Study 15

From the Washington Post:

A Silenced Drug Study Creates An Uproar

By Shankar Vedantam
Washington Post Staff Writer
Wednesday, March 18, 2009; A01

 

The study would come to be called “cursed,” but it started out just 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 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.”

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