. Gary L. Gitnick, a liver specialist who is chief of the division of digestive diseases at UCLA Medical School.

For his part, Misbin acknowledged that the FDA did not share with the public the warning conveyed by his report. “The severity of the problem is what has not been made public,” he told The Times.

Misbin said that, although he has no way of proving it, he suspects that as many as half of the patients using Rezulin may be complying with the recommended monitoring. This is crucial, he stressed, especially for those patients in jeopardy of incurring severe liver injury.

“If those patients [are not monitored] and have the drug continued,” Misbin said, “they would almost certainly lose their livers.”

As concern mounted, FDA regulators and Warner-Lambert representatives traded calls to try to assess the scope of the death and injuries, agency officials said.

Rather than restrict or withdraw Rezulin, the FDA and Warner-Lambert agreed to send a letter to doctors and issue a press release regarding the liver dangers. The FDA recommended on Nov. 3, 1997, that patients be tested within the first two months of taking Rezulin, every three months during the first year of treatment and periodically thereafter.

Within weeks, however, the FDA determined that even this warning was insufficient.

When reports of three more deaths arose, Rezulin was withdrawn in Britain. That action on Dec. 1, 1997, FDA officials said, triggered more scurrying within the agency.

Fleming, the FDA’s team leader, said he broached with the company the idea of restricting the use of Rezulin. Fleming said he suggested to executives that they consider advising doctors that the drug should not be taken by itself as a “mono-therapy.”

The company’s representatives “were totally against that idea,” Fleming said, and he dropped it, with their assurance that Rezulin would no longer be promoted for this use.

Warner-Lambert executives told The Times that they remain convinced that Rezulin is effective and safe as a mono-therapy. They noted that the FDA did not formally propose restricting this use.

Instead, the FDA announced on Dec. 1, 1997, that the agency and Warner-Lambert were recommending more extensive testing of patients during the first eight months of use.

At the same time, in Kansas City, Mo., Rezulin patient JoAnn Ottmers was suffering the late stages of liver failure.

One of her doctors, endocrinologist William L. Isley, informed the head of the FDA that Ottmers had undergone a liver transplant on Dec. 18, 1997.

In a three-page letter dated the next day, Isley pointedly questioned why the FDA had granted “fast-track” approval to Rezulin.

“In light of the extremely serious adverse effects of this drug and the unproven benefits . . . I think it is highly incumbent upon the Food and Drug Administration to reassess the risk/benefit ratio of this drug,” Isley told the FDA’s lead deputy commissioner, Dr. Michael A. Friedman.

Meanwhile, Rezulin sales were soaring, making it one of America’s hottest new drugs. At Warner-Lambert’s annual corporate meeting last spring, company officials cited another reason for Rezulin’s rosy outlook:

The National Institutes of Health had selected the drug for inclusion in a special government study, testing whether certain medications could prevent or delay the onset of Type 2 diabetes.

“Rezulin is now being studied in [the] diabetes prevention trial sponsored by the National Institutes of Health . . . ,” Ronald M. Cresswell, research chairman of Warner-Lambert’s drug division, told shareholders. “This may be just the beginning of Rezulin’s growth, if post-marketing studies show positive results.”

Within days of that April 28 pronouncement, new trouble emerged:

Audrey LaRue Jones, a volunteer in the NIH trial who was taking Rezulin, had sudden liver failure. Jones, a high school English teacher, did not have diabetes. Nor did the other trial participants

She was in good health a month earlier when she was tested at a St. Louis hospital, her family said. But without warning, her condition turned.

Misbin, the FDA diabetes specialist, said that she “developed irreversible liver failure” shortly after having been found healthy by the precautionary testing.

“The patient now came back one month later and all hell broke loose,” said Misbin, who reviewed the Jones case for the FDA. “She went on to develop liver failure, [have] a transplant--and she died.”

Word of the death May 17 unsettled some doctors who were prescribing Rezulin because the strictest precautions existed in the NIH clinical trial. She had undergone the same tests that the FDA and Warner-Lambert had maintained would prevent such tragedies.

Three specialists assigned by NIH to study the death determined that the woman’s liver failure was “probably” caused by Rezulin. Warner-Lambert disagreed. But on June 4, NIH officials announced that they were immediately eliminating Rezulin as one of two drugs being tested in the six-year, $150-million government study.

At Warner-Lambert, spokesman Mock said, executives “believe” that Rezulin did not cause the woman’s death. They also noted that the company is undertaking its own diabetes-prevention study using Rezulin and that the FDA has signaled its approval of the research.

