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.)


The New York Times

December 17, 2006

Eli Lilly Said to Play Down Risk of Top Pill

By ALEX BERENSON

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)

The New York Times

December 18, 2006

Drug Files Show Maker Promoted Unapproved Use

By ALEX BERENSON

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)

The New York Times

December 21, 2006

Disparity Emerges in Lilly Data on Schizophrenia Drug

By ALEX BERENSON

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.


latimes.com

Secrecy's dangerous side effects

When legal settlements allow companies to hide their mistakes, what we don't know can hurt us.

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.


The New York Times

January 31, 2008

Lilly Considers $1 Billion Fine to Settle Case

By ALEX BERENSON

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.


The New York Times

March 26, 2008

Lilly Settles Alaska Suit Over Zyprexa

By ALEX BERENSON

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 . . .


Department of Justice SealDepartment of Justice

FOR IMMEDIATE RELEASE
Thursday, January 15, 2009

Eli Lilly and Company Agrees to Pay $1.415 Billion to Resolve Allegations of Off-label Promotion of Zyprexa

$515 Million Criminal Fine Is Largest Individual Corporate Criminal Fine in History; Civil Settlement up to $800 Million

American pharmaceutical giant Eli Lilly and Company today agreed to plead guilty and pay $1.415 billion for promoting its drug Zyprexa for uses not approved by the Food and Drug Administration (FDA), the Department of Justice announced today. This resolution includes a criminal fine of $515 million, the largest ever in a health care case, and the largest criminal fine for an individual corporation ever imposed in a United States criminal prosecution of any kind. Eli Lilly will also pay up to $800 million in a civil settlement with the federal government and the states.

Eli Lilly agreed to enter a global resolution with the United States to resolve criminal and civil allegations that it promoted its antipsychotic drug Zyprexa for uses not approved by the FDA, the Department said. Such unapproved uses are also known as "off-label" uses because they are not included in the drug’s FDA approved product label.

Assistant Attorney General for the Civil Division Gregory G. Katsas and acting U.S. Attorney for the Eastern District of Pennsylvania Laurie Magid today announced the filing of a criminal information against Eli Lilly for promoting Zyprexa for uses not approved by the FDA. Eli Lilly, headquartered in Indianapolis, is charged in the information with promoting Zyprexa for such off-label or unapproved uses as treatment for dementia, including Alzheimer’s dementia, in elderly people.

The company has signed a plea agreement admitting its guilt to a misdemeanor criminal charge. Eli Lilly also signed a civil settlement to resolve civil claims that by marketing Zyprexa for unapproved uses, it caused false claims for payment to be submitted to federal insurance programs such as Medicaid, TRICARE and the Federal Employee Health Benefits Program, none of which provided coverage for such off-label uses.

The plea agreement provides that Eli Lilly will pay a criminal fine of $515 million and forfeit assets of $100 million. The civil settlement agreement provides that Eli Lilly will pay up to an additional $800 million to the federal government and the states to resolve civil allegations originally brought in four separate lawsuits under the qui tam provisions of the federal False Claims Act. The federal share of the civil settlement amount is $438 million. Under the terms of the civil settlement, Eli Lilly will pay up to $361 million to those states that opt to participate in the agreement.

Under the Food, Drug, and Cosmetic Act (FDCA), a company must specify the intended uses of a product in its new drug application to the FDA. Before approving a drug, the FDA must determine that the drug is safe and effective for the use proposed by the company. Once approved, the drug may not be marketed or promoted for off-label uses.

The FDA originally approved Zyprexa, also known by the chemical name olanzapine, in Sept. 1996 for the treatment of manifestations of psychotic disorders. In March 2000, FDA approved Zyprexa for the short-term treatment of acute manic episodes associated with Bipolar I Disorder. In Nov. 2000, FDA approved Zyprexa for the short term treatment of schizophrenia in place of the management of the manifestations of psychotic disorders. Also in Nov. 2000, FDA approved Zyprexa for maintaining treatment response in schizophrenic patients who had been stable for approximately eight weeks and were then followed for a period of up to eight months. Zyprexa has never been approved for the treatment of dementia or Alzheimer’s dementia.

