Update: leaked documents hit the internet! go here:
Also see Jim's Year End update on PsychRights work and the Dear Doctor campaign at http://www.psychrights.org
December 17, 2006
Eli Lilly Said to Play Down Risk of Top Pill
By ALEX BERENSON
New York Times
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 Zyprexaâ€™s links to obesity and its tendency to raise blood sugar â€” both known risk factors for diabetes.
Lillyâ€™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 Zyprexaâ€™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 Lillyâ€™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 Zyprexaâ€™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.
â€œOlanzapine-associated weight gain and possible hyperglycemia is a major threat to the long-term success of this critically important molecule,â€ Dr. Alan Breier wrote in a November 1999 e-mail message to two dozen Lilly employees that announced the formation of an â€œexecutive steering committee for olanzapine-associated weight changes and hyperglycemia.â€ Hyperglycemia is high blood sugar.
At the time Dr. Breier, who is now Lillyâ€™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 â€œunless we come clean on this, it could get much more serious than we might anticipate,â€ according to an e-mail message from one Lilly manager to another.
And in that year and 2001, the documents show, Lillyâ€™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 Zyprexaâ€™s real-world use.
â€œIn summary, there is no scientific evidence establishing that Zyprexa causes diabetes,â€ the company said.
Lilly also said the documents should not have been made public because they might â€œcause unwarranted fear among patients that will cause them to stop taking their medication.â€
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 â€” which include e-mail, marketing material, sales projections and scientific reports â€” are replete with references to Zyprexaâ€™s importance to Lillyâ€™s future and the need to keep concerns about diabetes and obesity from hurting sales. But that effort became increasingly difficult as doctors saw Zyprexaâ€™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 Zyprexaâ€™s reputation. â€œAlthough M.D.â€™s like objective, educational materials, having our reps provide some with diabetes would further build its association to Zyprexa,â€ 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 Zyprexaâ€™s side effects. Lilly sales material encouraged representatives to promote Zyprexa as a â€œsafe, gentle psychotropicâ€ 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 Lillyâ€™s assertion that Zyprexa does not cause more cases of diabetes than other psychiatric drugs. â€œWhen somebody gains weight, they need more insulin, they become more insulin resistant,â€ 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 & Johnsonâ€™s Risperdal and AstraZenecaâ€™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.
â€œPatients should be told the truth about drugs like Zyprexa,â€ Mr. Gottstein said.
Lilly originally provided the documents, under seal, to plaintiffsâ€™ 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 â€œillegal.â€ 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 Vioxxâ€™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 patientsâ€™ 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, Zyprexaâ€™s sales soared.
But as sales grew, reports rolled in to Lilly and drug regulators that the medicine caused significant 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 sales force should be told, â€œDonâ€™t introduce the issue!!!â€ 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 Lillyâ€™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.
Since then, Lilly has acknowledged Zyprexaâ€™s effect on weight but has argued that it does not necessarily correlate to diabetes. But Zyprexaâ€™s share of antipsychotic drug prescriptions is falling, and some psychiatrists say they no longer believe the information Lilly offers.
â€œFrom my personal experience, at first my concerns about weight gain with this drug were very significantly downplayed by their field representatives,â€ said Dr. James Phelps, a psychiatrist in Corvallis, Ore. â€˜Their continued efforts to downplay that, I think in retrospect, was an embarrassment to the company.â€
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.
â€œI wind up using it as an emergency medicine, where itâ€™s superb,â€ he said. â€œBut Iâ€™m trying to get my patients off of Zyprexa, not put them on.â€
The New York Times
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December 18, 2006
Drug Files Show Maker Promoted Unapproved Use
By ALEX BERENSON
NEW YORK TIMES
Eli Lilly encouraged primary care physicians to use Zyprexa, a powerful drug for schizophrenia and bipolar disorder, in patients who did not have either condition, according to internal Lilly marketing materials.
The marketing documents, given to The New York Times by a lawyer representing mentally ill patients, detail a multiyear promotional campaign that Lilly began in Orlando, Fla., in late 2000. In the campaign, called Viva Zyprexa, Lilly told its sales representatives to suggest that doctors prescribe Zyprexa to older patients with symptoms of dementia.
