The study would come to be called "cursed," but it started out merely as Study 15.
It was a long-term trial of the antipsychotic drug Seroquel. The common wisdom in psychiatric circles was that newer drugs were far better than older drugs, but Study 15's results suggested otherwise.
As a result, newly unearthed documents show, Study 15 suffered the same fate as many industry-sponsored trials that yield data drug makers don't like: burial. It took eight years before a taxpayer-funded study rediscovered what Study 15 had found -- and raised serious concerns about an entire new class of expensive drugs.
Study 15 was silenced in 1997, the same year Seroquel was approved by the Food and Drug Administration to treat schizophrenia. The drug went on to be prescribed to hundreds of thousands of patients around the world and has earned billions for London-based AstraZeneca International.
The results of Study 15 were never published or shared with doctors, even as less rigorous studies that came up with positive results for Seroquel were published and used in marketing campaigns. The results of Study 15 were provided only to the FDA, which says that it does not have the authority to make such studies public.
AstraZeneca spokesman Tony Jewell defended the Seroquel research and said the company had disclosed the drug's risks. Since 1997, the drug's labeling has noted that weight gain and diabetes were seen in study patients, although the company says the data are not definitive. The label states that the metabolic disorders may be related to patients' underlying diseases.
The FDA, Jewell added, had access to Study 15 when it declared Seroquel safe and effective. The trial, which compared patients taking Seroquel and an older drug called Haldol, "did not identify any safety concerns," AstraZeneca said in an e-mail. Jewell added, "A large proportion of patients dropped out in both groups, which the company felt made the results difficult to interpret."
Details of Study 15 have emerged through lawsuits, which allege that Seroquel caused weight gain, hyperglycemia and diabetes in thousands of patients. The Houston-based law firm Blizzard, McCarthy & Nabers, one of several that have filed about 9,210 lawsuits over Seroquel, publicized the documents, which show that the patients taking Seroquel in Study 15 gained an average of 11 pounds in a year -- alarming company scientists and marketing executives. A Washington Post analysis found that about four out of five patients quit taking the drug in less than a year, raising doubts about its effectiveness.
An FDA report in 1997, moreover, said Study 15 did offer useful safety data. The FDA said the study showed that patients taking higher doses of the drug gained more weight.
In approving Seroquel, the agency said that 23% of patients taking the drug in all available studies experienced significant weight gain, compared with 6% of control-group patients taking sugar pills. In 2006, the FDA warned AstraZeneca against minimizing metabolic problems in sales pitches.
In the years since, taxpayer-funded research has found that newer antipsychotic drugs such as Seroquel, which are 10 times more expensive, offer little advantage over older ones. The older drugs cause involuntary muscle movements known as tardive dyskinesia, and the newer ones have been linked to metabolic problems.
Far from dismissing Study 15, internal documents show that company officials were worried because 45% of the Seroquel patients had experienced what AstraZeneca physician Lisa Arvanitis called "clinically significant" weight gain.
In an e-mail dated Aug. 13, 1997, Arvanitis reported that across all patient groups and treatment regimens, regardless of how numbers were crunched, patients taking Seroquel gained weight.
In a separate note, company strategist Richard Lawrence praised AstraZeneca's efforts to put a "positive spin" on "this cursed study" and said of Arvanitis: "Lisa has done a great 'smoke and mirrors' job!"
Two years after those exchanges, in 1999, the documents show that the company presented different data at an American Psychiatric Assn. conference and at another European meeting. The conclusion: Seroquel helped psychotic patients lose weight.
The claim was based on a company-sponsored study by a Chicago psychiatrist, who reviewed the records of 65 patients who switched their medication to Seroquel. But documents show that AstraZeneca held the doctor in light regard and had concerns about his methods.