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Lilly Draws Wrath Over Discontinued Insulin


Dec 1, 1999

Reprinted with permission from The Indianapolis Star

Some Diabetes Patients Insist Their Health is Jeopardized by Replacement of Animal-based Product with Biosynthetic

A high school Spanish teacher in California, Linda Vernier relies on beef-pork insulin from Eli Lilly and Co. to stay healthy.

Last year, Vernier, who is diabetic, saw her lifeline snipped. Her mother dropped off Vernier's monthly insulin supply with a bright red warning from Lilly that the product, once known in the United States as standard insulin, was being discontinued.

Vernier becomes emotional talking about her medical plight.

"They don't care that I die," she said about Lilly, her voice quavering. "How can this happen in the United States?"

Vernier is among hundreds, or maybe thousands, of Americans with diabetes who insist they can't use the newer biosynthetic human insulins that have steadily shoved the older animal-based insulins off the market.

Theirs is a heavily anecdote-driven campaign about patient choice, with views that run counter to mainline medicine's, including that of the American Diabetes Association.

This is the kind of controversy that wasn't supposed to happen.

Biosynthetic human insulin was hailed from its launch in 1983 as a dramatic improvement in diabetes care. Some 3 million diabetic Americans now depend on it every day. Made with human DNA, the biosynthetics are the first insulins that are structurally the same as the kind the body produces. They don't trigger the allergic reactions or other side effects that animal insulins often cause.

But those selling points no longer impress Vernier. Or David G. Groves. Or Robin A. Harrison.

Each suffered bad experiences on biosynthetic human insulin. Each has become a vocal advocate of keeping animal insulins on the market.

And their main beef is with Lilly, the Indianapolis company whose name is synonymous with diabetes care, but which now finds itself in the unfamiliar role of being painted by customers as uncaring.

"They're playing some vicious Orwellian games," fumed Groves, a 53-year-old business consultant from Birmingham, Ala.

Groves, who blames biosynthetic human insulin for his near-death in a car accident, wages his campaign on an Internet Web site complete with foot-noted copies of medical articles.

Vernier and a friend run another Web page. It is dedicated to "helping folk like school teacher Linda Vernier survive Eli Lilly's unwise discontinuance of Iletin 1," as the longtime beef-pork brand is called.

Vernier's Web site has an activist bent, calling on disgruntled insulin users to buy Lilly stock and speak out at the company's next annual meeting in the spring.

Harrison has taken a different tack. A 39-year-old free-lance writer from Durham, N.C., she heads up the U.S. affiliate of Insulin Dependent Diabetes Trust, a patients group that promotes animal insulins in Great Britain.

"I kind of feel like Lilly has sold me out," said Harrison, who went on beef-pork insulin in 1996 after eight problem-filled years on biosynthetic human.

Like others, she has stocked her refrigerator with Iletin 1 to tide her over while she seeks federal approval to import a replacement animal insulin from overseas.

Her group, with a mailing list of 60 people, decided it was hopeless to keep trying to persuade Lilly to make Iletin 1, she said.

The controversy also simmers north of the border, where animal insulin was invented. Iletin 1, which contains 85 percent beef insulin and 15 percent pork, was the last beef insulin left in Canada. Some users there believe they've been left in the lurch, said Dr. Andrew Farquhar, a family doctor in British Columbia.

"To my knowledge, this is the first time in the history of medicine that a product is being pulled without any consultation with patients and for which there is not a superior (replacement) product," Farquhar said.

"It's an issue that really upsets me."

Biosynthetic breakthrough

Earning such widespread ire from insulin users is practically unheard of for Lilly, which produces 80 percent of the nation's insulin. The U.S. insulin business is a duopoly, with Danish firm Novo Nordisk supplying the rest.

Over the decades, Lilly has worked to earn the goodwill of the diabetes community by serving as a clearinghouse of information on the disease, running a program to give free insulin to the poor, and awarding 50 college scholarships a year to students with diabetes.

Lilly has maintained its lead role in insulin from the very start. In 1922-23, it collaborated with insulin's inventors at the University of Toronto to become the first commercial producer of insulin in the United States. The wondrous product allowed thousands of people who were dying of the then-fatal imbalance in blood sugar to enjoy near-normal lives.

In 1983, Lilly achieved another milestone by bringing the first biosynthetic human insulin to market.

The breakthrough in biotechnology marked the start of the phase-out of animal insulins.

Widely used in the United States until then, Iletin 1 saw its user numbers drop to about 75,000 by last year, according to the Juvenile Diabetes Association. Some diabetes activists say the real count was closer to 300,000. Even so, either number is a small fraction of the more than 3 million people using human insulin in the United States.

Given the success of human insulins, dwindling use of Iletin 1, and the cost of producing up to 25 different formulations of it, Lilly decided a "product deletion" was in order.

"Animal insulin is the Lindbergh of the space shuttle age," said Dr. John H. Holcombe, senior clinical research physician for diabetes care at Lilly. "It's antiquated."

Lilly said it did consult patients before making its decision, and provided free medical "transition kits" for doctors to give patients.