A Lilly executive said that she could not comment on specific documents but that the company had never promoted Zyprexa for off-label uses and that it always showed the marketing materials used by its sales representatives to the Food and Drug Administration, as required by law.
â€œWe have extensive training for sales reps to assure that they provide information to the doctors thatâ€™s within the scope of the prescribing information approved by the F.D.A.,â€ Anne Nobles, Lillyâ€™s vice president for corporate affairs, said in an interview yesterday.
Zyprexa is not approved to treat dementia or dementia-related psychosis, and in fact carries a prominent warning from the F.D.A. that it increases the risk of death in older patients with dementia-related psychosis. Federal laws bar drug makers from promoting prescription drugs for conditions for which they have not been approved â€” a practice known as off-label prescription â€” although doctors can prescribe drugs to any patient they wish.
Yet in 1999 and 2000 Lilly considered ways to convince primary care doctors that they should use Zyprexa on their patients. In one document, an unnamed Lilly marketing executive wrote that these doctors â€œdo treat dementiaâ€ but â€œdo not treat bipolar; schizophrenia is handled by psychiatrists.â€
As a result, â€œdementia should be first message,â€ of a campaign to primary doctors, according to the document, which appears to be part of a larger marketing presentation but is not marked more specifically.
Later, the same document says that some primary care doctors â€œmight prescribe outside of label.â€
Ms. Nobles said that the company had never promoted its drug for any conditions except schizophrenia and bipolar disorder. Older patients who seem to have dementia may actually have schizophrenia that has gone untreated, Ms. Nobles said.
Several psychiatrists outside the company said yesterday that they strongly disagreed with Lillyâ€™s claim. Schizophrenia is a severe disease that is almost always diagnosed when patients are in their teens or 20s. Its symptoms could not be confused with mild dementia, these doctors said.
Zyprexa is by far Lillyâ€™s best-selling product, with $4.2 billion in sales in 2005, 30 percent of its overall revenues. About two million people worldwide received it last year. Based in Indianapolis, Lilly is the sixth-largest American drug company.
The issue of off-label marketing is controversial in the drug industry. Nearly every company is under either civil or criminal investigation for alleged efforts to expand the use of its drugs beyond the specific illness or condition for which they are approved.
Lilly faces federal and state investigations over its marketing of Zyprexa. In its annual report for 2005, Lilly said that it faced an investigation by federal prosecutors in Pennsylvania and that the Florida attorney generalâ€™s office had subpoenaed the company â€œseeking production of documents relating to sales of Zyprexa and our marketing and promotional practices with respect to Zyprexa.â€
Since Lilly introduced Zyprexa in 1996, about 20 million patients worldwide have received the drug, which helps control the hallucinations and delusions associated with schizophrenia and severe mania. But Zyprexa also causes weight gain in many patients, and the American Diabetes Association found in 2004 that Zyprexa was more likely to cause diabetes than other widely used drugs for schizophrenia.
Lilly says that no link between Zyprexa and diabetes has been proven.
As part of the â€œViva Zyprexaâ€ campaign, in packets for its sales representatives, Eli Lilly created the profiles of patients whom it said would be suitable candidates for Zyprexa. Representatives were told to discuss the patient profiles with doctors. One of the patients was a woman in her 20s who showed mild symptoms of schizophrenia, while another was a man in his 40s who appeared to have bipolar disorder.
The third patient was â€œMartha,â€ a widow with adult children â€œwho lives independently and has been your patient for some time.â€ Martha was described as being agitated and having disturbed sleep, but without the symptoms of paranoia or mania that typically marked a person with schizophrenia or bipolar disorder.
Ms. Nobles said that Lilly had actually intended Marthaâ€™s profile to represent a patient with schizophrenia. But psychiatrists outside the company said this claim defied credibility, especially given Marthaâ€™s age. Instead, she appeared to have mild dementia, they said.