At the FDA, officials continue to support Rezulin. In response to the NIH death, the FDA agreed, again, with Warner-Lambert to add still more liver testing for patients. These latest changes recommend that patients submit to monthly tests for eight months instead of six. Doctors are advised to ensure that patients get tested weekly at the first indication of liver injury.

Once again, however, the FDA declined to withdraw the drug from the market.

The agency’s posture baffles some doctors who treat diabetes patients and rely on the government to screen drugs for safety and effectiveness.

“It’s shaken my faith in the FDA,” said Isley. “I just want them to do their job.”

Tomorrow: Warner-Lambert’s promotion of Rezulin, from Wall Street to the National Institutes of Health.

Times librarian Janet Lundblad provided research for this article. Also contributing was researcher John Beckham in Chicago and artist Rebecca Perry. The Times retained Thomas J. Moore, fellow in health policy at George Washington University Medical Center, as a consultant.

(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)

Rezulin by the Numbers

Key facts on the diabetes pill Rezulin, which has been linked to 33 liver-failure deaths.

Day approved: Jan. 29, 1997

Manufacturer: Warner Lambert Co.

Months on market: 21

Sales through Sept. 30: $965-million

Patients who have used Rezulin: About 1 million

Cost per 400-mg. pill: $5.56

Used for: Controlling blood-sugar levels

Source: Interviews, Securities ad Exchange Commission

Researched by JANET LUNDBLAD / Los Angeles Times

(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)

On the Fast Track

In January of last year, the Food and Drug-Administration approved a Type 2 diabetes pill called Rezulin on a “fast-track” schedule despite explicit warnings of the drug’s dangers. The FDA and the drug maker, Warner-Lambert Co., have continued to stand behind the drug despite at least 33 liver-failure deaths.

Oct. 9, 1996

Event: A veteran FDA medical officer assigned to examine Rezulin identifies liver and heart problems associated with the drug. He submits a report recommending that Rezulin be rejected.

Action: The medical officer is recused by the FDA from examining the drug after complaints from Warner-Lambert.

Dec. 11, 1996

Event: An FDA advisory committee, composed of academics and practicing physicians, meets to consider whether to recommend that Rezulin be approved.

Action: The committee votes unanimously to recommend approval of Rezulin without receiving the veteran medical officer’s findings.

Jan. 31, 1997

Event: FDA announces approval of Rezulin in record time without any recommendation that doctors monitor patients to guard against the drug’s potential to cause sudden liver injury.

Action: FDA asks Warner-Lambert for additional study of the drug’s effect on the heart. The study is ongoing.

Oct. 31, 1997

Event: Warner-Lambert informs doctors and FDA officials of “rare reports of liver problems in the use of the drug” including one confirmed death and one liver transplant.

Action: FDA and Warner-Lambert recommend that patients’ liver functions be checked “routinely” within the first two months of Rezulin use and “periodically thereafter.”

Nov. 12, 1997

Event: An FDA diabetes specialist tells his bosses that it is “reasonable” to estimate that 2%, or 12,350, of the 650,000 patients using Rezulin would experience liver injury. He estimated that, in 2,000 of these patients, the injuries could be life threatening.

Action: Senior FDA officials recommend liver testing but do not disclose the number of lives at stake. The agency over the next month announces that it is aware of four liver-failure deaths and one transplant.

Dec. 1, 1997

Event: Rezulin is withdrawn from the market in Britain because of safety concerns. This triggers an 18.5% plunge in Warner-Lambert’s stock on the New York Stock Exchange.

Action: FDA declines to withdraw Rezulin or to narrow its use in the United States, announcing that “at present the agency continues to find the benefits outweigh the risks.” FDA recommends that patients submit to liver-function testing “more frequently.”

May 17, 1998

Event: A recipient of Rezulin in a government diabetes-prevention experiment dies after liver failure and a transplant. The National Institutes of Health quickly banishes the drug from the experiment.

Action: FDA continues to endorse use of Rezulin by the general public. Two months later, the FDA supports Warner-Lambert’s call for Rezulin patients to submit to even more extensive testing for liver injury.

Researched by JANET LUNDBLAD / Los Angeles Times

Sources: Food and Drug Administration, National Institutes of Health, Warner-Lambert Co. and interviews

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Where to Get Help

For more information about diabetes drugs, contact these sources:

Food and Drug Administration

Web site: https://www.fda.gov/cder

Los Angeles district office: (949) 798-7714

By mail: Food and Drug Administration

19900 MacArthur Blvd., Suite 300

Irvine, CA 92612

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