News

The study would come to be called "cursed," but it started out just as Study 15.

Washington Post
A Silenced Drug Study Creates An Uproar
By Shankar Vedantam
March 18, 2009

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 drugmakers don't like: It
got buried. 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 -- including
nearly $12 billion in the past three years.

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 aimed at physicians and in
television ads aimed at consumers. The results of Study 15 were provided
only to the Food and Drug Administration -- and the agency has strenuously
maintained that it does not have the authority to place such studies in the
public domain.

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."

The saga of Study 15 has become a case study in how drug companies can
control the publicly available research about their products, along with
other practices that recently have prompted hand-wringing at universities
and scientific journals, remonstrations by medical groups about conflicts of
interest, and threats of exposure by trial lawyers and congressional
watchdogs. 

Even if most doctors are ethical, corporate grants, gifts and underwriting
have compromised psychiatry, said an editorial this month in the American
Journal of Psychiatry, the flagship journal of the American Psychiatric
Association.

"The public and private resources available for the care of our patients
depend upon the public perception of the integrity of our profession as a
whole," wrote Robert Freedman, the editor in chief, and others. "The subsidy
that each of us has been receiving is part of what has fueled the excesses
that are currently under investigation."

Details of Study 15 have emerged through lawsuits now playing out in
courtrooms nationwide alleging 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 pointed doubts about its effectiveness.

An FDA report in 1997, moreover, said Study 15 did offer useful safety data.
Mentioning few details, the FDA said the study showed that patients taking
higher doses of the drug gained more weight.

In approving Seroquel, the agency said 23 percent of patients taking the
drug in all studies available up to that point experienced significant
weight increases, compared with 6 percent of control-group patients taking
sugar pills. In 2006, FDA warned AstraZeneca against minimizing metabolic
problems in its sales pitches.

In the years since, taxpayer-funded research has found that newer
antipsychotic drugs such as Seroquel, which are 10 times as 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 percent of the Seroquel patients had experienced
what AstraZeneca physician Lisa Arvanitis termed "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: "I'm not sure there is yet any type
of competitive opportunity no matter how weak."

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 Association
conference and at a 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. It found that patients lost an average of nine pounds over 10
months.

Within the company, meanwhile, officials explicitly discussed misleading
physicians. The chief of a team charged with getting articles published,
John Tumas, defended "cherry-picking" data.

"That does not mean we should continue to advocate" selective use of data,
he wrote on Dec. 6, 1999, referring to a trial, called COSTAR, that also
produced unfavorable results. But he added, "Thus far, we have buried Trials
15, 31, 56 and are now considering COSTAR."

Although the company pushed the favorable study to physicians, the documents
show that AstraZeneca held the psychiatrist in light regard and had concerns
that he had modified study protocols and failed to get informed consent from
patients. Company officials wrote that they did not trust the doctor with
anything more complicated than chart reviews -- the basis of the 1999 study
showing Seroquel helped patients lose weight.

For practicing psychiatrists, Study 15 could have said a lot not just about
safety but also effectiveness. Like all antipsychotics, Seroquel does not
cure the diseases it has been approved to treat -- schizophrenia and bipolar
disorder -- but controls symptoms such as agitation, hallucinations and
delusions. When government scientists later decided to test the
effectiveness of the class of drugs to which Seroquel belongs, they focused
on a simple measure -- how long patients stayed on the drugs.
Discontinuation rates, they decided, were the best measure of effectiveness.

Study 15 had three groups of about 90 patients each taking different
Seroquel doses, according to an FDA document. Approximately 31 patients were
on Haldol. The study showed that Seroquel failed to outperform Haldol in
preventing psychotic relapses.

In disputing Study 15's weight-gain data, company officials said they were
not reliable because only about 50 patients completed the year-long trial.
But even without precise numbers, this suggests a high discontinuation rate
among patients taking Seroquel. Even if every single patient taking Haldol
dropped out, it appears that at a minimum about 220 patients -- or about 82
percent of patients on Seroquel -- dropped out.

Eight years after Study 15 was buried, an expensive taxpayer-funded study
pitted Seroquel and other new drugs against another older antipsychotic
drug. The study found that most patients getting the new and supposedly
safer drugs stopped taking them because of intolerable side effects. The
study also found that the new drugs had few advantages. As with older drugs,
the new medications had very high discontinuation rates. The results caused
consternation among doctors, who had been kept in the dark about trials such
as Study 15.

The federal study also reported the number of Seroquel patients who
discontinued the drug within 18 months: 82 percent.

Jeffrey Lieberman, a Columbia University psychiatrist who led the federal
study, said doctors missed clues in evaluating antipsychotics such as
Seroquel. If a doctor had known about Study 15, he added, "it would raise
your eyebrows." 

Letters to the editor: letters@washpost.com

WINHS Editors Note:

SEROQUEL is an antipsychotic medication purported to be a mood-stabilizing drug which is manufactured by AstraZeneca. It was approved by the FDA to treat both the "highs and lows" of bipolar disorder. Seroquel's acknowledged side effects include potential heart failure, sudden death, pneumonia in older adults with dementia-related conditions.

Drugs.com provides some additional information about Seroquel and warns; "You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old."

We bring this to you attention because AstraZeneca, one of the largest international pharmaceutical companies, is now enmeshed in significant controversy. In fact, a front page report by Shankar Vedantam in a recent Washington Post article, (full text below). about AstraZeneca's manipulation of research findings involving its antipsychotic, Seroquel (quetiapine) gets to the heart of the corrupting influence that pharmaceutical companies have on American medicine--both on its research and clinical practice guidelines--psychiatry, in particular has been compromised to its very own core.