New evidence keeps emerging that the medical profession has sold its soul in exchange for what can only be described as bribes from the manufacturers of drugs . . . It is long past time for leading medical institutions and professional societies to adopt stronger ground rules to control the noxious influence of industry money on what doctors prescribe for their patients. (New York Times editorial: “Seducing the Medical Profession,” February 2, 2006)

December 19, 2006

Editorial

Playing Down the Risks of a Drug

It was bad enough when studies showed that the newest and most heavily promoted drugs for treating schizophrenia weren’t worth their high cost. Now the disturbing tale of their excessive use has taken a tawdry turn with revelations that a pharmaceutical giant, Eli Lilly, has consistently played down the risks of its best-selling antipsychotic drug, Zyprexa, and has promoted it for unapproved uses.

The details were spelled out in The Times this week by Alex Berenson, who drew on hundreds of internal Lilly documents that have surfaced in legal proceedings. Although Lilly says the documents present an inaccurate picture, they offer persuasive evidence that the company engaged in questionable behavior to prop up its best-selling drug, which creates almost 30 percent of Lilly’s revenue.

Zyprexa belongs to a class of drugs that were billed as a significant advance over the first generation of antipsychotic drugs but turned out to have serious flaws. Zyprexa, for example, has a tendency to raise blood sugar and to promote obesity, both of which are risk factors for diabetes. Some 30 percent of the patients taking Zyprexa gain 22 pounds or more after a year on the drug, with some gaining 100 pounds or more. Yet the documents show that Lilly encouraged its sales representatives to play down these adverse effects when talking to doctors.

The documents also show that Lilly encouraged primary care physicians — far less sophisticated than psychiatrists in treating mental illness — to prescribe the drug for older patients with symptoms of dementia even though it was approved only for schizophrenia and bipolar disorder. It is illegal for companies to promote drugs for unapproved uses, but nearly every major drug company is under civil or criminal investigation for alleged efforts to do so.

Lilly contends that it has never promoted Zyprexa for unapproved uses and has always shown its marketing materials to the Food and Drug Administration, as required by law. Both claims ought to be tested in Congressional hearings that should focus on how well the industry complies with existing laws and how effectively the F.D.A. regulates the industry’s marketing materials.

The most startling fact about 2002 is that the combined profits for the ten drug companies in the Fortune 500 ($35.9 billion) were more than the profits for all the other 490 businesses put together ($33.7 billion) . . . When I say this is a profitable industry, I mean really profitable. It is difficult to conceive of how awash in money Big Pharma is. (Marcia Angell, former Editor-in-Chief of the world's most prestigious medical journal, The New England Journal of Medicine.)

December 17, 2006

Eli Lilly Said to Play Down Risk of Top Pill

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. 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.”

[Medicine is afflicted with a] disease: an over-powerful, under-regulated drug industry and a research establishment and publishing industry in its thrall . . . Between the interests of the public and the commercial interests of drug companies stand two potential safeguards—journal peer review and drug regulation . . . [it is] clear that peer review in its current form is unequal to the task . . . Drug regulators too seem unequal to their task. Critics focus on their close relationship with industry; their lack of transparency; their lack of systematic post marketing surveillance; and an emphasis on efficacy over patient safety, which favours industry. . . . I suggest a radical solution. As with most good ideas, it is not mine alone. Marcia Angell (personal communication) and [others] have also had it, but here is my version. Drug companies should not be allowed to evaluate their own products. (Fiona Godlee, M.D., Editor, British Medical Journal)

December 18, 2006

Drug Files Show Maker Promoted Unapproved Use

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.

“We have extensive training for sales reps to assure that they provide information to the doctors that’s within the scope of the prescribing information approved by the F.D.A.,” Anne Nobles, Lilly’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 — a practice known as off-label prescription — 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 “do treat dementia” but “do not treat bipolar; schizophrenia is handled by psychiatrists.”

As a result, “dementia should be first message,” 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 “might prescribe outside of label.”

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 Lilly’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 Lilly’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 general’s office had subpoenaed the company “seeking production of documents relating to sales of Zyprexa and our marketing and promotional practices with respect to Zyprexa.”

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 “Viva Zyprexa” 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 “Martha,” a widow with adult children “who lives independently and has been your patient for some time.” 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 Martha’s profile to represent a patient with schizophrenia. But psychiatrists outside the company said this claim defied credibility, especially given Martha’s age. Instead, she appeared to have mild dementia, they said.