The company made the beef-pork mix in an aging plant across Delaware Street from its corporate headquarters. It was the last manufacturing building left on the Near-Downtown campus of office and research buildings.

The liquid insulin, typically sold in clear glass vials, was made the old-fashioned way, from ground-up pancreas glands of cows and hogs.

The last batch of insulin was produced in November, and the plant was torn down earlier this year. Lilly is building a parking garage on the site.

Remaining supplies of Iletin 1 are expected to be gone from pharmacy shelves by early next year. The only animal insulin Lilly now offers is a pure-pork product called Iletin 2.

Lilly hasn't spelled out its reasons for keeping Iletin 2, which has even fewer users than Iletin 1.

They may have to do with the fact that the pork brand remains the insulin of choice for a few diabetes clinics that treat children. Or that many pet owners buy Iletin 2 to treat diabetes in dogs and cats.

Lilly also could be heeding a 1996 Rockefeller Foundation-funded study that recommended animal insulin be kept as an option for diabetics in all countries. The so-called Bellagio Report was written in Italy by an international group of 10 doctors and animal-insulin activists.

Lilly rival Novo Nordisk stopped selling beef insulin in the United States in 1994, but also retained a pure pork product.

Whatever the reasons they're kept on the market, the pork insulins don't do much good for many Iletin 1 users.

They say turning to pork insulin isn't an option because their bodies can't use it as well as the mainly beef insulin. That may be because pork's amino acid structure is slightly different from beef's.

Warning signs

Critics link biosynthetic human insulin to one of the most frightening conditions a diabetic can suffer: hypoglycemia unawareness.

The dread condition occurs when insulin users fail to experience the telltale physical symptoms, such as dizziness or sweating, that warn them their blood-sugar levels could soon fall low enough to plunge them into a coma.

Normally, the pancreas automatically controls sugar levels in the blood, which are as critical to the body's functioning as oxygen in the brain.

Diabetics must rely on their own intuition to control "hypo" episodes by quickly consuming a sugary drink or snack to restore their sugar. Losing that awareness means a diabetic can slide into unconsciousness at any time - a horrifying prospect, especially for parents of small children, drivers or those who work at intricate or potentially dangerous tasks.

Lancet A 1987 study of patients who had switched to biosynthetic human insulin found a significant number had more difficulty recognizing hypoglycemia's onset. The findings, the authors reported in the British medical journal Lancet, amounted to a good argument for keeping animal insulins on the market.

Other studies have found no such problem with biosynthetic human insulins. They include several blind trials using patients who had complained that human insulin masked signs of hypo. But when given animal or human insulin in controlled studies without being told which they were getting, most patients couldn't tell a difference.

"Current evidence argues against human insulin causing hypoglycemia unawareness," said the authors of a 1991 review of the issue in the medical journal Endocrine Reviews.

"There's just a whole bunch of studies, one canceling out the other," said Scott King, publisher of Diabetes Health magazine in San Francisco, who in 1997 angered Lilly officials by breaking the news that it was taking Iletin 1 off the market.

The oft-conflicting science hasn't stopped the U.S. Food and Drug Administration from requiring this product label warning to be put on biosynthetic human insulin in bold-faced type:

"A few patients who have experienced hypoglycemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different."

Tricky adjustment

What's less disputed is that biosynthetic human insulins can be trickier to use than the old animal-based product. Sometimes a lot trickier.

That alone makes some people not want to use them.

Injected in the body, biosynthetic human insulins tend to be faster-acting and shorter-lasting than animal-based. Compared to beef-pork insulin, for instance, which can be effective all day, the effective duration of one dose of regular human insulin is 10 to 14 hours shorter.

As a result of its shorter staying power, human insulin often requires more-frequent injections and more needle-pricking blood tests.

People switching from animal insulin "need to relearn their body," said Connie Shella, medical information administrator for diabetes at Lilly.

That upsets some animal-insulin activists. They don't want to switch from an insulin they like and know to one that can be more difficult to use - and, they believe, may even be life-threatening.

Among those who say so is Groves. He was a senior vice president of a Florida bank in 1986, when he switched from animal to human insulin.

The change wiped out his ability to tell when he was drifting into the danger level of low blood-sugar, he said.

"I would be walking down the street and fall unconscious," he said.

In April 1987, he said, he went hypo while driving and plowed into a parked car, shattering his jaw and crushing his left leg.

In the aftermath of the accident, Grove lost his job and his marriage. He also filed a lawsuit seeking $4.5 million from Novo, whose human insulin he was using. He settled out of court in 1997 for what he said was "a lot less."

Groves, who runs a diabetes chat group on the Internet, believes his is still the only U.S. hypoglycemia lawsuit filed against a human-insulin manufacturer.

Hypo skepticism

Lilly and the nation's leading diabetes groups reject the notion that biosynthetic human insulins blunt a user's sense of oncoming hypos.

Hypoglycemia unawareness "is not a property of the source of the insulin," said Dr. Bruce R. Zimmerman, president of the American Diabetes Association and a professor of medicine at Mayo Medical School in Rochester, Minn.

Those who believe otherwise are "emotional," he said, and "the science behind them is not there."

