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Recently plaintiff lawyers stated that marketing executives at British drug maker AstraZeneca PLC for years blocked efforts by company scientists to raise concerns that the antipsychotic drug Seroquel caused weight gain and other problems. Internal documents that were released as part of ongoing lawsuits against the company brought by patients alleging they were harmed by the blockbuster drug for schizophrenia and bipolar disorder.

Some of the internal e-mails and other documents, released on May 19, 2009 to the AP, demonstrate efforts to keep public information about Seroquel positive amid a spirited debate between the company’s scientists and its marketing executives.

AstraZeneca spokesman Tony Jewell said that since the drug was approved in late 1997, the label or detailed package insert has stated that diabetes, high blood sugar and weight gain have been observed in patients in clinical studies.

He noted that the FDA in the past several years has approved Seroquel as safe for new uses bipolar mania, then bipolar depression and then an extended-release version.

Other internal e-mails and planning documents suggest the company pondered uses for which Seroquel was not approved by the FDA, including in dementia patients, though none of the documents indicate the company actually marketed the drug for those uses.

Doctors are allowed to prescribe drugs for unapproved uses, but drug makers can’t promote them for those uses.
A strategic plan dated 2000 suggested a “key success factor” would be to “broaden Seroquel use on and off label,” specifically targeting educational programs “to share off label data.”

Seroquel was AstraZeneca’s No. 2 drug in sales last year, with revenue of $4.5 billion.

U.S. District Judge Anne C. Conway in Orlando, Florida, who has been coordinating pretrial details of nearly 6,000 federal Seroquel lawsuits, recently ordered them returned to the federal courts where they were filed.

First, she is settling issues such as which of the many documents plaintiff lawyers obtained through pretrial discovery should be available for use in those trials and open to the public. AstraZeneca has claimed its documents are confidential but agreed to release hundreds in February and 400 more on May 20, 2009.

In a chain of e-mails in one document, a scientists’ safety evaluation committee in June 2000 recommended removing “limited” before the words “weight gain” in the list of Seroquel side effects, because many patients gained significant weight.

Marketing staff suggested trying other explanations, such as whether patients took other drugs that could be blamed. One marketing executive, Medical Affairs Manager Richard Owen, then wrote that such a change “is potentially damaging to Seroquel.”

The change in the drug’s label was finally made in 2002. That was after Barry Arnold, the vice president for clinical drug safety, complained repeatedly to the physician in charge of Seroquel drug safety about “Commercial (executives) having such an influence.”

Later in 2002, Simon Hagger, global brand manager for Seroquel, e-mailed nearly 20 marketing staffers to say “we are under clear instruction from the highest level within AstraZeneca at this time not to discuss details surrounding trial 41,” outside the company. That patient study, concluded that year, found elevated levels of blood sugar.

AstraZeneca, the world’s fifth-biggest drug maker, has been trying to get Seroquel approved in the U.S. for treating patients with depression and anxiety disorder, a group that includes more than 20 million people.

In April, a panel of FDA scientific advisers said Seroquel’s side effects, including weight gain, high blood sugar and potential heart problems, were too troubling to make it a first choice against depression or anxiety. On a split vote, the panel said Seroquel could be used as an added therapy for patients taking other medicines but not getting relief from depression. The FDA has yet to issue a final ruling.

“Going back almost 20 years, AstraZeneca has conducted 118 studies on the safety and efficacy of Seroquel,” company spokesman Jewell said, adding some studies continue.

AstraZeneca faces roughly 15,000 lawsuits over Seroquel, about 60% of them in state courts. The first state trial is set to begin in Delaware on June 29. No federal trials have been held yet.

A February 27, 2009, article in the Wall Street Journal tells the story of how AstraZeneca PLC instructed its sales representatives within the United States to tell doctors that its powerful psychiatric drug, Seroquel, didn’t cause diabetes even though a company physician had at one point stated years earlier that such a link was probable in some individuals.

