Margaret Cronin Fisk, Elizabeth Lopatto and Jef Feeley
June 12, 2009
Eli Lilly & Co. urged doctors to prescribe Zyprexa for elderly patients with dementia, an unapproved use for the antipsychotic, even though the drugmaker had evidence the medicine didn’t work for such patients, according to unsealed internal company documents.
In 1999, four years after Lilly sent study results to the U.S. Food and Drug Administration showing Zyprexa didn’t alleviate dementia symptoms in older patients, it began marketing the drug to those very people, according to documents unsealed in insurer suits against the company for overpayment.
Regulators required Lilly and other antipsychotic drug- makers in April 2005 to warn that the products posed an increased risk to elderly patients with dementia. The documents show the health dangers in marketing a drug for an unapproved use, called off-label promotion, said Sidney Wolfe, head of the health research group at Public Citizen in Washington.
“By definition, off-label means there is no clear evidence that the benefits of a drug outweigh the risks,” Wolfe said. “The reason why off-label promotion is illegal is that you can greatly magnify the number of people who will be harmed.”
In 1999, when Lilly began its marketing push, Zyprexa’s only approved use was for patients suffering from schizophrenia, according to the FDA. In 2008, Zyprexa was Lilly’s best-selling drug, with $4.7 billion in sales, while antipsychotics as a group topped U.S. drug sales last year, with $14.6 billion.
In a request for a December 2003 meeting over a proposed label change, Lilly told the FDA that data from seven studies showed Zyprexa didn’t alleviate symptoms of Alzheimer’s or other dementia.
The studies found death rates among older dementia patients taking Zyprexa were “significantly greater” than those who didn’t get the medicine, the company said, according to the unsealed documents.
“Plaintiffs are releasing one-sided, cherry-picked documents obtained in discovery to selected news media in an effort to try their cases in the media,” said Lilly spokeswoman Marni Lemons, who added that the company will fight the lawsuit. She declined to answer specific questions about the studies.
Lilly pleaded guilty in January to a federal misdemeanor charge of illegally marketing Zyprexa for off-label uses to elderly consumers. The company admitted illegal promotions from September 1999 through March 2001, while denying such practices beyond that date.
The documents also revealed Lilly officials wrote medical journal studies about Zyprexa and then asked doctors to put their names on the articles, a practice called “ghostwriting.”
Lilly employees compiled a guide to hiring scientists to write favorable articles, complained to journal editors when publication was delayed and submitted rejected articles to other outlets, according to the documents.
Lilly’s internal documents, which number about 10,000 pages, were unsealed as part of suits against the drugmaker by health insurers and pension plans seeking to recoup monies spent on Zyprexa. The insurance plans contend the papers indicate that Lilly promoted the antipsychotic to doctors treating elderly patients even after March 2001.
The plaintiffs cite documents including a 2002 business plan calling for expanding prescriptions in off-label use. They also point to notes from Lilly sales representatives through 2003 recording efforts to press doctors to prescribe elderly patients Zyprexa for mood symptoms, irritability and insomnia.
$6.8 Billion in Damages
Insurers and other so-called third-party payers contend Lilly should pay as much as $6.8 billion in damages for downplaying Zyprexa’s health risks, including excessive weight gain and the risk of contracting diabetes, and marketing the drug for unapproved uses to pump up profits.
Bloomberg News obtained copies of the documents after U.S. District Judge Jack Weinstein in Brooklyn, New York, ordered their release on May 1. In September, Weinstein allowed insurers and other payers to sue Lilly as a group after finding “sufficient evidence of fraud” to let the case go to trial. Lilly appealed that ruling.
The Indianapolis-based drugmaker agreed in January to pay $1.42 billion to the U.S. government and more than 30 states to settle off-label marketing allegations over Zyprexa. The agreement included a $615 million penalty for the federal criminal charge.
Lilly has paid $1.2 billion so far to settle more than 32,000 individual claims by patients, the company said in an April 30 securities filing. About 140 claims remain, Lilly reported.
The company also faces suits from 12 states over its Zyprexa marketing practices. Cases brought by South Carolina and Connecticut officials are set for trial later this year.
The unsealed documents support the claims of the insurers suing Lilly, said lawyer Thomas Sobol, of Seattle-based Hagens Berman Sobol Shapiro LLP. His firm represents the plaintiffs suing the drugmaker for overcharging on Zyprexa and provided Bloomberg News with copies of the documents.
Bloomberg News filed a letter brief asking the court to unseal the documents.
Zyprexa was initially approved in 1996 for use with schizophrenia sufferers. In 2000, Lilly received the FDA’s approval to sell it to those dealing with the mania stage of bipolar disorder.
The drug has never been approved for use with dementia patients, according to the FDA’s Web site.
Even before the drug was on the market, Lilly researchers were eyeing whether elderly dementia patients could benefit from taking the antipsychotic, according to the unsealed documents.
A 1995 company study of users taking between 1 to 8 milligrams of Zyprexa “did not show efficacy in alleviating the psychotic symptoms and behavioral disturbances in elderly” patients suffering from “primary degenerative dementia of the Alzheimer’s type,” according to a study summary that was unsealed.
The company also noted that three patients taking Zyprexa died during a study or within 30 days of its completion, while only one control-group patient expired, according to the unsealed documents.
J. Alan Webber, a Lilly executive, acknowledged in a Feb. 16, 1995, note that FDA official Paul Leber wasn’t impressed with study results in connection with Zyprexa’s effectiveness in treating older dementia patients.
“Dr. Leber was not enthusiastic about study HGAO (psychotic demented elderly) with respect to the indication for use, and extensive discussion did not resolve the disagreement,” Webber said, according to the documents.
Back to the FDA
In 1998, Lilly went back to the FDA seeking approval to market Zyprexa to those battling Alzheimer’s, the most common form of dementia, the company said in its 2003 request for a meeting on a proposed label change. Lilly withdrew its bid to promote Zyprexa for Alzheimer’s cases in 1999, according to the document.
In a November 2000 memo to Lilly salespeople, company executives said the dementia marketing initiative was abandoned because the FDA questioned Zyprexa’s effectiveness in treating the ailment.
“It was withdrawn due to vagueness on the FDA’s part regarding a definition of efficacy,” Lilly officials said in the document.
In a 2003 memo to FDA regulators citing the clinical studies, Lilly researchers acknowledged the death rates among older dementia patients on Zyprexa in the reviews were two times higher than their counterparts taking placebos.
Deaths among the patients taking Zyprexa in the studies were “significantly greater than placebo-treated patients (3.5 percent v. 1.5 percent, respectively),” Lilly officials said, according to the unsealed documents.
The studies didn’t find Zyprexa was effective in treating dementia, the company acknowledged in this document.
Lilly recognized this earlier, according to a 2002 document entitled “Zyprexa in serious mental illness (65 plus years) — A Strategy Review.”
“The treatment of serious mental illness for people over the age of 65 has been identified as a growing opportunity for Zyprexa,” the authors wrote. “Unfortunately, attempts to gain the data to support an application for an indication in the treatment of dementia have to date been unsuccessful.”
Lilly, which first marketed Zyprexa to psychiatrists, sought to expand its customer base in 1999 by focusing on long term-care facilities, particularly nursing homes, according to the unsealed documents.
Primary Care Physicians
It later began targeting primary care physicians, known as PCPs, as another potentially lucrative Zyprexa market. Such physicians frequently deal with dementia patients, according to the unsealed files.
Another benefit to the strategy was that many of those practitioners were “unaware of Zyprexa weight gain issue,” according to a December 1999 Lilly sales memo, referring to one of the drug’s possible side-effects.