ot: Eli Lilly Said to Play Down Risk of Zyprexa

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December 17, 2006

Eli Lilly Said to Play Down Risk of Top Pill

By ALEX BERENSON

http://www.nytimes.com/2006/12/17/business/17drug.html

The drug maker Eli Lilly has engaged in a decade-long effort to play down

the health risks of Zyprexa, its best-selling medication for

schizophrenia, according to hundreds of internal Lilly documents and

e-mail messages among top company managers.

The documents, given to The Times by a lawyer representing mentally ill

patients, show that Lilly executives kept important information from

doctors about Zyprexa’s links to obesity and its tendency to raise blood

sugar — both known risk factors for diabetes.

Lilly’s own published data, which it told its sales representatives to

play down in conversations with doctors, has shown that 30 percent of

patients taking Zyprexa gain 22 pounds or more after a year on the drug,

and some patients have reported gaining 100 pounds or more. But Lilly was

concerned that Zyprexa’s sales would be hurt if the company was more

forthright about the fact that the drug might cause unmanageable weight

gain or diabetes, according to the documents, which cover the period 1995

to 2004.

Zyprexa has become by far Lilly’s best-selling product, with sales of $4.2

billion last year, when about two million people worldwide took the drug.

Critics, including the American Diabetes Association, have argued that

Zyprexa, introduced in 1996, is more likely to cause diabetes than other

widely used schizophrenia drugs. Lilly has consistently denied such a

link, and did so again on Friday in a written response to questions about

the documents. The company defended Zyprexa’s safety, and said the

documents had been taken out of context.

But as early as 1999, the documents show that Lilly worried that side

effects from Zyprexa, whose chemical name is olanzapine, would hurt sales.

“Olanzapine-associated weight gain and possible hyperglycemia is a major

threat to the long-term success of this critically important molecule,”

Dr. Alan Breier wrote in a November 1999 e-mail message to two-dozen Lilly

employees that announced the formation of an “executive steering committee

for olanzapine-associated weight changes and hyperglycemia.” Hyperglycemia

is high blood sugar.

At the time Dr. Breier, who is now Lilly’s chief medical officer, was the

chief scientist on the Zyprexa program.

In 2000, a group of diabetes doctors that Lilly had retained to consider

potential links between Zyprexa and diabetes warned the company that

“unless we come clean on this, it could get much more serious than we

might anticipate,” according to an e-mail message from one Lilly manager

to another.

And in that year and 2001, the documents show, Lilly’s own marketing

research found that psychiatrists were consistently saying that many more

of their patients developed high blood sugar or diabetes while taking

Zyprexa than other antipsychotic drugs.

The documents were collected as part of lawsuits on behalf of mentally ill

patients against the company. Last year, Lilly agreed to pay $750 million

to settle suits by 8,000 people who claimed they developed diabetes or

other medical problems after taking Zyprexa. Thousands more suits against

the company are pending.

On Friday, in its written response, Lilly said that it believed that

Zyprexa remained an important treatment for patients with schizophrenia

and bipolar disorder. The company said it had given the Food and Drug

Administration all its data from clinical trials and reports of adverse

events, as it is legally required to do. Lilly also said it shared data

from literature reviews and large studies of Zyprexa’s real-world use.

“In summary, there is no scientific evidence establishing that Zyprexa

causes diabetes,” the company said.

Lilly also said the documents should not have been made public because

they might “cause unwarranted fear among patients that will cause them to

stop taking their medication.”

As did similar documents disclosed by the drug maker Merck last year in

response to lawsuits over its painkiller Vioxx, the Lilly documents offer

an inside look at how a company marketed a drug while seeking to play down

its side effects. Lilly, based in Indianapolis, is the sixth-largest

American drug maker, with $14 billion in revenue last year.

The documents — which include e-mail, marketing material, sales

projections and scientific reports — are replete with references to

Zyprexa’s importance to Lilly’s future and the need to keep concerns about

diabetes and obesity from hurting sales. But that effort became

increasingly difficult as doctors saw Zyprexa’s side effects, the

documents show.

In 2002, for example, Lilly rejected plans to give psychiatrists guidance

about how to treat diabetes, worrying that doing so would tarnish

Zyprexa’s reputation. “Although M.D.’s like objective, educational

materials, having our reps provide some with diabetes would further build

its association to Zyprexa,” a Lilly manager wrote in a March 2002 e-mail

message.

But Lilly did expand its marketing to primary care physicians, who its

internal studies showed were less aware of Zyprexa’s side effects. Lilly

sales material encouraged representatives to promote Zyprexa as a “safe,

gentle psychotropic” suitable for people with mild mental illness.

Some top psychiatrists say that Zyprexa will continue to be widely used

despite its side effects, because it works better than most other

antipsychotic medicines in severely ill patients. But others say that

Zyprexa appears no more effective overall than other medicines.

And some doctors who specialize in diabetes care dispute Lilly’s assertion

that Zyprexa does not cause more cases of diabetes than other psychiatric

drugs. “When somebody gains weight, they need more insulin, they become

more insulin resistant,” Dr. Zonszein, the director of the clinical

diabetes center at Montefiore Medical Center in the Bronx, said when asked

about the drug.