Documents ranging from unpublished study results to earlier undisclosed depositions are among more than 100 the British drug manufacturer agreed to unseal on February 26, 2009; in lawsuits brought by plaintiffs who allege they were harmed by the multibillion-dollar antipsychotic drug. Many of the cases have been consolidated in the U.S. District Court for the Middle District of Florida.

In an August 15, 2005, voicemail message addressed to company salespeople, an AstraZeneca employee named Christine Ney followed up on a “weight and diabetes sell sheet” they had recently been sent. The sales representatives should assuage doctors’ fears about their patients’ weight gains, she said in the voicemail, by telling them that data showed no causal link between diabetes and the drug.

“Our objective is to neutralize customer objections to Seroquel’s weight and diabetes profile,” Ms. Ney said, according to a transcript of the voicemail message. She then instructed representatives to “refocus the call” away from diabetes to the drug’s tolerability, the transcript shows.

The voicemail to the sales representatives raises questions about whether there was a contradiction between Ms. Ney’s instructions and an AstraZeneca drug-safety expert’s own assessment of Seroquel’s link to diabetes years earlier. In a 2000 position paper about the safety of Seroquel sent to Dutch regulatory authorities, an AstraZeneca doctor named Wayne Geller wrote that there was a relationship between the drug and diabetes.

“There is reasonable evidence to suggest that Seroquel therapy can cause impaired glucose regulation including diabetes melliutus in certain individuals,” Dr. Geller wrote.

AstraZeneca acted “responsibly and appropriately as it developed and marketed Seroquel,” company spokesman Tony Jewell says. “From the time it was first approved, the Seroquel labeling alerted physicians that diabetes mellitus, hyperglycemia and weight gain had been observed in clinical trials. We’ve continued to update the label as the findings have developed.”

Mr. Jewell says the document written by Dr. Geller doesn’t accurately reflect the company’s position in 2000. “In fact, it was not Dr. Geller’s ultimate view either. It was an initial draft for discussion purposes. After rigorous discussion of the scientific evidence, Dr. Geller and his colleagues concluded the evidence did not establish that Seroquel causes diabetes.”

Dr. Geller retracted his statement in a May 2008 deposition with plaintiffs’ attorneys. In response to a plaintiffs’ attorney’s question, Dr. Geller responded that the statement was “an artifact of an earlier discussion document.” AstraZeneca declined to make Dr. Geller and Ms. Ney, who are both still employed by the company, available for comment. Neither could be reached for comment.

AstraZeneca had argued that the documents should remain under seal because they contained proprietary information that could hurt the company if it was revealed to competitors and could harm the public if interpreted out of context. But the company agreed to make public most of the documents following negotiations with plaintiffs’ attorneys that concluded in the early hours of February 26, 2009.

“AstraZeneca believes communications from the FDA [Food and Drug Administration] to doctors is the appropriate way to notify patients and the public about a medicine’s benefits and risks, not a court proceeding,” Mr. Jewell says.

Makers of antipsychotic drugs have come under intense scrutiny over whether they knew early on that the powerful psychiatric medicines which are used to treat schizophrenia and bipolar disorder caused serious side effects such as diabetes. Most of the drugs were approved for sale in the 1990s, but their side effects didn’t become widely known until earlier this decade. The drug makers have also been accused of marketing the drugs outside of their approved indications, which is against U.S. law.

Internal company documents proved damaging to Eli Lilly & Co., which agreed to pay $1.4 billion to settle off-label promotion claims last month with the U.S. attorney for the Eastern District of Pennsylvania. Company e-mails and memos leaked in 2006 showed that Lilly played down the health risks of its antipsychotic drug, Zyprexa.

In 2007, Bristol-Myers Squibb Co. agreed to pay $515 million to settle another federal investigation over its marketing practices for its antipsychotic drug, Abilify.

