Tuesday, March 31, 2009

U doctor scrutinized over drug research


U doctor scrutinized over drug research


Questions raised after positive review of drug conflicts with maker's

By Jeremy Olson
jolson@pioneerpress.com
Updated: 03/18/2009 11:10:15 PM CDT

A top University of Minnesota psychiatrist's ties to a drug maker have come
under scrutiny because he reported that the company's blockbuster
antipsychotic, Seroquel, was significantly superior to other drugs - despite
evidence to the contrary.

Two months after an internal analysis by the company, AstraZeneca, found
Seroquel was no better than an older, cheaper antipsychotic, Dr. S. Charles
Schulz used much of the same data to publicly report that the company's drug
was "more effective."

The disconnect between the company's private findings in March 2000 and the
psychiatrist's optimistic report to the American Psychiatric Association in
May 2000 are further evidence to critics that the drug industry can shape,
revise or even conceal negative research.

It also feeds concerns that drug companies are paying noted doctors such as
Schulz, the U's chair of psychiatry, for research results that advance their
marketing agendas.

Schulz has received $112,000 in consulting fees and university grants from
2002 through 2007 from AstraZeneca, according to state records, and nearly
$450,000 from rival drug maker Eli Lilly.

"I hope that our findings help physicians better understand the dramatic
benefits of newer medications like SEROQUEL," Schulz said in an AstraZeneca
news release on his 2000 report, "because, if they do, we may be able to
help ensure patients receive these medications first."

Fresh questions have surfaced about Schulz's old research because his name
came up in documents AstraZeneca released late last month to attorneys who
have sued the company. The release included the startling AstraZeneca
analysis and e-mails about whether to forward this negative information to
Schulz for his presentation.

"The data don't look good," one executive wrote. "In fact, I don't think we
can even get a paper out of this."

An Internet psychiatry blog first raised questions March 2 about the
research Schulz presented at the APA conference and why it lacked any of the
company's findings.

"It raises troubling questions when an independent academic author presents
results that are in direct opposition to the underlying data," wrote the
blogger, an anonymous academic.

In an interview with the Pioneer Press last week, Schulz defended his
research and presentation of Seroquel as accurate and ethical. However, he
acknowledged the corporate press release from his APA presentation might
have exaggerated in calling Seroquel "significantly superior."  "You know,"
he said, "I can't disagree with that."

Sales of Seroquel rocketed over the past decade, turning it from a
second-choice antipsychotic to a first-choice drug with one of the highest
market shares in its class. But enthusiasm for Seroquel has ebbed after U.S.
Food and Drug Administration required the makers of second-generation
antipsychotics in 2003 to include warnings about the increased risk of
diabetes.

A national comparative study also reported in 2005 that four newer
antipsychotics, including Seroquel, were no better than Trilafon, an older
drug.

CONFLICTING FINDINGS

The outlook was different in 2000, when Seroquel was new and psychiatrists
hoped it could match the effectiveness of Haldol but cause fewer side
effects. While Haldol's arrival in the 1950s helped revolutionize the
treatment of schizophrenia, the drug also caused a high rate of dystonia and
other disfiguring movement disorders.

AstraZeneca asked Schulz to conduct a "meta-analysis," a review of four
existing studies that compared the effectiveness of Seroquel with Haldol and
placebo pills. His initial look created optimism - showing in three of the
four trials that more patients responded favorably to treatment with
Seroquel than Haldol.

The results compelled AstraZeneca to look deeper into the data for more
positives. What they got were negatives. On a rating scale, patients in
these same four studies showed a greater reduction in behavioral symptoms
when taking Haldol instead of Seroquel, according to the analysis.

Company officials were caught off guard, according to copies of their
e-mails.

"My guess is that we all (including Schulz) saw the good stuff, i.e. the
meta analyses of responder rates that showed we were superior to placebo and
haloperidol and then thought that further analyses would be supportive and
that a paper was in order," e-mailed John Tumas, a head of AstraZeneca's
publications team, at the time.

Schulz in an interview said his APA study included the initial "response
rate" analysis, and not the additional findings from the company. He later
published a paper in 2003 that was similar to the AstraZeneca analysis,
measuring changes in patient behaviors and finding that Seroquel was "at
least as good as" Haldol.

However, even this 2003 study has drawn skepticism.

Schulz used data from five clinical trials to produce the paper, including
the four already used in the AstraZeneca analysis. Despite the similar
sources of data, the results in these two reports are notably different.

The AstraZeneca document found that Haldol, on average, improved patient
scores on the behavioral rating scale by 3.31 more points than Seroquel. In
Schulz's paper, Haldol was only 0.12 points better. Likewise, AstraZeneca
found that Haldol was slightly better at reducing depression and anxiety,
but Schulz reported that Seroquel was slightly better.

"These two things, they don't go together," said Glen Spielmans, an
assistant professor of psychology at Metropolitan State University, who has
reviewed the documents. "Either the (company) analysis was wrong or Schulz's
presentation was wrong."

The added fifth study showed little difference between Haldol and Seroquel
overall, and certainly couldn't account for the three-point difference
between Schulz's report and AstraZeneca's conclusions.

"Somehow, three points vanish," Spielmans said. "It's not just the spin. The
numbers are different, too."

Schulz said it probably wasn't just the fifth study but updates to the other
four studies that made the difference. He said he can "understand the
suspicions" of his work, but in the end his 2003 report only said that
Seroquel and Haldol were equivalent. Other well-accepted studies at the time
had reached the same conclusion.

The strategies in this instance seem textbook for pharmaceutical company
research, said Dr. Erick Turner, an Oregon researcher who previously
reviewed psychotic drugs for the FDA.

His study last year in the New England Journal of Medicine found that
positive drug studies are almost always published, whereas negative studies
are either not published, distorted to emphasis any positives, or combined
with positive studies to dilute their impact.

Meta-analysis reports can also be distorted, he said, by mixing a few
negative studies with more positive ones to forecast a desired outcome.

"They just blanket the universe with these glowing reports," he said, "and
the negative stuff is in there a little bit."

CHANGING PRACTICES

Schulz's research is not a central focus of the lawsuits against
AstraZeneca, which accuse the London-based company of withholding
information about Seroquel's elevated risk of diabetes and obesity.
Attorneys for patients who suffered these side effects are trying to prove a
pattern of cover-ups by the company, though.

Schulz said he was never asked by AstraZeneca to sell or spin his results,
nor has he ever agreed to withhold negative research. Case in point: Schulz
published an industry-funded study in 2008 that found that another
antipsychotic, Zyprexa, was no better than a placebo pill in treating
borderline personality disorder.

Schulz said he has cut back his role with drug companies - mostly forgoing
paid lectures to clinics - because of the perception of bias. University of
Minnesota leaders are also considering tighter rules about how and when
industry money can be accepted.

"As these issues have begun to unfold, I decided I didn't want to do
anything that would hurt my institution," he said. "I've curtailed
activities for that reason."

Schulz does have ongoing research projects funded by industry. An Eli Lilly
grant allowed him to examine the potential of medical imaging to analyze
brain activity in mental disorders and to then select the best treatment.

A U spokesman said that the dean of the medical school, Dr. Deborah Powell,
is aware of the controversy over Schulz's research and has offered him her
full support.

Dr. Carl Elliot, a U bioethics professor, said the conflicting AstraZeneca
studies are suspicious, but it's difficult to know if Schulz is at fault.

"Was Schulz fooled?" Elliott asked. "Or was he complicit?"

Jeremy Olson can be reached at 651-228-5583.

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