AstraZeneca: “Smoke-and-Mirror Job”

The lid of another pharmaceutical company’s Pandora Box has been lifted: Lawyers agreed to unseal most AstraZeneca documents that had been collected during  Seroquel litigation in Florida. The unsealed documents reveal that the company “buried” unfavorable studies that showed the drug posed a serious risk for diabetes.

The Wall Street Journal reports (below) that these court documents “suggest” that AstraZeneca told U.S. sales reps to say their antipsychotic drug didn’t cause diabetes, even though a 2000 position paper about the safety of Seroquel sent to Dutch regulatory authorities, an AstraZeneca doctor, Wayne Geller MD, 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."

WSJ cites a 1997 document that describes internal company deliberations over how to report "Study 15," a study comparing Seroquel to Haldol, an older-generation psychiatric drug.  

In a 1997 e-mail Richard Lawrence, an AstraZeneca official boasted that the company had engaged in a “great smoke-and-mirrors job” in dealing with U.S. and Canadian investigators on the trial’s results.

 “Adopting the approach Don has outlined should minimize (and dare I venture to suggest) could put a positive spin (in terms of safety) on this cursed study.”

 Bloomberg News cites a 1999 email by John Tumas, an AstraZeneca publications manager company:

“The larger issue is how we face the outside world when they begin to criticize us for suppressing data.”

 Lawyers for AstraZeneca urged the judge not to lift the seal on nine other files, including some that reveal what AstraZeneca told foreign regulators about Seroquel.Judge David Baker’s response:

“The court has a duty to make sure things are not inappropriately kept secret.”  

Indeed, American consumers should not be exposed to drugs whose hazards and lack of efficacy are concealed from physicians, public health agencies that approve payment for drugs, and consumers who bear the adverse health consequences of  such drugs. 

More than 15,000 patients have sued AstraZeneca, claiming the company withheld information of a connection between diabetes and Seroquel use from doctors and patients.  Yet, the FDA is considering EXPANDING the use of Seroquel

 posted by Vera Hassner Sharav

 

~~~~~~~~~~~~~

The Wall Street Journal

FEBRUARY 27, 2009, page B3

AstraZeneca Papers Raise Seroquel Issues

By SHIRLEY S. WANG and AVERY JOHNSON

ORLANDO, Fla. — AstraZeneca PLC instructed its U.S. sales representatives 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 unsealed in a federal court case here show.

The documents — ranging from unpublished study results to previously undisclosed depositions — are among more than 100 the U.K. drug maker agreed to unseal Thursday 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 Aug. 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 late Thursday night.

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 Thursday morning.

"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 Thursday.

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 minimise (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 late Thursday, and AstraZeneca declined to discuss the emails. Ed Blizzard, an attorney with the Houston law firm Blizzard, McCarthy & Nabers, who is one of the lawyers for the plaintiffs, says the document refers to the fact that "the weight gain data was bad, and that's why we believe the study was buried."

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.

—Jeanne Whalen contributed to this article.

Write to Shirley S. Wang at shirley.wang@wsj.com and Avery Johnson at avery.johnson@WSJ.com

Copyright 2008 Dow Jones & Company, Inc. All Rights Reserved

~~~~~~~~~~~~

http://www.bloomberg.com/apps/news?pid=20670001&refer=home&sid=aS_.NqzMArG8

 BLOOMBERG NEWS

AstraZeneca Seroquel Studies ‘Buried,’ Papers Show

By Jef Feeley and Margaret Cronin Fisk

 

Feb. 27 (Bloomberg) — Unfavorable studies about the antipsychotic drug Seroquel were “buried” by AstraZeneca Plc, according to an internal e-mail unsealed as part of litigation over the medicine.

The drugmaker failed to publicize results of at least three clinical trials of Seroquel and engaged in “cherry picking” of data from one of those studies for use in a presentation, an AstraZeneca official said in a December 1999 e-mail unsealed yesterday under an agreement between the company and lawyers for patients. The company faces about 9,000 lawsuits claiming it failed to properly warn users that Seroquel can cause diabetes and other health problems.

“The larger issue is how we face the outside world when they begin to criticize us for suppressing data,” John Tumas, an AstraZeneca publications manager, told colleagues in the e-mail.

More than 15,000 patients have sued AstraZeneca, claiming the company withheld information of a connection between diabetes and Seroquel use from doctors and patients. Many of the lawsuits also claim AstraZeneca promoted Seroquel, approved by the U.S. Food and Drug Administration for schizophrenia and bipolar disorder, for unapproved uses.

“AstraZeneca has studied Seroquel extensively and shared all relevant and required data with the FDA — both before and after the agency approved it as safe and effective,” Tony Jewell, AstraZeneca’s spokesman, said in an e-mailed statement.

‘Acted Responsibly’  

“None of the documents can obscure the fact that AstraZeneca acted responsibly and appropriately as it developed and marketed Seroquel,” Jewell said.

Seroquel, which generated sales of $4.45 billion in 2008, is company’s second-biggest seller after the ulcer treatment Nexium. The company has denied wrongdoing in its handling of the drug and is vowing to fight the lawsuits in court.