“It’d be very unusual for this to be a schizophrenic patient,” said Dr. John March, chief of child and adolescent psychiatry at Duke University medical center. “Schizophrenia is a disease of teenagers and young adults.” Dr. March serves on Lilly’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. Lilly’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 “Zyprexa Limitless” and began to focus on people with mild bipolar disorder who had previously been diagnosed as depressed — 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 “Donna,” a single mother in her mid-30s whose “chief complaint is, ‘I feel so anxious and irritable lately.’ ” Several doctors’ appointments earlier, she was “talkative, elated, and reported little need for sleep.”

Lilly’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 “presented 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,” the doctor wrote. The representative then suggested that the doctor prescribe Zyprexa.

“I 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 — neither of which the presented patient had been diagnosed with,” the doctor wrote.

He added that he had never contacted the F.D.A. before but was “genuinely concerned about the promotion of this powerful drug to my peer community of primary care physicians outside of its approved and intended purpose.”

Tara Ryker, a spokeswoman for Lilly, said the company no longer uses “Martha” or “Donna” in its marketing. “We are constantly developing new promotional materials and new profiles,” 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.

“The courts should have this information before they order this stuff injected into people’s unwilling bodies,” 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 “Viva Zyprexa” documents also provide color about Lilly’s efforts to motivate its sales force as they marketed Zyprexa — whose generic name is olanzapine — 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 “maxed out on a pretty sweet incentive,” he said.

“Olanzapine is the molecule that keeps on giving,” Mr. Bandick said.

. . . Soaring numbers of American children are being prescribed anti-psychotic drugs — in many cases, for attention deficit disorder or other behavioral problems for which these medications have not been proven to work, a study found.

The number of children prescribed antipsychotic drugs jumped fivefold between 1995 and 2002, to an estimated 2.5 million, the study said. That was an increase from 8.6 of every 1,000 children to nearly 40 out of 1,000 children. More than half of the prescriptions, however, were for attention deficit and other nonpsychotic conditions, the researchers said . . .

The drugs [including Zyprexa and Risperdal], which typically costs several dollars per pill, are considered safer than older antipsychotics — at least in adults — but they still can have serious side effects, including weight gain, elevated cholesterol and diabetes.

Anecdotal evidence suggests similar side effects occur in children. (Lindsey Tanner, Associated Press journalist, “Anti-Psychotics’ Use for Kids Skyrockets,” San Francisco Chronicle, 17 March 2006)

December 21, 2006

Disparity Emerges in Lilly Data on Schizophrenia Drug

For at least a year, Eli Lilly provided information to doctors about the blood-sugar risks of its drug Zyprexa that did not match data that the company circulated internally when it first reviewed its clinical trial results, according to company documents.

The original results showed that patients on Zyprexa, Lilly’s pill for schizophrenia, were 3.5 times as likely to experience high blood sugar levels as those taking a placebo, according to a February 2000 memo sent to top Lilly scientists. The memo is one of hundreds of internal Lilly documents provided to The New York Times by a lawyer in Alaska who represents mentally ill patients.

But the results that Lilly eventually provided to doctors until at least late 2001 were very different. Those results indicated that patients taking Zyprexa were only slightly more likely to suffer high blood sugar as those taking a placebo, or an inactive pill.

Another Lilly report, from November 1999, shows that Lilly found after examining 70 clinical trials that 16 percent of patients taking Zyprexa for a year gained more than 66 pounds.

The company did not publicly disclose that figure, instead focusing on data from a smaller group of clinical trials that showed about 30 percent of patients gained 22 pounds.

Weight gain and high blood sugar are important risk factors for diabetes, and the question of whether Zyprexa causes diabetes has been a subject of scientific debate for several years.

Lilly says no link has ever been proven.

In response to questions about the difference between its first view of the data and its subsequent public description, Lilly issued a statement yesterday saying that the later figures were accurate and the information in February 2000 was out of context.

In yesterday’s statement, the company said that after the February 2000 memo, it re-examined its clinical trial results and found errors in its “final, standard quality check of the data.”

But the February 2000 document, which is labeled “Confidential,” does not indicate that the figures it contains are preliminary. In fact, in a footnote, it explains that the data exclude patients “from whom there was a probable lab error.”

A separate document from November 1999 includes handwritten figures identical to those from the February document, with additional detail about the increases in blood sugar that patients suffered.

The revised figures were shared with the Food and Drug Administration, Lilly said. It did not say whether it had ever disclosed the initial data to the F.D.A.

The F.D.A. did not respond to requests for comment yesterday.