The criminal information, filed in the Eastern District of Pennsylvania, alleges that from Sept. 1999 through at least Nov. 2003, Eli Lilly promoted Zyprexa for the treatment of agitation, aggression, hostility, dementia, Alzheimer’s dementia, depression and generalized sleep disorder. The information alleges that Eli Lilly’s management created marketing materials promoting Zyprexa for off-label uses, trained its sales force to disregard the law and directed its sales personnel to promote Zyprexa for off-label uses.

The information alleges that beginning in 1999, Eli Lilly expended significant resources to promote Zyprexa in nursing homes and assisted-living facilities, primarily through its long-term care sales force. Eli Lilly sought to convince doctors to prescribe Zyprexa to treat patients with disorders such as dementia, Alzheimer’s dementia, depression, anxiety, and sleep problems, and behavioral symptoms such as agitation, aggression, and hostility.

The information further alleges that the FDA never approved Zyprexa for the treatment of dementia, Alzheimer's dementia, psychosis associated with Alzheimer's disease, or the cognitive deficits associated with dementia.

The information also alleges that building on its unlawful promotion and success in the long-term care market, Eli Lilly executives decided to market Zyprexa to primary-care physicians. In Oct. 2000, Eli Lilly began this off-label marketing campaign targeting primary care physicians, even though the company knew that there was virtually no approved use for Zyprexa in the primary-care market. Eli Lilly trained its primary-care physician sales representatives to promote Zyprexa by focusing on symptoms, rather than Zyprexa’s FDA approved indications.

The qui tam lawsuits alleged that between Sept. 1999 and the end of 2005, Eli Lilly promoted Zyprexa for use in patients of all ages and for the treatment of anxiety, irritability, depression, nausea, Alzheimer’s and other mood disorders. The qui tam lawsuits also alleged that the company funded continuing medical education programs, through millions of dollars in grants, to promote off-label uses of its drugs, in violation of the FDA’s requirements.

"Off-label promotion of pharmaceutical drugs is a serious crime because it undermines the FDA’s role in protecting the American public by determining that a drug is safe and effective for a particular use before it is marketed," said Gregory G. Katsas, Assistant Attorney General for the Civil Division. "This settlement demonstrates the Department’s ongoing diligence in prosecuting cases involving violations of the Food, Drug, and Cosmetic Act, and recovering taxpayer dollars used to pay for drugs sold as a result of off-label marketing campaigns."

"When pharmaceutical companies ignore the government’s process for protecting the public, they undermine the integrity of the doctor-patient relationship and place innocent people in harm’s way," said acting U.S. Attorney for the Eastern District of Pennsylvania, Laurie Magid. "Off-label marketing created unnecessary risks for patients. People have an absolute right to their doctor’s medical expertise, and to know that their health care provider’s judgment has not be clouded by misinformation from a company trying to build its bottom line."

The global resolution includes the following agreements:

  • A plea agreement signed by Eli Lilly admitting guilt to the criminal charge of misbranding. Specifically, Eli Lilly admits that between Sept. 1999 and March 31, 2001, the company promoted Zyprexa in elderly populations as treatment for dementia, including Alzheimer’s dementia. Eli Lilly has agreed to pay a $515 million criminal fine and to forfeit an additional $100 million in assets.
  • A civil settlement between Eli Lilly, the United States and various States, in which Eli Lilly will pay up to $800 million to the federal government and the states to resolve False Claims Act claims and related state claims by Medicaid and other federal programs and agencies including TRICARE, the Federal Employees Health Benefits Program, Department of Veterans Affairs, Bureau of Prisons and the Public Health Service Entities. The federal government will receive $438,171,544 from the civil settlement. The state Medicaid programs and the District of Columbia will share up to $361,828,456 of the civil settlement, depending on the number of states that participate in the settlement.
  • The qui tam relators will receive $78,870,877 from the federal share of the settlement amount.
  • A Corporate Integrity Agreement (CIA) between Eli Lilly and the Office of Inspector General of the Department of Health and Human Services. The five-year CIA requires, among other things, that a Board of Directors committee annually review the company’s compliance program and certify its effectiveness; that certain managers annually certify that their departments or functional areas are compliant; that Eli Lilly send doctors a letter notifying them about the global settlement; and that the company post on its website information about payments to doctors, such as honoraria, travel or lodging. Eli Lilly is subject to exclusion from Federal health care programs, including Medicare and Medicaid, for a material breach of the CIA and subject to monetary penalties for less significant breaches.