The company said today that the FDA asked for more information on its application to expand the use of Seroquel XR to include adults with generalized anxiety disorder, following a similar request in December seeking additional data on the drug for major depression in adults. The agency has scheduled an advisory panel meeting on April 8 to review the drug’s safety and effectiveness, AstraZeneca said on Feb. 25.

AstraZeneca fell 153 pence, or 6.5 percent, to 2,204 pence at 11:11 a.m. in London trading.

The U.K. drugmaker agreed to release more than 100 files with information about the drug after Bloomberg News filed a motion this month to unseal records in the case.

Unsealed Documents

The company and lawyers for former Seroquel users agreed to unseal thousands of documents just before appearing yesterday before U.S. Magistrate Judge David A. Baker in Orlando, Florida, for a hearing on that motion.

The London-based drugmaker is urging the judge to continue the confidential designation on nine other files, including some that involve what AstraZeneca told foreign regulators about Seroquel and sales representatives’ notes on doctors’ meetings. The company’s U.S. headquarters is in Wilmington, Delaware.

“The court has a duty to make sure things are not inappropriately kept secret,” Baker said at yesterday’s hearing.

One unsealed document showed AstraZeneca officials considered Trial 15, one of the studies Tumas described as ‘buried,” to be a problem because it didn’t produce favorable results on the issue of weight gain for patients taking the drug. Gaining weight can be a factor in the development of diabetes.

‘Smoke-And-Mirrors Job’

Richard Lawrence, an Astra Zeneca official, said in a February 1997 e-mail that the company had engaged in a “great smoke-and-mirrors job” in dealing with U.S. and Canadian investigators on the trial’s results.  “Adopting the approach Don has outlined should minimize (and dare I venture to suggest) could put a positive spin (in terms of safety) on this cursed study,” Lawrence said in the e- mail. It isn’t clear from the e-mail which person Lawrence is referring to.

In his December 1999 e-mail, Tumas pointed out that AstraZeneca had “buried trials 15, 31, 56,” and was considering a study listed as COSTAR. The focuses of the trials weren’t specified in the e-mail. He also noted “there is growing pressure from outside the industry to provide access to all data from clinical trials conducted by industry.”

Tumas chastised colleagues for using favorable data produced by Trial 15 without disclosing the full study results, according to his unsealed e-mail. “There has been a precedent set regarding ‘cherry picking of data,” he said. The data was used in “the recent Velligan presentations,” he noted. “Thus far, I am not aware of any repercussions regarding interest in the unreported data.”

‘Ethical Behavior’

The publications manager indicated that AstraZeneca had a favorable reputation for engaging in “ethical behavior” when it came to disclosing study results on its drugs. “We must decide if we wish to continue to enjoy this distinction,” he wrote. “The reporting of the COSTAR results will not be easy,” he added. “We must find a way to diminish the negative findings. But, in my opinion, we cannot hide them.”

Among the unsealed documents was a March 2000 e-mail from Tumas in which he noted a study comparing Seroquel to Risperdal, Johnson & Johnson’s rival antipsychotic drug, produced data “that don’t look good.”

The results showed that Seroquel failed to best Risperdal in at least five different categories and only out-performed the placebo used in the study, according to study data made public yesterday. Those categories included mood, anxiety and hostility, the documents showed.

Zyprexa Settlements

Seroquel is part of class of newer antipsychotic drugs, including Risperdal and Eli Lilly & Co.’s Zyprexa, which studies have linked to an increased risk of diabetes. That research prompted the FDA in September 2003 to require AstraZeneca and other drugmakers to warn doctors of the risks.

Lilly has agreed to pay at least $1.2 billion to settle lawsuits filed by about 31,000 patients who used Zyprexa. The Indianapolis-based drugmaker said last month it would pay an additional $1.42 billion to resolve claims by state and federal officials that it marketed the drug for unapproved uses. Lilly also agreed to plead guilty to a criminal charge.

AstraZeneca officials have vowed to defend the Seroquel cases “on their individual merits” and have refused to settle any claims. Lawyers for former Seroquel users contend that AstraZeneca knew of Seroquel’s risks years before the FDA required a stronger warning.

The first two lawsuits set for trial in federal court in Orlando were dismissed last month when U.S. District Judge Anne Conway determined the plaintiffs couldn’t prove Seroquel contributed to their development of diabetes.

First Trial

The first Seroquel trial is set for April in state court in Delaware.  AstraZeneca officials have criticized lawyers for former Seroquel users for pushing to have documents in the case unsealed. “It is not surprising that plaintiffs’ lawyers have resorted to these tactics to distract attention from their lack of success on the merits of the claims,” Jewell said in his statement.

The case is In Re Seroquel Products Litigation, 06-MD-01769, U.S. District Court, Middle District of Florida (Orlando).

To contact the reporters on this story:

Margaret Cronin Fisk in Southfield, Michigan, at mcfisk@bloomberg.net; Jef Feeley in Wilmington, Delaware, at jfeeley@bloomberg.net.