â€œItâ€™d be very unusual for this to be a schizophrenic patient,â€ said Dr. John March, chief of child and adolescent psychiatry at Duke University medical center. â€œSchizophrenia is a disease of teenagers and young adults.â€ Dr. March serves on Lillyâ€™s scientific advisory board.
Diagnostic criteria for schizophrenia include delusions, hallucinations, disorganized and incoherent speech, and grossly disorganized behavior. They also include so-called negative symptoms like social isolation and a flattening of the voice and facial expressions.
The documents also show that Lilly encouraged primary care doctors to treat the symptoms and behaviors of schizophrenia and bipolar disorder even if the doctors had not actually diagnosed those diseases in their patients. Lillyâ€™s market research had found that many primary care doctors did not consider themselves qualified to treat people with schizophrenia or severe bipolar disorder.
The campaign was successful, the documents show. By March 2001, about three months after the start of Viva Zyprexa, the campaign had led to 49,000 new prescriptions, according to a presentation that Michael Bandick, the brand manager for Zyprexa, gave at a national meeting of Lilly sales representatives in Dallas. Mr. Bandick did not say how many of those new prescriptions were for older patients with dementia.
Over all, sales of Zyprexa doubled between 1999 and 2002, rising from $1.5 billion to $3 billion in the United States. In 2002, the company changed the name of the primary care campaign to â€œZyprexa Limitlessâ€ and began to focus on people with mild bipolar disorder who had previously been diagnosed as depressed â€” even though Zyprexa has been approved only for the treatment of mania in bipolar disorder, not depression.
In a 2002 guide for representatives, Lilly presented the profile of â€œDonna,â€ a single mother in her mid-30s whose â€œchief complaint is, â€˜I feel so anxious and irritable lately.â€™ â€ Several doctorsâ€™ appointments earlier, she was â€œtalkative, elated, and reported little need for sleep.â€
Lillyâ€™s efforts to promote Zyprexa to primary care doctors disturbed some physicians, the documents show. In August 2001, a doctor in Virginia sent an e-mail message to Lilly and the F.D.A., complaining about a presentation from a Lilly sales representative who had discussed the hypothetical Martha with him.
The representative â€œpresented an elderly female patient who was presented to her physician by her family complaining of insomnia, agitation, slight confusion, and had no physical finding to explain her state,â€ the doctor wrote. The representative then suggested that the doctor prescribe Zyprexa.
â€œI inquired what Zyprexa was indicated for she then indicated that many physicians might prescribe an antipsychotic for this patient. I then asked for her package insert and read to her that her product was indicated for schizophrenia and bipolar mania â€” neither of which the presented patient had been diagnosed with,â€ the doctor wrote.
He added that he had never contacted the F.D.A. before but was â€œgenuinely concerned about the promotion of this powerful drug to my peer community of primary care physicians outside of its approved and intended purpose.â€
Tara Ryker, a spokeswoman for Lilly, said the company no longer uses â€œMarthaâ€ or â€œDonnaâ€ in its marketing. â€œWe are constantly developing new promotional materials and new profiles,â€ she said.
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 yesterday that the information in the documents should be available to patients and doctors, as well as judges who oversee the hearings that are required before people can be forced to take psychiatric drugs.
â€œThe courts should have this information before they order this stuff injected into peopleâ€™s unwilling bodies,â€ 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. Last year, Lilly agreed to pay $700 million to settle about 8,000 of the claims, but thousands more are pending. 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.
The â€œViva Zyprexaâ€ documents also provide color about Lillyâ€™s efforts to motivate its sales force as they marketed Zyprexa â€” whose generic name is olanzapine â€” to primary care doctors.
At the 2001 meeting in Dallas with Zyprexa sales representatives, Mr. Bandick praised 16 representatives by name for the number of prescriptions they had convinced doctors to write, according to a script prepared in advance of the meeting. More than 100 other representatives had convinced doctors to write at least 16 extra prescriptions and thus â€œmaxed out on a pretty sweet incentive,â€ he said.
â€œOlanzapine is the molecule that keeps on giving,â€ Mr. Bandick said.