Seroquel, Sex And Major Conflicts Of Interest Between AstraZeneca Exec And British Researcher, US Ghostwriter

There's been much news of conflict of interest between pharmaceutical companies and outside researchers possibly biasing the results of studies of psychiatric drugs over the last year. Notably, Sen. Charles Grassley (R-Iowa) has exposed researchers at Harvard University, Emory University and George Washington University, among others, as being locked in questionable alliances with companies such as Johnson & Johnson and GlaxoSmithKline. The researchers get hundreds of thousands of dollars and, then, perform research favorable to a company's drugs and often tout those drugs before their peers, claiming their research is independent of bias. The entire affair, along with revelations about how continuing medical education programs are funded, has given psychiatry a serious image problem and led to calls by everyone from the New York Times to this website to clean up the research system in America.

Now, a new tale of conflict of interest has cropped up, one involving a senior medical official at AstraZeneca responsible for the drug Seroquel who had sexual relationships with a British researcher, who studied the drug and wrote positively of it, and with an American medical ghostwriter, who among other things assisted in writing two published academic papers known as BOLDER I and BOLDER II, in the American Journal of Psychiatry in 2005 and the Journal of Clinical Psychopharmacology in 2006 that were at the heart of Seroquel's 2006 approval by the FDA for bipolar depression. According to court records, there is evidence Macfadden gave one of the women prescription painkillers and exchanged emails with them showing relationship of "control and dependence."

Simply put, I've never seen anything quite like these conflicts in my years of working the mental health beat.

"Anything like this clearly makes the data suspect if not dubious," says David Egilman, a Brown University professor and expert witness in one of the Zyprexa class action lawsuits (he was the initial leaker of the Zyprexa documents) and an expert on clinical trials and conflict of interest. "What are the journals, the FDA and the medical boards going to do when it becomes public?"

There are obviously all kinds of questions about conflict of interest in these relationships. Those questions, in my opinion, extend to the integrity of data, statistical methodology, study findings, publications, medical communications and drug approval applications tied to the BOLDER studies, as well as to many recent AstraZeneca-funded studies of Seroquel use in bipolar depression, as well as to several publications on schizophrenia and Seroquel.

The FDA did not respond to repeated requests for comment. I specifically pressed the FDA on the conflicts of interest, whether the agency had any regulations on these sorts of pharma exec/researcher relationships, and if the agency would launch a review of Seroquel's bipolar depression indication. The agency didn't even care enough to issue a "no comment," opting for silence instead.

Robert Freedman, editor the American Journal of Psychiatry, did not respond to a request for comment. The American Psychiatric Association, which publishes the AJP, did not respond to a request for comment. Richard Shader and David Greenblatt, editors of the Journal of Clinical Psychopharmacology, did not respond to a request for comment. I asked both journals' officials about how they would address the conflicts of interest and if they would review the published articles. But in an email from Greenblatt, which I was perhaps mistakenly copied on, Greenblatt wrote, "I suggest we say nothing further to this guy." All that anyone from the journal had written me was a brief email saying they get back to me if they had any comment.

I was unable to locate Macfadden for an interview.

"Any normal person hearing this story would question the validity of the data and would want it checked out independently," says Egilman. "The FDA should be in the catgeroy of normal people. But it wouldn't shock me if they don't do anything."

To its credit, AstraZeneca did respond to several questions.

"AstraZeneca had no knowledge of these relationships at the time," says Laura Woodin, an AstraZeneca spokeswoman in an email. Macfadden's relationships with the women ran from 2002 to 2006, according to court records. "Dr. MacFadden is no longer employed with the Company." Woodin added, "AstraZeneca has audited and stands behind the integrity of its Seroquel trial data."

Macfadden left AstraZeneca in 2006.

I'm not naming the women involved in this matter. They are not named in publicly-available court documents and there is argumentation in the court record that the relationships may have been ones of dependence for them.

A FLORIDA COURT FILING

Details for this story became available to me last week from a recent filing in open court, made available to me by a Florida reader of this site. The filing is from a federal court case in Orlando, Fla. involving accusations that AstraZeneca did not provide appropriate warnings about Seroquel and its tendency to induce diabetes in some patients. In the midst of pretrial motions in the case, attorneys for AstraZeneca filed a motion asking the court to exclude evidence of the personal and sexual relationships of Wayne Macfadden, a psychiatrist licensed in New Jersey, arguing they weren't relevant to the case. From 2001 to 2006, Macfadden was the US medical director for Seroquel and director of clinical research for central nervous system efforts by AstraZeneca. In a deposition in the case in 2008, given under oath, Macfadden admitted to a lengthy sexual relationship with a researcher at the Institute of Psychiatry, King's College in London, England and with a ghostwriter who worked at Parexel MMS (Medical Marketing Services) in the USs, according to court records. Neither woman is named in court papers, due to the obviously sensitive nature of their dealings with Macfadden. Both women were intimately tied to publications favorable to Seroquel and AstraZeneca, according to court records.

Officials at the Institute of Psychiatry did not respond to a request for comment. Parexel MMS did not respond to a request for comment.

Plaintiffs' attorneys filed their own motion last month, arguing that Macfadden's relationships with the women were "relevant and highly probative evidence of one high level AstraZeneca employee's determination to exploit his sexual relationships with these women in order to elevate Seroquel's status in the prescribing medical community through supposedly 'independent' publications of Seroquel safety and efficacy data," according to the plaintiffs' filing. "Moreover, the mere existence of these relationships calls into question the integrity of the scientific work product of those involved." You can read the plaintiffs' motion here (5 MB pdf).

