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AZ Seroquel Emails Detail Off-Label Promotion; What Did CEO Brennan Know?

A new batch of email and memos from the federal litigation over AstraZeneca's antipsychotic Seroquel detail company executives discussing off-label promotion, the stretching of data to make claims that Seroquel did not cause weight gain, the cover-up of a trial that showed negative results and suggestions that researchers who "slow up" the publication of positive studies should be fired.

(Download the documents for yourself here.) Previously, documents in the trial allegedly showed how AstraZeneca knew as far back as 1997 that Seroquel caused weight gain and diabetes; and that Seroquel's research director traded sex for study results with his female counterparts.

AZ responded in the WSJ:

Tony Jewell, a spokesman for AstraZeneca, denied that the company sought to encourage off-label uses of the drug. "These documents do not advocate the inappropriate promotion of Seroquel," he said. Instead, they "show the company was seeking to explore additional indications for Seroquel and included that in clinical-development plans designed to support efforts to investigate potential additional indications," he added.
Among the documents released this morning are an email from Jacquie Downes sent on March 2, 2001, communicating that year's pr strategy for Seroquel. It reads:
Seroquel 2001 PR Plan: Seroquel is widely used outside the schizophrenia indication ... 2001 communications will focus on increasing the existing off-label usage of Seroquel
Objectives of the PR Plan
To encourage and support use outside schizophrenia into a broad range of other patient populations including bipolar disorder and the elderly.
... through aggressive communication
A May 26, 2004, email from William Hess, indicates that AZ had a system for creating off-label information. He wrote:
The slides were originally budgeted and paid for by Joan Shaw (all off-label slides are financed outside of commercial for obvious reasons) and were completed to the agreed specifications.
An undated 2004 draft memo from CEO David Brennan on the subject of off-label use in children shows that Brennan had some awareness that his sales reps were promoting the drug to psychiatrists who were specialists in treating children. Brennan wrote:
... the Seroquel team has confirmed that child and adolescent psychiatrists treat a significant percentage of patients (approximately 40%) over the age of 18. Accordingly the team has determined that it continues to be appropriate to have PSSs call on these physicians, directing their efforts to the use of Seroquel in adult patients only.
The effort continued into 2005, according to a Feb 15, 2005, "Seroquel U.S. Brand Team - Project Brief":
Objectives: To provide researchers and prescribers with pharmacokinetic data on quetipine for the treatment of psychotic disorders in children and adolescents.
Other emails describe how AZ execs either ignored, hid or manipulated data they did not like. One email indicates that AZ staff were under orders "from the highest level" not to discuss certain trials where the results had been bad for Seroquel. Here's a selection of emails on how AZ handled bad data:

March 2, 2001 email from Martin Brecher:

We stretched to make the weight neutral claim ... Not compelling, but defensible.
Aug 19, 2002 email from Scott French on "Trial 41":
...the primary outcome of the Seroquel SR study ... is 'red' [meaning not significant for Seroquel's efficacy].

The results are are summarized as:

The 300 mg dose group had no separation from placebo for any efficacy endpoint.

The 600mg does group was statistically significantly better than placebo for change from baseline for total PANSS.

The 800 mg does group approached but did not meet statistical significance compared to placebo for change from baseline for total PANSS.

This information should be kept in the strictest confidence ... Please do not forward this message.

Sept. 9, 2002 email from Seroquel global brand manager Simon Hagger:
...we are under clear instruction from the highest level within AstraZeneca at this time not to discuss details surrounding trial 41 with any external customers.
August 7, 2003 email from Hagger on investigator initiated trials:
- They are able to spin the data in many different ways through an effective publications team

- negative data usually remains well hidden.

Nov. 24, 2004 Parexel meeting minutes [Parexel was an outside company AZ hired to help it prepare research publications]:
Trial 104 + 105: The team agreed that from a commercial perspective, the data must be published quickly in order to support key claims for the brand. Therefore, if the authors recommend anything that will slow up this process, AZ should consider asking them to step down from this project.
An email conversation between several AZ execs (which you can download here) also shows that some employees continued distributing certain studies even after the company itself had ordered staff not to. On Jan. 25, 2005, emails between Anders Grano, Stephanie Daniels and Jamie Mullen* show this discussion:
Anders: The study by Reinstein showing the favorable switch from clozapine to Seroqual has been very popular among Swedish psychiatrists. In fact so popular that we have run out of copies. Do you know ... if maybe there is a "secret stash" somewhere?

Daniels: ... is this the Reinstein study we're not supposed to be using any more??

Mullen: This is the study. Goes to show you that if there's a huge need for data to support a message, the data will find its way out (despite our guidance to the contrary).

UPDATE: In an email to BNET, Grano said that it has never been forbidden to supply healthcare professionals with peer reviewed published articles, particularly in Sweden where laws are among the strictest.

*This item has been corrected to reflect the fact Mullen, not Grano, wrote the final email quoted. Apologies for the error.

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