AstraZeneca faces more than 9,000 lawsuits from patients who allege they have been harmed by Seroquel. Most of the cases have been consolidated into one group being heard in the Florida federal court. The first two of these cases, considered bellwethers that would have helped predict the outcomes of the remaining lawsuits, were supposed to have been tried earlier this month, but the judge dismissed them on the grounds that the evidence failed to prove that Seroquel had caused their diabetes.

More than 2,300 other cases have also been dismissed. A separate tranche of state cases is also working its way through the courts, with the first set to go to trial in Delaware, where AstraZeneca has its U.S. headquarters. The company says it will defend itself vigorously against the suits.

Pennsylvania, Montana, Arkansas and South Carolina have all sued AstraZeneca, alleging that they were bilked into paying for the medicine for off-label usage and seeking reimbursement for alleged injuries sustained by individuals as a result of the drug. AstraZeneca acknowledges that the U.S. attorney for the Eastern District of Pennsylvania, Laurie Magid, is investigating Seroquel but wouldn’t say when the investigation started or what it involves. A spokeswoman for Ms. Magid declined to comment.

When Seroquel was approved in 1997, it contained information in the “adverse reactions” section of the product label concerning diabetes, hyperglycemia and weight gain that had been observed in clinical trials, says Mr. Jewell. In 2003, the FDA mandated a stricter precaution, upgrading the diabetes risk to the label’s “warnings” section -even though the agency said at the time that it wasn’t certain that a causal relationship existed.

Last month Seroquel’s label was updated to include data on children and adolescents, including blood-glucose levels, cholesterol, weight gain and increased appetite. It also voluntarily agreed to move information about increased blood sugar to the “warnings” section of the label, according to a company lawyer’s testimony in court .

Among the unsealed documents, another set goes back to the late 1990s and raises further questions about whether AstraZeneca kept a lid on unflattering Seroquel studies.

A document dated Feb. 12, 1997, describes internal company deliberations over how to report “Study 15,” a study comparing Seroquel to Haldol, an older-generation psychiatric drug. In the document, an AstraZeneca employee named Richard Lawrence writes to his team that one of his colleagues had done a great “smoke and mirrors job,” and another had suggested an approach that “should minimize (and dare I venture to suggest) could put a positive spin (in terms of safety) on this cursed study.”

It isn’t clear what Mr. Lawrence’s comments were referring to. He couldn’t be reached, and AstraZeneca declined to discuss the emails.

In a series of emails in 1999, AstraZeneca executives discuss withholding the results of another Seroquel study, known as COSTAR. That study compared Seroquel to Risperdal, another antipsychotic drug made by Johnson & Johnson.

On Dec. 6, 1999, an AstraZeneca employee named John Tumas, the publications manager for Seroquel, wrote to his colleagues, “There is growing pressure from outside the industry to provide access to all data resulting from clinical trials conducted by industry. Thus far, we have buried” certain studies. Referring to COSTAR, he added: “We must find a way to diminish the negative findings. But in my opinion we cannot hide them.”

Mr. Tumas couldn’t be reached late Thursday. AstraZeneca’s Mr. Jewell declined to comment about the 1990s e-mails and documents other than to note that the FDA “vetted and substantiated the safety data for Seroquel,” including the data from both Study 15 and COSTAR. “The FDA has approved the medicine as a safe and effective treatment for schizophrenia and bipolar disorder,” he says.

On January 15, 2009, researchers revealed that a widely used class of antipsychotic drugs that includes bestsellers Zyprexa, Risperdal and Seroquel are just as likely perhaps even more likely to cause a fatal heart attack as older antipsychotic drugs like Haloperidol.

The findings, which run contrary to a long-standing belief, add to a growing drumbeat of criticism about this class of drugs, known as atypical antipsychotics. Zyprexa, Risperdal and Seroquel are among the 10 most commonly prescribed medications in the world, with annual sales estimated at $14.5 billion.

