selling seroquel V: driving the brand…

Posted on Saturday 26 February 2011

In an earlier series [seroquel IX: weighty matters…], we looked at how the weight gain data was handled before Seroquel was approved by the F.D.A. – mainly minimized and explained away [seroquel X: matters cerebral Serebral…]. Dr Lisa Arvanitis, Director of the Seroquel effort summed things up about weight gain in an email a month before Seroquel was approved:
The magnitude of weight gain at 52 weeks [regardless of the pool or cohort] is about 5 Kg which is more that the short-term six week weight gain… The proportion of patients with clinically significant weight gain at 52 weeks [regardless of the pool or cohort] is about 45% and this is more than the % at 6 weeks… Therefore I’m not sure there is yet any competitive opportunity no matter how weak…
She was responding to an email in which they were looking at the possibility of using weight neutral as plus in their advertising. They continued using the weight neutral idea until 2000 when cracks began to appear, though they were still trying – actually publishing a weight neutral study [selling seroquel II: into the fray…]. I can’t find any early references to their being worried about Diabetes. When the F.D.A. first inquired about Diabetes in 2000, AstraZeneca  responded promptly – no evidence of Diabetes.

It looks as if from 2000 until 2004, the people at AstraZeneca spent much of their their time trying to refute the growing truth of weight gain and Diabetes with Seroquel. They were worried about the coming of a new Atypical Antipsychotic – Zeldox [Geodon] and Pfizer’s ability to win the weight neutral wars. By 2001, they had settled on weight neutral in the long term. The reports of Diabetes continued and made it to the WSJ and NYT by 2003.
3 Schizophrenia Drugs May Raise Diabetes Risk, Study Says
New York Times

August 25, 2003

Three drugs commonly prescribed for schizophrenia and other psychotic illnesses increased patients’ risk of developing diabetes when compared with older antipsychotic medications, researchers said yesterday, presenting the results from a long-awaited study of patients treated at veterans hospitals and clinics across the country.

The drugs — Zyprexa, made by Eli Lilly, Risperdal, made by Jannsen Pharmaceutica, and Seroquel, made by AstraZeneca — were associated with higher rates of diabetes than older generation drugs for schizophrenia like Haldol, the study found. But the increased risk was statistically significant only for Zyprexa and Risperdal, the researchers said, possibly because of the smaller number of subjects who took Seroquel…
AstraZeneca was still saying that, “There remains no reliable evidence suggesting a causal relationship between Seroquel and diabetes,” but they were privately checking among themselves to see if that was still the "party line." As late as 2004, a sales brochure read:
    SEROQUEL® and Diabetes: What We Know
      • In clinical trials, SEROQUEL has shown no difference in mean change of random glucose measurements compared to either placebo or other antipsychotics.
      • In patients taking SEROQUEL, post-marketing reports of diabetes or diabetes-related events are very rare [<0.01%]. These reports were confounded by pre-existing or co-existing risk factors and/or had limited information.
      • The results of retrospective epidemiology studies of SEROQUEL and diabetes have been inconsistent and inconclusive.
      • Many patients with psychiatric illness have other characteristics that may contribute to metabolic abnormalities.

      Factor Schizophrenia % Bipolar Disorder % General Population %

      Smoking 73 35-55 25
      Obesity 18 30 33
      Diabetes 13 26 7.0
Meanwhile, the evidence mounted. When the data from this article was presented at the 2003 APA:
A survey of reports of quetiapine-associated hyperglycemia and diabetes mellitus
J Clin Psychiatry
. 2004 Jun;65(6):857-63.
by Koller EA, Weber J, Doraiswamy PM, Schneider BS
Division of Metabolic and Endocrine Drug Products
Center for Drug Evaluation and Review
US Food and Drug Administration, Rockville, MD, USA.