THE BRITISH AFFAIR

The quality of the plaintiffs' filing that ought to make things easy for the federal court judge to rule upon are that most of the factual statements in the filing come directly from Macfadden's own deposition in the case. A hearing expected to be held in the case on Feb. 26. In addition to arguments on the AstraZeneca and plaintiffs' competing motions on Macfadden, the judge is also expected to take up AstraZeneca's earlier motion to have numerous other documents in the case sealed from public view and the Bloomberg wire service's counter-motion, fighting the proposed seal.

According to the plaintiffs' filing, Macfadden was responsible for a host of Seroquel-related activities at AstraZeneca during his five-year tenure. Macfadden planned Seroquel's clinical trials. He was involved in "ongoing diabetes discussions" at AstraZeneca. He advised the company on decision-making regarding the monitoring of glucose in clinical trials. He was "actively involved" in the marketing and promotion of the drug and sat on multiple marketing teams, including the so-called bipolar execution and strategy team (BEST). Macfadden was also a liaison to "key opinion leaders," researchers who promoted Seroquel to the medical community.

Also worth noting is that "In an effort to expand Seroquel prescribing beyond the field of psychiatry, Macfadden was consulted on the decision to market Seroquel to primary care physicians who treated patients with dementia," according to the plaintiffs' filing.

Sometime in 2002, according to the plaintiffs' filing, Macfadden "became involved in a sexual relationship with an IOP researcher who, as well as being involved in other Seroquel-related projects, participated in the clinical research and abstract preparation relating to the effectiveness of Seroquel for use in the treatment of schizophrenia."

There were also emails and other correspondence between the two as well as between Macfadden and the Parexel ghostwriter. The emails are currently under court seal, but details are alluded to in the filing.

"The IOP researcher suggested that Macfadden would 'punish' her if she even looked at studies that were favorable to Seroquel's competitors," reads the filing, referring to exchanges between Macfadden and the British researcher. "He actively encouraged her to conduct research the results of which would be favorable to Seroquel and AstraZeneca, and promised sexual favors in exchange for intelligence on Astrazeneca's competitiors."

According to the filing, during the time she was involved with Macfadden, the IOP researcher published several papers attesting to the effectiveness of Seroquel and of atypical antipsychotics in general. Her research was presented at unnamed conferences and was sent to American physicians in response to what are known as "physician information requests."

The British researcher mostly focused on schizophrenia, but it appears she may have written about Seroquel's use in other disorders.

THE AMERICAN GHOSTWRITER

As for the American ghostwriter, she worked for Parexel MMS where she was responsible for the Seroquel global publications business, "including the publication of BOLDER I and BOLDER II on which Macfadden was listed as an author," reads the plaintiffs' filing. She is openly credited on both studies as well as on other studies advancing Seroquel as a treatment for bipolar depression. What's more, she was responsible for posters and abstracts presented at medical conferences and medical association meetings, according to the filing.

Sometime in 2004, Macfadden and this woman became involved in a sexual relationship, according to the filing, at the same time that Macfadden was still involved with the British researcher. "In addition to his sexual involvement with the Parexel program manager, it appears he [Macfadden] also provided her with prescription painkillers."

Macfadden is a licensed physician in New Jersey.

Remember, it's the BOLDER I and II studies that were the basis of Seroquel's approval for bipolar depression. AstraZeneca says its hands are clean in regards to the two studies.

"We are not aware of a relationship any AstraZeneca clinical trial employee had with anyone outside AstraZeneca who was involved in the collection or analysis of any clinical data for the BOLDER studies," says AstraZeneca's Woodin in an email.

"CONTROL AND DEPENDENCE"

"The nature of their communications suggest a level of control and dependence between Macfadden and these women," reads the plaintiff's filing in part. "There is no doubt that Macfadden's relationships were never disclosed to the FDA or the medical community, though Macfadden agreed that sexual relationships between clinical researchers and management members of pharmaceutical companies can create bias which can affect the integrity of the science. Macfadden also acknowledged that sexual relationships can affect a person's judgment. Although Macfadden denies that his multiple sexual relationships with these women created a conflict of interest, he in fact teased the IOP researcher about the obvious conflict of interest as he reviewed drafts of her papers on Seroquel."

"Every time we think we've hit bottom [regarding the behavior of Big Pharma employees], we haven't," says Vera Sharav of the Alliance for Human Research Protection and a longtime critic of Big Pharma's alliance with academic psychiatry. "What is off-limits when it comes to the promotion of psychiatric drugs?"

In an email, AstraZeneca notes that its personnel work in teams, partly as a way to catch various oversights. Macfadden may have elevated the teamwork concept at AstraZeneca to new levels.

A footnote on page 10 of the plaintiffs' filing notes, "Macfadden has admitted to additional sexual affairs with a clinical researcher assistant at AstraZeneca and a clinical researcher in California also involved in the Seroquel clinical trials."

It is not clear what published studies, if any, these additional two women may have been involved in.

Two cases in the Florida federal court lawsuit were tossed out by a judge last month, but could be reinstated upon appeal. A plaintiffs' attorney did not respond to a request for comment.

Posted by Philip Dawdy at February 25, 2009 12:01 AM
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