"OIG’s Corporate Integrity Agreement will increase the transparency of Eli Lilly’s interactions with physicians and strengthen Eli Lilly’s accountability for its compliance with the law," said Department of Health and Human Services Inspector General Daniel R. Levinson. "This historic resolution demonstrates the Government’s commitment to improve the integrity of drug promotion activities."

In addition to the $1.415 billion criminal and civil settlement announced today, Eli Lilly previously agreed to pay $62 million to settle consumer protection lawsuits brought by 33 states. The state consumer protection settlements were announced on Oct. 7, 2008.

"Today's announcement of the filing of a criminal charge and the unprecedented terms of this settlement demonstrates the government's increasing efforts aimed at pharmaceutical companies that choose to put profits ahead of the public's health," said Special Agent-in-Charge Kim Rice of FDA's Office of Criminal Investigations. "The FDA will continue to devote resources to criminal investigations targeting pharmaceutical companies that disregard the safeguards of the drug approval process and recklessly promote drugs for uses for which they have not been proven to be safe and effective."

"The illegal scheme used by Eli Lilly significantly impacted the integrity of TRICARE, the Department of Defense's healthcare system," said Ed Bradley, Special Agent-in-Charge, Defense Criminal Investigative Service. "This illegal activity increases patients’ costs, threatens their safety and negatively affects the delivery of healthcare services to the over nine million military members, retirees and their families who rely on this system. Today’s charges and settlement demonstrate the ongoing commitment of the Defense Criminal Investigative Service and its partners in law enforcement to investigate and prosecute those that abuse the government's healthcare programs at the expense of the taxpayers and patients."

"This case should serve as still another warning to all those who break the law in order to improve their profits," said Patrick Doyle, Special Agent-in-Charge of the Office of Inspector General for the Department of Health and Human Services in Philadelphia.  "OIG, working with our law enforcement partners, will pursue and bring to justice those who would steal from vulnerable beneficiaries and the taxpayers."

The civil settlement resolves four qui tam actions filed in the Eastern District of Pennsylvania: United States ex rel. Rudolf, et al., v. Eli Lilly and Company, Civil Action No. 03-943 (E.D. Pa.); United States ex rel. Faltaous v. Eli Lilly and Company, Civil Action No. 06-2909 (E.D. Pa.); United States ex rel. Woodward v. Dr. George B. Jerusalem, et al., Civil Action No. 06-5526 (E.D. Pa.); and United States ex rel. Vicente v. Eli Lilly and Company, Civil Action No. 07-1791 (E.D. Pa.). All of those cases were filed by former Eli Lilly sales representatives.

The criminal case is being prosecuted by the U.S. Attorney’s Office for the Eastern District of Pennsylvania and the Office of Consumer Litigation of the Justice Department’s Civil Division. The civil settlement was reached by the U.S. Attorney’s Office and the Commercial Litigation Branch of the Justice Department’s Civil Division.

This matter was investigated by the FDA’s Office of Criminal Investigations, the Defense Criminal Investigative Service and the Department of Health and Human Services Office of Inspector General.

Assistance was provided by representatives of FDA’s Office of Chief Counsel and the National Association of Medicaid Fraud Control Units.

The Corporate Integrity Agreement was negotiated by the Office of Inspector General of the Department of Health and Human Services.

Eli Lilly's guilty plea and sentence is not final until accepted by the U.S. District Court.