OBJECTIVE: To explore the clinical characteristics of hyperglycemia in patients treated with quetiapine.
METHOD: A pharmacovigilance survey of spontaneously reported adverse events in quetiapine-treated patients was conducted using reports from the U.S. Food and Drug Administration MedWatch program (January 1, 1997, through July 31, 2002) and published cases using the search terms hyperglycemia, diabetes, acidosis, ketosis, and ketoacidosis.
RESULTS: We identified 46 reports of quetiapine-associated hyperglycemia or diabetes and 9 additional reports of acidosis that occurred in the absence of hyperglycemia and were excluded from the immediate analyses. Of the reports of quetiapine-associated hyperglycemia, 34 patients had newly diagnosed hyperglycemia, 8 had exacerbation of preexisting diabetes mellitus, and 4 could not be classified. The mean +/- SD age was 35.3 +/- 16.2 years (range, 5-76 years). New-onset patients (aged 31.2 +/- 14.8 years) tended to be younger than those with preexisting diabetes (43.5 +/- 16.4 years, p = .08). The overall male:female ratio was 1.9. Most cases appeared within 6 months of quetiapine initiation. The severity of cases ranged from mild glucose intolerance to diabetic ketoacidosis or hyperosmolar coma. There were 21 cases of ketoacidosis or ketosis. There were 11 deaths.
CONCLUSION: Atypical antipsychotic use may unmask or precipitate hyperglycemia. UPDATE: An additional 23 cases were identified since August 1, 2002, the end of the first survey, by extending the search through November 30, 2003, bringing the total to 69.
The F.D.A. finally acted:
January 30, 2004
Dear Healthcare Provider,
AstraZeneca Pharmaceuticals LP would like to inform you of important labeling changes regarding SEROQUEL® [quetiapine fumarate]. The FDA has asked all manufacturers of atypical antipsychotics, including AstraZeneca, to add a Warnings statement descibing the increased risk of hyperglycemia and diabetes in patients taking these medications, including SEROQUEL. Accordingly, the SEROQUEL Prescribing Information has been updated with the addition of the following information: etc…
And by July 2004, the official labeling for Seroquel contained the following:
Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including Seroquel. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available…
Weight Gain: In schizophrenia trials the proportions of patients meeting a weight gain criterion of >7% of body weight were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significantly greater incidence of weight gain for SEROQUEL (23%) compared to placebo (6%). In mania monotherapy trials the proportions of patients meeting the same weight gain criterion were 21% compared to 7% for placebo and in mania adjunct trials the proportion of patients meeting the same weight criterion were 13% compared to 4% for placebo…
However, in October 2004, we hear this to the Seroquel Global Brand Team:
We are really on a roll.
Enjoy the standalone – those of you attending.
I know you are all working flat out – but I can tell you that SET , and everyone in AZ, really appreciates the work you are doing and the impact you are having.
Keep driving the brand……………..I never thought that I could say Seroquel is AstraZeneca’s major megabrand….Now I can….
Thanks for what you are doing.
The Team had succeeded in holding weight gain and Diabetes in check for 7 years, half the patent life of the drug [14 years] – long enough to become a megabrand [known as a blockbuster on the financial page]. They had known about the weight gain before Seroquel was approved ["smoke and mirrors"], and were fighting Diabetes claims from early on, but they kept it out of the light. So when the epidemic of patients began to sue, AstraZeneca‘s legal bills and liability costs went up.
Astra Settles Claims Related to Seroquel
Wall Street Journal

AUGUST 10, 2010

LONDON — AstraZeneca PLC said Monday it has reached a $198 million settlement over claims in the U.S. regarding its best-selling antipsychotic drug Seroquel. The U.K. pharmaceutical company has faced thousands of product-liability lawsuits alleging that the use of Seroquel caused diabetes and other injuries, and that the company failed to adequately warn of the drug’s risks.

The company has also faced long-running allegations it improperly promoted the drug, which is approved to treat schizophrenia, bipolar disorder and depression. The settlement relates to 17,500 product-liability claims, and the company said the mediation process over claims is continuing in both federal and state jurisdictions. "We remain committed to a strong defense effort, but will also continue to participate in good faith in court-ordered mediation," AstraZeneca said Monday in a statement…
AstraZeneca Said to Pay $150 Million to Settle Seroquel Suits
Bloomberg Business Week

By Jef Feeley
February 17, 2011

AstraZeneca Plc agreed to pay $150 million to settle more lawsuits claiming its antipsychotic drug Seroquel causes diabetes, pushing the amount the drugmaker has paid to resolve cases over the medicine to almost $350 million, people familiar with the accords said. AstraZeneca, the U.K.’s second-biggest drugmaker, will resolve about 6,000 cases alleging the company knew Seroquel could cause diabetes and failed to adequately warn patients, two people familiar with the settlements said. They spoke on the condition of anonymity because they weren’t authorized to speak publicly about the accords. The cases settled for an average of about $25,000, the people said.

The settlements signal AstraZeneca is seeking to put the Seroquel litigation behind it as it works to overcome setbacks in its drug-development pipeline, said Jeremy Batstone-Carr, London-based analyst for Charles Stanley & Co., who rates the drugmaker’s shares as “accumulate.” “Legal cases represent one of the great imponderables that can act on shareholder sentiment,” Batstone-Carr said. “You try to clear the decks and get investors as great a degree of certainty as possible.”

The settlement, which resulted from a court-ordered mediation, leaves AstraZeneca now facing only about 4,000 Seroquel claims, the people said. The London-based drugmaker announced last summer it had resolved about two-thirds of the 26,000 suits over the drug that had been filed in courts around the U.S…
The original claim – weight neutral – was never true and they knew it wasn’t true, something that has ended up costing AstraZeneca $868 M plus legal fees so far [$520 M FDA-Fines + $198 M + $150 M]. The standard complaint is that they are getting off cheap, just a drop in the bucket compared to their profit margin – as if higher fines would deter such corporate behavior. Others feel that these things will continue until the actual executives involved in the deception are directly convicted of criminal behavior. But for the moment, AstraZeneca‘s Seroquel stands before us as the paradigm for how to play this game and win.
    February 26, 2011 | 9:46 AM

    found this at pharmagossip blog

    “sound science” HAH! what a crock this company is unethical!

    February 26, 2011 | 12:44 PM

    Thanks Mickey – hope you had a great break.

    Funny you should use the phrase “a drop in the bucket” in your last para:

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