The 2000 memo indicates that it was prepared as Lilly considered changing Zyprexa’s prescription label to provide doctors with more information about the drug’s potential to raise blood-sugar levels.

The issue was crucially important to the sales prospects of Zyprexa, which was introduced in 1996. Psychiatrists were already increasingly aware by 2000 that Zyprexa caused severe weight gain in many patients.

“In 1999, we already were thinking this drug causes weight gain — that’s clear — and there could be a lot of other metabolic consequences of that,” Dr. David N. Osser, a psychiatry professor at Harvard University, said yesterday. “The weight gain itself is a known risk factor for diabetes.”

The February 2000 memo was prepared as background for a meeting of Lilly scientists to the possible changes for Zyprexa’s label.

According to the memo, Lilly scientists initially wanted to propose a relatively straightforward statement on the label that high blood sugar had been observed in patients taking Zyprexa in clinical trials. That change was never made.

Lilly’s analysis in early 2000 came at a time when some doctors and regulatory agencies were beginning to question whether Zyprexa could cause increases in blood sugar or diabetes. Although Lilly says that no link between Zyprexa and diabetes has ever been proven, the American Diabetes Association found in 2004 that Zyprexa was more likely to cause diabetes than other, similar drugs.

Zyprexa is by far Lilly’s best-selling product, with $4.2 billion in sales in 2005, which represented 30 percent of Lilly’s overall revenue. Zyprexa’s active ingredient is a potent chemical that binds to receptors in the brain to reduce the hallucinations and delusions associated with schizophrenia and acute bipolar disorder. About two million people worldwide took Zyprexa last year.

At the February 2000 meeting for which the memo was prepared, the agenda was to discuss Zyprexa’s tendency to cause high blood sugar, which is medically known as hyperglycemia.

According to the memo, Lilly had reviewed data from its clinical trials and found that “the incidence of treatment-emergent hyperglycemia in olanzapine group (3.6%) was higher than that in the placebo group (1.05%).” Olanzapine is the generic name for Zyprexa.

But when Lilly subsequently discussed the clinical trial results with doctors, it used a different comparison. Lilly told doctors that Zyprexa had caused 3.1 percent of patients — not 3.6 percent — to have high-blood sugar. And it said that 2.5 percent of patients on the placebo — not 1.05 percent — had high-blood sugar. As a result, the rates of high blood sugar in the two groups seemed almost identical in the revised data.

Secrecy's dangerous side effects

By Richard Zitrin

RICHARD ZITRIN practices law in San Francisco and teaches at UC Hastings College of the Law. He is also the founder of the Center for Applied Legal Ethics at the University of San Francisco.

February 8, 2007

DRUG GIANT Eli Lilly & Co. recently settled 18,000 lawsuits brought by people claiming they were injured by the side effects of its biggest-selling drug, Zyprexa, which is used to treat schizophrenia and bipolar disorder. But the $500 million in settlements says less about the dangers of the drug than the dangers of secrecy.

About 18 months earlier, Lilly had settled 8,000 other Zyprexa cases for $700 million. But those settlements required the plaintiffs to return all sensitive documents obtained through the legal discovery process to Lilly — a requirement that kept the strongest smoking-gun evidence out of public view. The plaintiffs also had to agree "not to communicate, publish or cause to be published, in any public or business forum or context, any statement, whether written or oral, concerning the specific events, facts or circumstances giving rise to [their] claims."

Lilly had strong motivation to settle. The documents contained evidence that Zyprexa caused large, often enormous, weight gain in many patients, significantly increasing the risk of dangerously high blood-sugar levels and diabetes. They also showed that Lilly knew about the problems in 1999, largely through its own research. Other documents outlined a marketing scheme to encourage physicians to prescribe Zyprexa for elderly patients with early signs of dementia. This strategy not only had no clinical evidence to support it, it promoted an "off-label" use not approved by the Food and Drug Administration, a violation of federal law.

Lilly gave the original 8,000 plaintiffs ample incentive to settle. Those plaintiffs received substantial compensation, and by agreeing to secrecy, they surely avoided years of scorched-earth litigation, extremely costly in terms of time, money and emotion.

When secrecy is the price of a legal settlement, wrongdoers hide their mistakes as if they never happened and continue with business as usual. That's what happened in the Lilly case. The thousands of plaintiffs and dozens of lawyers involved in the 2005 settlements kept their part of the bargain, while Lilly continued to sell Zyprexa in huge quantities — a reported $4.2 billion in sales in 2005 — without warning either patients or doctors about the drug's dangers.