October 2, 2010

Side Effects May Include Lawsuits

By DUFF WILSON

FOR decades, antipsychotic drugs were a niche product. Today, they’re the top-selling class of pharmaceuticals in America, generating annual revenue of about $14.6 billion and surpassing sales of even blockbusters like heart-protective statins.

While the effectiveness of antipsychotic drugs in some patients remains a matter of great debate, how these drugs became so ubiquitous and profitable is not. Big Pharma got behind them in the 1990s, when they were still seen as treatments for the most serious mental illnesses, like hallucinatory schizophrenia, and recast them for much broader uses, according to previously confidential industry documents that have been produced in a variety of court cases.

Anointed with names like Abilify and Geodon, the drugs were given to a broad swath of patients, from preschoolers to octogenarians. Today, more than a half-million youths take antipsychotic drugs, and fully one-quarter of nursing-home residents have used them. Yet recent government warnings say the drugs may be fatal to some older patients and have unknown effects on children.

The new generation of antipsychotics has also become the single biggest target of the False Claims Act, a federal law once largely aimed at fraud among military contractors. Every major company selling the drugs — Bristol-Myers Squibb, Eli Lilly, Pfizer, AstraZeneca and Johnson & Johnson — has either settled recent government cases for hundreds of millions of dollars or is currently under investigation for possible health care fraud.

Two of the settlements, involving charges of illegal marketing, set records last year for the largest criminal fines ever imposed on corporations. One involved Eli Lilly’s antipsychotic, Zyprexa; the other involved a guilty plea for Pfizer’s marketing of a pain pill, Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon; Pfizer settled that part of the claim for $301 million, without admitting any wrongdoing.

The companies all say their antipsychotics are safe and effective in treating the conditions for which the Food and Drug Administration has approved them — mostly, schizophrenia and bipolar mania — and say they adhere to tight ethical guidelines in sales practices. The drug makers also say that there is a large population of patients who still haven’t taken the drugs but could benefit from them.

AstraZeneca, which markets Seroquel, the top-selling antipsychotic since 2005, says it developed such drugs because they have fewer side effects than older versions.

“It’s a drug that’s been studied in multiple clinical trials in various indications,” says Dr. Howard Hutchinson, AstraZeneca’s chief medical officer. “Getting these patients to be functioning members of society has a tremendous benefit in terms of their overall well-being and how they look at themselves, and to get that benefit, the patients are willing to accept some level of side effects.”

The industry continues to market antipsychotics aggressively, leading analysts to question how drugs approved by the Food and Drug Administration for about 1 percent of the population have become the pharmaceutical industry’s biggest sellers — despite recent crackdowns.

Some say the answer to that question isn’t complicated.

“It’s the money,” says Dr. Jerome L. Avorn, a Harvard medical professor and researcher. “When you’re selling $1 billion a year or more of a drug, it’s very tempting for a company to just ignore the traffic ticket and keep speeding.”

NEUROLEPTIC drugs — now known as antipsychotics — were first developed in the 1950s for use in anesthesia and then as powerful sedatives for patients with schizophrenia and other severe psychotic disorders, who previously might have received surgical lobotomies.

But patients often stopped taking those drugs, like Thorazine and Haldol, because they could cause a range of involuntary body movements, tics and restlessness.

A second generation of drugs, called atypical antipsychotics, was introduced in the ’90s and sold to doctors more broadly, on the basis that they were safer than the old ones — an assertion that regulators and researchers are continuing to review because the newer drugs appear to cause a range of other side effects, even if they cause fewer tics.

Contentions that the new drugs are superior have been “greatly exaggerated,” says Dr. Jeffrey A. Lieberman, chairman of the psychiatry department at Columbia University. Such assertions, he says, “may have been encouraged by an overly expectant community of clinicians and patients eager to believe in the power of new medications.”

“At the same time,” he adds, “the aggressive marketing of these drugs may have contributed to this enhanced perception of their effectiveness in the absence of empirical evidence.”