In 2003, after reviewing data provided by Lilly and other drug makers, the

F.D.A. said that the current class of antipsychotic drugs may cause high

blood sugar. It did not specifically single out Zyprexa, nor did it say

that the drugs had been proven to cause diabetes.

The drugs are known as atypical antipsychotics and include &

’s Risperdal and AstraZeneca’s Seroquel. When they were introduced

in the mid-1990s, psychiatrists hoped they would relieve mental illness

without the tremors and facial twitches associated with older drugs. But

the new drugs have not proven significantly better and have their own side

effects, said Dr. Lieberman, the lead investigator on a federally

sponsored clinical trial that compared Zyprexa and other new drugs with

one older one.

The Zyprexa documents were provided to the Times by B. Gottstein, a

lawyer who represents mentally ill patients and has sued the state of

Alaska over its efforts to force patients to take psychiatric medicines

against their will. Mr. Gottstein said the information in the documents

raised public health issues.

“Patients should be told the truth about drugs like Zyprexa,” Mr.

Gottstein said.

Lilly originally provided the documents, under seal, to plaintiffs lawyers

who sued the company claiming their clients developed diabetes from taking

Zyprexa. Mr. Gottstein, who is not subject to the confidentiality

agreement that covers the product liability suits, subpoenaed the

documents in early December from a person involved in the suits.

In its statement, Lilly called the release of the documents “illegal.” The

company said it could not comment on specific documents because of the

continuing product liability suits.

In some ways, the Zyprexa documents are reminiscent of those produced in

litigation over Vioxx, which Merck stopped selling in 2004 after a

clinical trial proved it caused heart problems. They treat very different

conditions, but Zyprexa and Vioxx are not entirely dissimilar. Both were

thought to be safer than older and cheaper drugs, becoming bestsellers as

a result, but turned out to have serious side effects.

After being pressed by doctors and regulators, Merck eventually did test

Vioxx’s cardiovascular risks and withdrew the drug after finding that

Vioxx increased heart attacks and strokes.

Lilly has never conducted a clinical trial to determine exactly how much

Zyprexa raises patients’ diabetes risks. But scientists say conducting

such a study would be exceedingly difficult, because diabetes takes years

to develop, and it can be hard to keep mentally ill patients enrolled in a

clinical trial.

When it was introduced, Zyprexa was the third and most heralded of the

atypical antipsychotics. With psychiatrists eager for new treatments for

schizophrenia, bipolar disorder, and dementia, Zyprexa’s sales soared.

But as sales grew, reports rolled in to Lilly and drug regulators that the

medicine caused massive weight gain in many patients and was associated

with diabetes. For example, a California doctor reported that 8 of his 35

patients on Zyprexa had developed high blood sugar, including two who

required hospitalization.

The documents show that Lilly encouraged its sales representatives to play

down those effects when talking to doctors. In one 1998 presentation, for

example, Lilly said its salespeople should be told, “Don’t introduce the

issue!!!” Meanwhile, the company researched combinations of Zyprexa with

several other drugs, hoping to alleviate the weight gain. But the

combinations failed.

To reassure doctors, Lilly also publicly said that when it followed up

with patients who had taken Zyprexa in a clinical trial for three years,

it found that weight gain appeared to plateau after about nine months. But

the company did not discuss a far less reassuring finding in early 1999,

disclosed in the documents, that blood sugar levels in the patients

increased steadily for three years.

In 2000 and 2001, more warning signs emerged, the documents show. In four

surveys conducted by Lilly’s marketing department, the company found that

70 percent of psychiatrists polled had seen at least one of their patients

develop high blood sugar or diabetes while taking Zyprexa, compared with

about 20 percent for Risperdal or Seroquel. Lilly never disclosed those

findings.

By mid-2003, Lilly began to change its stance somewhat, publicly

acknowledging that Zyprexa can cause severe obesity. Marketing documents

make clear that by then Lilly believed it had no choice. On June 23, 2003,

an internal committee reported that Zyprexa sales were “below plan” and

that doctors were “switching/avoiding Zyprexa.”

Since then, Lilly has acknowledged Zyprexa’s effect on weight but has

argued that it does not necessarily correlate to diabetes. But Zyprexa’s

share of antipsychotic drug prescriptions is falling, and some

psychiatrists say they no longer believe the information Lilly offers.

“From my personal experience, at first my concerns about weight gain with

this drug were very significantly downplayed by their field

representatives,” said Dr. Phelps, a psychiatrist in Corvallis, Or.

‘Their continued efforts to downplay that, I think in retrospect, was an

embarrassment to the company.”

Dr. Phelps says that he tries to avoid Zyprexa because of its side effects

but sometimes still prescribes it, especially when patients are acutely

psychotic and considering suicide, because it works faster than other

medicines.

“I wind up using it as an emergency medicine, where it’s superb,” he said.

“But I’m trying to get my patients off of Zyprexa, not put them on.”

*

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