Part of the problem was that those plaintiffs had little control over their cases. They were consolidated — as these matters often are — in one huge federal case in which a committee of plaintiffs' lawyers has much more say over a settlement than in typical civil suits. In exchange for access to key Zyprexa data in the Lilly case, the committee agreed to a "protective order" that kept the information secret. That may have expedited things for their clients, but it was a public disservice.

Courts have the power to grant protective orders only to limit the disclosure of highly personal information and legitimate trade secrets. But when all the lawyers in a case agree, judges often grant protection even if the trade secrets in question show how the product does not work, not how it does. Neither lawyers nor judges should ever be party to such agreements. It is simply unacceptable as a matter of public policy to permit secret deals that conceal evidence of dangers to the public.

In the Zyprexa cases, the documents eventually were exposed when Alaska attorney James B. Gottstein, working on an entirely unrelated case, subpoenaed the records of one of the plaintiffs' expert witnesses. Gottstein not only used the documents in his lawsuit but, to his great credit, disclosed them to the New York Times and several healthcare groups. Gottstein was almost immediately ordered to return all the documents he had, but the train had left the station: The New York Times published articles about the dangers of Zyprexa, and excerpts from the documents began appearing on the Internet. Within two weeks, with much of the Zyprexa evidence now out in the open, Lilly settled the additional 18,000 cases. Negotiated secrecy, Lilly's primary goal, had become moot.

Some intrepid plaintiffs and their lawyers refuse to play the secrecy game. In Northern California, plaintiffs in dozens of Catholic Church sexual abuse cases have banded together and refused to keep the names and whereabouts of molesters secret. And recently, Eva Rowe, who lost her parents as the result of an explosion at a Texas oil refinery in 2005, refused to settle with BP unless the oil company agreed to release the millions of documents obtained as evidence. Rowe and her lawyer hope that the documents, which they say show how BP's under-funding and lackadaisical attitude created significant safety problems, will serve as an industry blueprint on how refinery safety should, and shouldn't, be handled.

Unfortunately, disclosure is still the exception. But we should have learned our lesson by now. From Zomax and Halcion in the 1980s to shredding Firestone tires and GM gas-tank fires in the 1990s, to Vioxx and Zyprexa today, when lawyers cut secret deals behind the public's back, what we don't know can and does hurt us. The civil justice system belongs to all of us, and no one should be allowed to use it to keep the public in the dark.

January 31, 2008

Lilly Considers $1 Billion Fine to Settle Case

Eli Lilly and federal prosecutors are discussing a settlement of a civil and criminal investigation into the company's marketing of the antipsychotic drug Zyprexa that could result in Lilly's paying more than $1 billion to federal and state governments.

If a deal is reached, the fine would be the largest ever paid by a drug company for breaking the federal laws that govern how drug makers can promote their medicines.

Several people involved in the investigation confirmed the settlement discussions, which began last year and took on new urgency this month. The people insisted on anonymity because they have not been authorized to talk about the negotiations.

Zyprexa has serious side effects and is approved only to treat people with schizophrenia and severe bipolar disorder. But documents from Eli Lilly show that from 2000 to 2003 the company encouraged doctors to prescribe Zyprexa to people with age-related dementia, as well as people with mild bipolar disorder who had previously had a diagnosis of depression.

Although doctors can prescribe drugs for any use once they are on the market, it is illegal for drug makers to promote their medicines for any uses not formally approved by the Food and Drug Administration.

Lilly may also plead guilty to a misdemeanor criminal charge as part of the agreement, the people involved with the investigation said. But the company would be allowed to keep selling Zyprexa to Medicare and Medicaid, the government programs that are the biggest customers of the drug.

Zyprexa is Lilly's most profitable product and among the world's best-selling medicines, with 2007 sales of $4.8 billion, about half in the United States.

Lilly would neither confirm nor deny the settlement talks.

"We have been and are continuing to cooperate in state and federal investigations related to Zyprexa, including providing a broad range of documents and information," Lilly said in a statement Wednesday afternoon. "As part of that cooperation we regularly have discussions with the government. However, we have no intention of sharing those discussions with the news media and it would be speculative and irresponsible for anyone to do so."

Lilly also said that it had always followed state and federal laws when promoting Zyprexa.

The Lilly fine would be distributed among federal and state governments, which spend about $1.5 billion on Zyprexa each year through Medicare and Medicaid.