Others agree. “They sold the story they’re more safe, when they aren’t,” says Robert Whitaker, a journalist who has written two books about psychiatric medicines. “They had to cover up the problems. Right from the start, we got this false story.”

The drug companies say all the possible side effects are fully disclosed to the F.D.A., doctors and patients. Side effects like drowsiness, nausea, weight gain, involuntary body movements and links to diabetes are listed on the label. The companies say they have a generally safe record in treating a difficult disease and are fighting lawsuits in which some patients claim harm.

The cases, both civil and criminal, against many of the world’s largest drug makers have unveiled hundreds of previously confidential documents showing that some company officials were aware they were using questionable tactics when they marketed these powerful, expensive drugs.

Such marketing, according to analysts and court documents, included payments, gifts, meals and trips for doctors, biased studies, ghostwritten medical journal articles, promotional conference appearances, and payments for postgraduate medical education that encourages a pro-drug outlook among doctors. All of these are tools that federal investigators say companies have used to exaggerate benefits, play down risks and promote off-label uses, meaning those the F.D.A. hasn’t approved.

Lawyers suing AstraZeneca say documents they have unearthed show that the company tried to hide the risks of diabetes and weight gain associated with the new drugs. Positive studies were hyped, the documents show; negative ones were filed away.

According to company e-mails unsealed in civil lawsuits, AstraZeneca “buried” — a manager’s term — a 1997 study showing that users of Seroquel, then a new antipsychotic, gained 11 pounds a year, while the company publicized a study that asserted they lost weight. Company e-mail messages also refer to doing a “great smoke-and-mirrors job” on an unfavorable study.

“The larger issue is how do we face the outside world when they begin to criticize us for suppressing data,” John Tumas, then AstraZeneca’s publications manager, wrote in a 1999 e-mail. “We must find a way to diminish the negative findings,” he added. “But, in my opinion, we cannot hide them.”

Tony Jewell, an AstraZeneca spokesman, said last week that the company had turned over all that material to the F.D.A. as part of the approval process and updated its label over the years to show the latest safety information.

Dr. Stefan P. Kruszewski, a Harvard-educated psychiatrist who once worked as a paid speaker for several drug makers, became a government informant and now consults for plaintiffs suing drug companies. Earlier in his career, he spoke at events for Pfizer, GlaxoSmithKline and Johnson & Johnson as an advocate of antipsychotics. He said one company offered him incentives of $1,000 or more every time he talked to an individual doctor about one of its drugs.

“When I started speaking for companies in the late 1980s and early ’90s, I was allowed to say what I thought I should say consistent with the science,” he recalls. “Then it got to the point where I was no longer allowed to do that. I was given slides and told, ‘We’ll give you a thousand dollars if you say this for a half-hour.’ And I said: ‘I can’t say that. It isn’t true.’ ”

Slides for one new antipsychotic drug contended that it had no neurological side effects. “They made it all up,” Dr. Kruszewski said. “It was never true.”

The antipsychotics found an easy route around regulations because of the leeway given to many big drug makers.

While drug companies are prohibited from promoting drugs for conditions for which they have not been proved safe and effective, their paid consultants, researchers and educators may do that for them verbally and in company-sponsored studies.

“They can give a small hint, and people will take the bait,” says Dr. Robert Rosenheck, a professor of psychiatry and public health at the Yale School of Medicine, who has received research support from drug makers and federal agencies. “Psychiatric disorders are vaguely defined enough that you can stretch definitions,” he says. “So many treatments are completely ineffective, people are willing to try anything.”

For their part, doctors are free to prescribe any approved drug for any medical condition they choose, even if the drug hasn’t been approved for that specific treatment. “Because they’re approved, they become an alternative for doctors who can’t think of what else to prescribe,” says Dr. Daniel J. Carlat, an associate professor of psychiatry at Tufts University. “Whether they’re useful or not is unclear.”

Analysts said that given the profits that were to be made, the murkiness of mental disorders, and holes in the regulatory regime, marketing excesses were bound to occur.