Zimmerman said he "feels enormous sympathy" for Iletin 1 users who face problems switching to a new insulin. He added that Lilly made its decision to drop Iletin 1 "based upon business reasons," and it's time for users and their doctors to come to grips with the medical implications.

"The reality of life is ... we are forced to adapt and change to circumstances beyond our control," he said.

Dr. Alan C. Moses, chief medical officer of the Joslin Diabetes Center of Harvard Medical School, said animal-insulin users who can't adapt to human insulin often aren't getting the proper professional help.

The help of a doctor or nurse is critical because "insulin is still a very imperfect drug" with "a narrow therapeutic window," he said.

During the past 1 1/2 years, calls to Lilly about Iletin 1 have dropped from close to 100 a month to fewer than 10, said Shella, who oversees a staff of 13 diabetes specialists who handle customer calls.

Holcombe, the Lilly physician, said analysis of those calls convinces him that most people who have problems switching from animal to human insulin haven't tried hard enough to get used to it, or lack guidance on tailoring doses to their bodies and lifestyles.

"We don't know of a single case where a patient has not been successfully transferred working with a doctor," he said.

Dissenting doctors

The Lilly physician might want to talk to Farquhar, a family doctor in the town of Kelowna, in western Canada. He has been diabetic since age 13.

In the 1980s, he switched from animal to human insulin, with disastrous results, he said.

A marathoner and triathlete, Farquhar said he began suffering low blood-sugar attacks, and once nearly passed out from one while sleeping.

"It really, really scared me. Next day, I switched back to beef-pork and never had a similar reaction."

Farquhar conceded "there isn't much supporting evidence" in medical studies that human insulin hides signs of coming hypo. "However, there's a ton of anecdotal evidence. We're not making this up."

The 53-year-old Canadian doctor said he's encountered many doctors who don't appreciate the fears some patients have of giving up their Iletin 1.

"They generally pooh-pooh the whole thing," he said. "It's inexplicable. One of the basic tenets of being a doctor is, 'Listen to your patients.'"

Another physician upset over Iletin 1 is Dr. Michael T. Swinyard, medical director of the diabetes program at Primary Children's Medical Center in Salt Lake City.

Swinyard said he's found many children he treats do better on animal insulin, because it lasts longer in their system and is easier to take.

"We are basically losing a tool that might help us manage the disease in those children. It's like telling a plumber who's come to fix the pipes in your house that he can use only one wrench and one setting."

The U.S. Food and Drug Administration advises patients with complaints about biosynthetic human insulin to call its MedWatch line, which tracks incidents of medical problems.

But information compiled by MedWatch isn't readily available, an FDA spokeswoman said. She said the agency releases MedWatch data only through a Freedom of Information Act request, which can take months to process.

Overseas alternatives

The loss of Iletin 1 has sent many users scrambling to stockpile remaining vials. Insulin can last for a year or more if refrigerated.

Congress has gotten involved in the issue of importing a substitute beef insulin.

U.S. Rep. George R. Nethercutt Jr., D-Wash., who chairs the House congressional diabetes caucus, is trying to ease regulatory red tape that makes imports a cumbersome procedure, said a Nethercutt spokesman.

Importing animal insulin can be done only by individual users with a doctor's permission. It's also several times more expensive than buying Iletin 1 over the counter, and insurance companies may not cover the cost.

"It's really frustrating, the hoops they're making us jump through," said Harrison, the head of the patients group. "Insulin is not like a narcotic or anything."

Most of those who plan to import beef insulin seem to be turning to CP Pharmaceuticals, a 27-year-old company with 340 employees that is the only beef and pork insulin manufacturer in Britain.

CP received a setback last week in its attempt to get licensed by the FDA to sell its beef insulin in the United States.

The FDA told CP it would be required to do lengthy testing of its insulin on humans to get a U.S. drug license, even though the nonprescription, basic form of insulin had been sold in the United States by other companies for decades.

CP said it doesn't have the money to perform the costly tests.

The news was immediately posted on Web sites by animal-insulin activists. William Welty, who runs the Vernier Web site, said the FDA's decision made him mad enough "to consider filing a class-action lawsuit" by insulin users against the FDA.

CP also had little luck trying to buy Lilly's animal insulin business. Company President Charles Savage said he met with Lilly officials in Indianapolis in 1997.

"At first the suggestion seemed to have been well-received, but a few weeks later we received a response in the negative," he said. "Since then, I have made two other attempts to make contact with Lilly, but have been rebuffed."

Meanwhile, Iletin 1 users who call Lilly to ask about finding a replacement beef insulin won't get much help.

Lilly's call center specialists are under orders not to refer customers to CP, or even to tell them that importing beef insulin is an option.

"We cannot," said Lilly products spokesman Jeffrey G. Newton. "It gets us into the realm of violating the spirit, if not the law, of the FDA by promoting unapproved products."

 

For more information on animal insulin, log on to Robin Harrison's Insulin Dependent Diabetes Trust Web Site at www.diabetes.pair.com.


Categories: Animal Insulin, Blood Sugar, Diabetes, Food, Insulin, Low Blood Sugar, Novo Nordisk, Type 1 Issues, Type 2 Issues



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