The fine would be in addition to $1.2 billion that Lilly has already paid to settle 30,000 lawsuits from people who claim that Zyprexa caused them to develop diabetes or other diseases. Zyprexa can cause severe weight gain in many patients and has been linked to diabetes by the American Diabetes Association.

Prescriptions for Zyprexa have skidded since 2003 over concerns about those side effects. But the drug continues to be widely used, especially among severely mentally ill patients. Many psychiatrists say that it works better than other medicines at calming patients who are psychotic and hallucinating. About four million Zyprexa prescriptions were written in the United States last year.

Federal prosecutors in Philadelphia are leading the settlement talks for the government, in consultation with the Justice Department in Washington. State attorneys general's offices are also involved. Lawyers at Pepper Hamilton, a firm based in Philadelphia, and Sidley Austin, a firm based in Chicago, are negotiating for Lilly.

Nina Gussack, a lawyer at Pepper Hamilton who is representing Lilly, said she could not comment on the case. Joseph Trautwein, an assistant United States attorney for the Eastern District of Pennsylvania, also declined to comment.

While a settlement has not been concluded and the negotiations could collapse, both sides want to reach an agreement, according to the people involved in the investigation.

Besides the escalating pressure of the federal criminal inquiry, Lilly faces a civil trial scheduled for March in Anchorage, in a lawsuit brought by the state of Alaska to recover money the state has spent on Zyprexa prescriptions. A loss in that lawsuit would damage Lilly's bargaining position in the Philadelphia talks.

While expensive for Lilly, the settlement would end a four-year federal investigation and remove a cloud over Zyprexa. While Zyprexa prescriptions are falling, its dollar volume of sales is rising because Lilly has raised Zyprexa's price about 40 percent since 2003.

Federal prosecutors have been investigating Lilly for its marketing of Zyprexa since 2004, and state attorneys general have been doing so since 2005. The people involved in the investigations said the inquiries gained momentum after December 2006, when The New York Times published articles describing Lilly's years-long efforts to play down Zyprexa's side effects and to promote the drug for conditions other than schizophrenia and severe bipolar disorder — a practice called off-label marketing.

Internal Lilly marketing documents and e-mail messages showed that Lilly wanted to persuade doctors to prescribe Zyprexa for patients with age-related dementia or relatively mild bipolar disorder.

In one document, an unidentified Lilly marketing executive wrote that primary care doctors "do treat dementia" but leave schizophrenia and bipolar disorder to psychiatrists. As a result, sales representatives should discuss dementia with primary care 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 "might prescribe outside of label."

In late 2000, Lilly began a marketing campaign called Viva Zyprexa and told sales representatives to suggest that doctors prescribe Zyprexa to older patients with symptoms of dementia.

The documents were under federal court seal when The Times published the articles, and Judge Jack B. Weinstein of United States District Court in Brooklyn rebuked The Times for publishing them.

The settlement negotiations in Philadelphia began several months ago, according to the people involved in the investigation.

Last fall, the two sides were close to a deal in which Lilly would have paid less than $1 billion to settle the case, which at the time consisted only of a civil complaint.

Then Justice Department lawyers in Washington pressed for a grand jury investigation to examine whether Lilly should be charged criminally for its promotional activities, according to the people involved in the negotiations. A few days ago, facing the possibility of both civil and criminal charges, Lilly opened new discussions with the prosecutors in Philadelphia.

March 26, 2008

Lilly Settles Alaska Suit Over Zyprexa

Eli Lilly has agreed to pay $15 million to the state of Alaska to settle a lawsuit claiming that the company’s schizophrenia drug Zyprexa caused patients to develop diabetes, Lilly and the state said Wednesday morning.

The settlement is something of a surprise, coming three weeks into a trial over the state’s claims in Anchorage. The state sued to recoup medical bills it said were generated by Medicaid patients who developed diabetes while taking Zyprexa. The case had not yet reached the jury, although closing arguments were expected this week.

Because Alaska is such a small state, with only 670,000 residents, the $15 million figure is a relatively large payment by Lilly. Many other states have sued Lilly with similar claims or are participating in settlement talks led by federal prosecutors in Pennsylvania.

If the $15 million payment to Alaska represents a benchmark for the broader talks, Lilly might need to pay billions of dollars to resolve the bigger cases. Lilly and the prosecutors have already discussed an overall settlement of the state and federal investigations and suits that would require Lilly to pay $1 billion to $2 billion in fines and restitution, according to people who have been briefed on the talks.

In addition, Lilly has already paid $1.2 billion to settle 30,000 individual lawsuits from people who say they developed diabetes after taking Zyprexa . . .