“If you have a lot of money on the table and you have clinical uncertainty over mental health conditions, where you don’t have a blood test or objective test for it, you see it’s kind of a combustible mixture,” says Dr. Mark Olfson, a Columbia University psychiatry professor and researcher.

DOCUMENTS produced in recent litigation and in Congressional investigations show that some leading academic doctors have worked closely with corporate benefactors to expand the use of antipsychotics.

The most well-known is Joseph Biederman, a Harvard medical professor and Massachusetts General Hospital researcher. His studies, examining prevalence of bipolar psychological disorders in children, helped expand practice standards, leading to a fortyfold increase in such diagnoses from 1994 to 2003. The increase was reported in a 2007 study by the Archives of General Psychiatry.

Between 2000 and 2007, he also got $1.6 million in speaking and consulting fees — some of them undisclosed to Harvard — from companies including makers of antipsychotic drugs prescribed for some children who might have bipolar disorder, a Senate investigation found in 2008.

Johnson & Johnson gave more than $700,000 to a research center that was headed by Dr. Biederman from 2002 to 2005, records show, and some of its work supported the company’s antipsychotic drug, Risperdal.

Dr. Biederman says that the money did not influence him and that some of his work supported other drugs.

“Dr. Biederman’s research does not promote a particular diagnosis or treatment,” his lawyer, Peter Spivack, wrote in an e-mail on Thursday.

The increase in pediatric bipolar diagnosis, the lawyer said, “cannot be attributed solely to Dr. Biederman’s work.” Treatment was expanded to help children and their families, he said.

Mr. Spivack said Dr. Biederman’s disclosure lapses were minor and inadvertent. A Harvard spokesman said they were still under review.

According to government investigators and plaintiffs’ lawyers, many of the studies of antipsychotics were conceived in marketing departments of pharmaceutical companies, written by ghostwriters and then signed by prominent physicians — giving the illusion that the doctors were undertaking their studies independently.

Such practices continue.

“The content is preplanned,” said one doctor who has worked as an uncredited medical writer for antipsychotic studies. Data is used selectively and interpreted for company benefit, said the doctor, who still works in medical writing and spoke on the condition of anonymity to preserve future job prospects.

“Review articles and original research articles have advertising messages in them,” the doctor said. “That’s part of the plan.”

Such papers influence medicine in many ways, as sales representatives show them to doctors and future research builds upon them.

ACCORDING to the Justice Department, drug companies trained sales reps to rebut valid medical concerns about unproved uses of antipsychotics. For example, the department says, Lilly produced a video called “The Myth of Diabetes” to sell Zyprexa, which became its all-time best-selling drug, even though evidence showed that Zyprexa could cause diabetes, as well as other metabolic problems.

Lilly salespeople also promoted a “5 at 5” drug regimen in nursing homes — 5 milligrams of Zyprexa at 5 p.m. to settle down agitated older patients for the night. A Lilly spokesman declined to say when those sales campaigns occurred. But in 2005, after a new analysis of 15 previous studies, the F.D.A. issued a public health advisory saying the use of antipsychotics to calm older dementia patients would increase risk of death from heart failure or pneumonia. The F.D.A. asked drug makers to add a special warning about that on packaging.

Over the years, as psychiatrists learned more about the drugs’ risks, companies promoted them more to family doctors, pediatricians and geriatricians. Pfizer paid more than 250 child psychiatrists to promote its antipsychotic, Geodon, at a time when it was approved only for adults, according to a government filing with the Pfizer settlement last year.

High-prescribing doctors pocketed extra money in the form of research payments, speaking fees, gifts, meals and junkets — some of which the government has specifically termed illegal “kickbacks.”

In its suit against AstraZeneca, the government produced documents showing that the company paid a Chicago psychiatrist, Dr. Michael Reinstein, nearly $500,000 over a decade to do research, travel and speak for it — even as he led a Medicaid practice he had described to the company as one of “the largest prescribers of Seroquel in the world.”

Dr. Reinstein and AstraZeneca have both denied any misconduct.