Researchers are especially concerned about the rising use of atypical antipsychotics in the elderly and the young both groups that are fragile and more susceptible to adverse effects of powerful medications.

Last week British researchers reported in the journal Lancet Neurology that Alzheimer’s patients given the drugs to control aggression were nearly twice as likely to die from any cause as patients who did not receive them.

Some studies have shown that as many as 40% of Alzheimer’s patients in nursing homes receive the drugs for unapproved use. The number of prescriptions for the drugs written for children and adolescents doubled to 4.4 million from 2003 to 2006, in part because of increases in diagnoses of bipolar disorder. Their efficacy in children and Alzheimer’s patients has never been demonstrated, experts said.

Eli Lilly & Co., the manufacturer of Zyprexa, settled a lawsuit with the federal government on January 15, 2009, paying a record $1.4 billion in civil and criminal charges to resolve complaints about the marketing of Zyprexa for unapproved uses. The company has already paid nearly $1.3 billion to states and consumers to settle other complaints about marketing and side effects.

“I am, and have been, very concerned about these drugs,” said Dr. Ian Cook, a psychiatrist at UCLA’s Geffen School of Medicine who was not involved in the new study. “These are powerful medications that affect the brain and the body, and we need to be very thoughtful in their use.”

No one, however, is urging abandonment of the atypical antipsychotics. The nub of the matter is that there are no other drugs with the same beneficial effects.

“The antipsychotics are a godsend,” said Dr. Alan Manevitz, a psychiatrist at Lenox Hill Hospital in New York who was not involved in the study. “They have taken people and unchained them from walls. We don’t want to throw out the baby with the bathwater.”

The drugs are approved only for treatment of schizophrenia and bipolar disorder in the general population. But their use has been expanding to treat aggression in young people and dementia in the elderly.

“We use them because they are somewhat useful in some patients and because we have no alternative,” said Dr. Dilip V. Jeste of UC San Diego.

Researchers already knew that atypical antipsychotics could produce excessive weight gain, increase the risk of diabetes and induce strokes and heart problems in the elderly. The Food and Drug Administration requires both conventional and atypical antipsychotics to carry a so-called black-box warning the strongest warning possible informing patients and physicians that the drugs are associated with increased risk of death in elderly patients treated for dementia.

In their federally funded study, published in the New England Journal of Medicine, the researchers analyzed Tennessee Medicaid records for the 15 years ending in 2005. They identified 44,000 users of conventional antipsychotics and 46,000 of atypical antipsychotics. They compared them with 186,600 matched patients taking neither.

The scientists found that patients taking either type of drug were about twice as likely to die of a heart attack as those not taking the drugs, with the risk of death increasing with dose and the length of time on the medication. There were about 3.3 excess deaths per year for every 1,000 patients taking the drugs.

The prescribing of drugs “is a balancing of risks and benefits. Our study gives more information on the risk side of things,” said study leader Dr. Wayne A. Ray of the Vanderbilt University School of Medicine.

Conventional antipsychotics, such as haloperidol (Haldol) and chlorpromazine (Thorazine), were stumbled on by chance in the 1950s and were found to have a powerful calming effect on psychotic patients, but also a number of side effects. Among the most disturbing was tardive dyskinesia, characterized by tremors and other movement disorders that are often irreversible.

The atypical antipsychotics, which also include Clozaril, Geodon and Abilify, were designed to avoid tardive dyskinesia, which is why they were perceived as safer, Ray said. “Today, nearly all people taking antipsychotics are taking the atypical ones,” he said.

In an editorial accompanying the paper, Dr. Sebastian Schneeweiss and Dr. Jerry Avorn of Brigham and Women’s Hospital in Boston argue that the danger can be mitigated by assessing patients’ cardiovascular risk before treatment and after a month on the drugs. Patients with a heightened risk could be counseled on ways to lower it, such as modifications of diet and exercise.