The evidence uncovered by litigation against AstraZeneca underscores the disconnect between the company's internal acknowledgement that the data analysis for its antipsychotic drug, Seroquel, was clearly negative (in March 2000) and the optimistic report by the chairman of psychiatry at the University of Minnesota, Charles Schulz MD who to the American Psychiatric Association (in May 2000)
The disconnect provides further evidence of how the prescription drug industry can shape, revise or even conceal negative research findings that affect the way doctors prescribe.
By early 2000, Seroquel had been on the market for three years. Psychiatrist Charles Schulz MD–who received hundreds of thousands of dollars as a paid consultant to AstraZeneca and Eli Lilly–presented a report at the APA meeting that he said was based on his analysis of 1,800 patients in four separate trials. His conclusion: patients on Seroquel were more likely to show marked improvement…that Seroquel was significantly superior to other drugs.
However, the company's analysis of the data contradicted his pronouncements. Minnesota press reports describe internal emails by AstraZeneca officials, such as John Tumas, warning on March 23, 2000, after an internal company analysis of the raw data that:
"The data don't look good…What seems to be the case is that we were highlighting the only good stuff… It is clear that a claim of superiority for Seroquel over Haloperidol (Haldol) could not be generated using these data…In fact, I don't think we can even get a paper out of this."
Nevertheless, when Dr. Schulz presented his report, AstraZeneca issued a news release headlined "An analysis suggests Seroquel (R) has greater efficacy than Haloperidol." It quoted Schulz saying: "I hope that our findings help physicians better understand the dramatic benefits of newer medications like Seroquel.''
Glen Spielmans, an assistant professor of psychology at Metropolitan State University, who has reviewed the documents smelled something fishy: "These two things, they don't go together. Either the (company) analysis was wrong or Schulz's presentation was wrong."
Question is: "Was Schulz fooled?" or, "Was he complicit?"
An anonymous academic Internet psychiatry blogger [who maintains his anonymity to protect him / her from retaliation] was first to raise questions about the research Schulz presented at the APA conference, asking 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."
Dr. Schulz went on to publish favorable reports about Seroquel (2003) using 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.
Schulz S.C.1; Thomson R.; Brecher M. The efficacy of quetiapine vs. haloperidol and placebo: a meta-analytic study of efficacy schizophrenia Research, Volume 62, Issue 2, Page 1
The documents brought to light Dr. Schulz's significant financial ties to AstraZeneca–raising more than a little doubt about the integrity of the process however the AstraZeneca would not reveal the amount it has paid Schulz in consulting and research fees, saying the information is proprietary. But the TwinCities newspaper reports that
"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."
"Is it any wonder that psychiatric research, and by implication psychiatric practice, is losing credibility due to the economic influence of big pharmaceutical companies," wrote Brent Robbins, a psychologist at Point Park University in Pittsburgh, on a blog site of the Society for Humanistic Psychology.
Robbins said he had contacted the Medical School to look into the matter.
"How can we trust science when the people who are conducting the science are only publishing or presenting on findings that favor the economic well-being of the company for which they are hired?''
But a spokesman for the University 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.
The basis for FDA's approval of Seroquel XR (extended release) in May 2007 was Study 132, which is also the basis for FDA's upcoming advisory hearing about expanding Seroquel XR approval for depression and anxiety. The favorable findings of Study 132–conducted off-shore in Bulgaria, Greece, India, Philippines, Romania, Russia, and South Africa.
Study 132 findings were presented by Dr. Charles Schulz in two favorable poster reports at the annual APA meeting (in 2007):
1. C Schulz, R Kahn, V Palazov, E Reyes, D Meulien, M Brecher, O Svensson, HM Andersson. "Efficacy of Once-Daily Extended Release Quetiapine Fumarate in Patients with Acute Schizophrenia." Annual Meeting of the American Psychiatric Association, 2007, San Diego, CA, research poster board NR04.
2. C Schulz, R Kahn, V Palazov, E Reyes, D Meulien, M Brecher, O Svensson, HM Andersson. "Efficacy of Once-Daily Extended Release Quetiapine Fumarate across Symptom Domains in Schizophrenia." Annual Meeting of the American Psychiatric Association, 2007, San Diego, CA, research poster board NR495.
The published report: Kahn RS, Schulz SC, Palazov VD, Reyes EB, Brecher M, Svensson O, Andersson HM, Meulien D; Study 132 Investigators. Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007 Jun;68(6):832-42.
Dr. Schulz' promotional statements are quoted by PRN Newswire :
"Clinical trial data demonstrate that SEROQUEL XR is a safe and effective treatment option for schizophrenia," said Dr. Charles Schulz, MD, Professor and Head, Department of Psychiatry, University of Minnesota Medical School. "For many patients with schizophrenia, SEROQUEL XR may offer a viable once- daily treatment while decreasing the number of tablets needed to be taken each day."
For witty spot-on darts aimed at the drug industry's paid militia in academia, see: Margaret Soltan's blog, University Diaries:
See also, Star Tribune. Once-secret drug-company records put U on the spot By MAURA LERNER and JANET MOORE March 18, 2009
This is not the end of the story–stay tuned
U doctor scrutinized over drug research
Questions raised after positive review of drug conflicts with maker's
By Jeremy Olson
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.
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."
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.