In April, AstraZeneca became the fourth major drug company in three years to settle a government investigation with a hefty payment — in its case, $520 million for what federal officials described as an array of illegal promotions of antipsychotics for children, the elderly, veterans and prisoners. Still, the payment amounted to just 2.4 percent of the $21.6 billion AstraZeneca made on Seroquel sales from 1997 to 2009.

LAST year, Eli Lilly and Pfizer settled investigations resulting in the largest criminal fines in United States history. Lilly paid a $515 million criminal fine as part of a broader, $1.4 billion settlement with the government. Pfizer later paid a $1.3 billion criminal fine as part of a broader, $2.3 billion settlement.

The Lilly case focused entirely on its antipsychotic drug Zyprexa, while Pfizer’s settlement included $301 million related to its antipsychotic, Geodon, along with marketing of other drugs.

In 2007, Bristol-Myers Squibb paid $515 million to settle federal and state investigations into marketing of its antipsychotic drug Abilify to child psychiatrists and nursing homes. Bristol-Myers Squibb, like AstraZeneca, denied any misconduct.

Johnson & Johnson is currently under investigation by the Justice Department, which says it paid kickbacks to induce Omnicare, the nation’s largest nursing home pharmacy, to recommend Risperdal, government filings show. Omnicare paid $98 million last November to settle civil charges.

J.& J. is fighting a government lawsuit and says in court filings that it was paying rebates — an argument endorsed in a filing by the industry trade group, the Pharmaceutical Research and Manufacturers of America.

Some officials at companies say they’ve made systemic changes to avoid illegal marketing of antipsychotics and other products.

“That was a blemish for us,” John C. Lechleiter, Eli Lilly’s chief executive, said in an interview. “We don’t ever want that to happen again. We put measures in place to assure that not only do we have the right intentions in integrity and compliance, but we have systems in place to support that.”

Jeffrey B. Kindler, Pfizer’s chief executive, voiced similar thoughts in an interview. “Never again,” he said. “I take this very seriously.”

Mr. Kindler is operating under Pfizer’s third corporate accountability agreement, a five-year promise to the federal government to reform sales behavior, monitor employees and disclose misconduct. The first was signed in 2002 for withholding rebates for Lipitor. The second, in 2004, was for illegal marketing of the seizure drug Neurontin. The third, last year, was for illegal marketing of the painkiller Bextra.

Pfizer officials say they inherited the first two situations with their acquisitions of two other companies, Warner-Lambert and Parke-Davis.

“It wasn’t our people,” says Douglas Lankler, a senior vice president and chief compliance officer at Pfizer.

Lew Morris, chief counsel for the inspector general of the Department of Health and Human Services, says he is serious about bolstering government efforts to reform or punish drug makers for illegal sales of antipsychotics.

“The message we want to send to the industry is it’s not just the same-old, same-old,” he said in an interview.

He agrees that few industry employees have gone to jail for white-collar crimes, but says this may change soon. “We’re targeting managers and executives who should have known,” he said.

Mr. Morris says some companies are “too big to debar” from government contracts, since doing so would just hurt patients needing medicine. But he says discussions are under way about forcing one health care company to sell off a subsidiary accused of fraud. And directors who ignore information may face more risk of shareholder suits, he says.

Over the next year, the government is adding at least 15 prosecutors and 100 investigators to pursue health care fraud.

The Pharmaceutical Research and Manufacturers of America, also strengthened its marketing code of conduct two years ago, banning gifts and meals, although salespeople can still bring meals to doctors’ offices.

Some companies are also disclosing their consulting and speaking payments, as required by the government agreements. And groups in charge of medical writing and postgraduate education have taken steps to disclose or reduce industry influence.

But more than 1,000 False Claims Act lawsuits are still under way, most of them focused on health care and many on lucrative antipsychotic drugs. For that reason alone, critics say they think the industry still hasn’t gone far enough to change questionable practices.

“The drug industry still rewards sales,” says Stephen A. Sheller, a lawyer who has represented whistle-blowers in the Lilly and AstraZeneca cases. “And it’s still easy to market these drugs to doctors who are rushed.”