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 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.
Joel 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 Johnson & Johnson’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. Jeffrey 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 James 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. James 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.”
The right to sew pharmaceutical companies
for side effect will be curtailed with in the next two years once they have obtained FDA approval—except in the case
of fraud. The GOP and the Bush administration supported a ruling by the Supreme
Court which exempts medical devices makers (an 8-1 ruling) and by logic and soon to be heard case it will extend to drugs
as well. This ruling pre-empts state courts and laws.
Lilly Settles With 18,000
Over Zyprexa for $500 Million (earlier
settle of $1.2 billion to 28,500)
By Alex Berenson, 1/5/07
At
http://www.nytimes.com/2007/01/05/business/05drug.html?_r=1&ref=health&oref=slogin
Eli Lilly agreed yesterday to pay up to $500 million to settle
18,000 lawsuits from people who claimed they had developed diabetes or other diseases after taking Zyprexa, Lilly’s
drug for schizophrenia and bipolar disorder. Including earlier settlements over
Zyprexa, Lilly has now agreed to pay at least $1.2 billion to 28,500 people who said they were injured by the drug. At least
1,200 suits are still pending, the company said. About 20 million people worldwide have taken Zyprexa since its introduction
in 1996.The settlement covers cases filed in state and federal courts by law firms or groups of firms for 18,000 clients,
Lilly said. The federal suits have been overseen in Brooklyn by Judge Jack B. Weinstein of the Eastern District of New York. The settlement will not affect continuing civil or criminal investigations of Zyprexa by state attorneys
general and federal prosecutors.
Both Lilly and lawyers for plaintiffs said
they were pleased with the agreement. With global sales of roughly $4.2 billion last year, Zyprexa is Lilly’s largest-selling
drug and a major contributor to the company’s profits. Lilly shares were relatively flat after the settlement announcement.
They rose 11 cents yesterday, to $52.36.
Zyprexa is the brand name for olanzapine,
a potent chemical that binds to receptors in the brain to reduce psychotic hallucinations and delusions. Clinical trials show
that in many patients, Zyprexa also causes severe weight gain and increases in cholesterol and blood sugar.
Documents provided to The New York Times
last month by a lawyer who represents mentally ill patients show that Lilly played down the risks of Zyprexa to doctors as
the drug’s sales soared after its introduction in 1996. The internal documents show that in Lilly’s clinical trials,
16 percent of people taking Zyprexa gained more than 66 pounds after a year on the drug, a far higher figure than the company disclosed to doctors.
The documents also show that Lilly marketed the drug as appropriate for patients who did not meet accepted diagnoses
of schizophrenia or bipolar disorder, Zyprexa’s only approved uses. By law, drug makers may promote their drugs only
for diseases for which the Food and Drug Administration has found the medicines to be safe and effective, though doctors may
prescribe drugs in any way they see fit.
In response to questions about the information
in the documents, Lilly has denied any wrongdoing and said it provided all relevant information to doctors and the F.D.A.
Lilly has also said it did not promote Zyprexa for conditions other than schizophrenia or bipolar disorder.
In 2004, a panel of the American Diabetes
Association found that Zyprexa caused diabetes more than other widely used antipsychotic drugs, in part because it tends to
cause much more weight gain. But the F.D.A. has never made a similar finding. Instead, the F.D.A. added a warning in 2003
to the label of Zyprexa and other new antipsychotic drugs about their tendency to cause high blood sugar.
In 2005, a $700 million agreement covered 8,000 patients, and the company has made 2,500 individual
settlements whose total value has not been disclosed, Lilly said. The 2005 settlement valued claims at about $90,000 a plaintiff,
while yesterday’s agreement values claims at about $27,000 a plaintiff, at most.
The lower value for the new claims comes
in part because of the F.D.A. label change, which has allowed Lilly to say that it adequately warned doctors of the risks
of Zyprexa after 2003. The label change may also help to protect Lilly from future lawsuits, analysts and lawyers say. In its statement, Lilly said the settlement did not change its view that Zyprexa is
a safe and effective treatment for mental illness. “We wanted to reduce
significant uncertainties involved in litigating such complex cases,” Sidney Taurel, Lilly’s chief executive,
said in the statement.
Richard Meadow, one of the lead lawyers for
the plaintiffs, said the deal was fair to both sides. “Prolonging this litigation further is in no one’s best
interest,” he said.
