Healthy Skepticism Library item: 14072

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Publication type: news

Eder A.
AstraZeneca defends drug's soaring sales
The News Journal (Delaware) 2008 Aug 3
http://www.delawareonline.com/apps/pbcs.dll/article?AID=/20080803/BUSINESS/308030008/1003

Full text:

Lawsuits claim Seroquel marketed to doctors illegally

When AstraZeneca’s schizophrenia drug Seroquel was introduced in 1997, it faced an uphill climb.

Three other so-called atypical antipsychotics had launched ahead of Seroquel, and the market for antipsychotic drugs was thought to have limited prospects. The most optimistic analysts thought sales of Seroquel would top out at about $800 million a year.

Today, Seroquel — born in a Fairfax lab, manufactured in Newark and crucial to the near-term fortunes of one of Delaware’s largest private employers — is the No. 1 antipsychotic in the United States and the eighth best-selling drug in the world, with more than $4 billion in sales last year.

The company says Seroquel’s amazing run is a result of its effectiveness across a variety of mental illnesses and better tolerability for many patients than its competitors.

“We do believe it’s critical for people with mental illness to get the treatment they need,” said Lisa Schoenberg, AstraZeneca’s vice president for specialty care.

But attorneys general in three states say Seroquel’s rise was fueled by an illegal marketing campaign designed to promote the powerful drug for unapproved uses — for children, for seniors with dementia and for sleeping disorders, to name a few.

As AstraZeneca seeks federal approval for new uses of the drug, it faces thousands of lawsuits from patients who say they are suffering from Seroquel’s potentially serious side effects.

They’re patients like Wanda Bernal of Claymont, who has taken Seroquel for two years for her sleeping disorder. Bernal said she was diagnosed six months ago with diabetes, a disease linked to antipsychotic drugs.

Yet even as she bemoans the drug’s side effects — the weight gain, the vivid dreams, the groggy feeling — Bernal reveals the reliance she has developed on Seroquel.

“I can’t stop taking it,” she said, “because if I do, I won’t be able to sleep at all.”

When atypical antipsychotics came out in the 1990s, they were touted as equally effective as the older generation of schizophrenia drugs like Haldol and Thorazine while causing fewer uncontrollable movement disorders.

The first atypical, Novartis’ Clozaril, was approved by the U.S. Food and Drug Administration in 1989 for treatment-resistant schizophrenia. But the drug caused a potentially fatal disorder called agranulocytosis in about 1 percent of patients, limiting its use.

Janssen Pharmaceutica, a subsidiary of health care giant Johnson & Johnson, received FDA approval in 1993 for Risperdal, an atypical that did not carry the risk of agranulocytosis, although it did have the same potential side effects as most drugs in the class — most notably weight gain, higher cholesterol and an increase in blood sugar levels.

Eli Lilly & Co. followed Risperdal in 1996 with Zyprexa, now the top-selling antipsychotic drug worldwide.

Quetiapine, the generic name for Seroquel, emerged from the Fairfax laboratory of the British firm ICI, which spun off its pharmaceutical and biosciences division Zeneca Group in 1993. Zeneca launched Seroquel commercially in 1997.

AstraZeneca was formed two years later with the merger of Zeneca and the Swedish company Astra. The new company chose to locate its U.S. headquarters in Fairfax. Today it employs about 4,500 in Delaware.

Seroquel, AstraZeneca’s No. 2 drug, is a vital piece of the company’s portfolio as sales of its top seller, heartburn treatment Nexium, decline because of cheaper generic competition.

Steadily growing sales
Sales of Seroquel have grown every year it has been on the market. From 2004 to 2007, sales nearly doubled to more than $4 billion. AstraZeneca said Thursday that second-quarter sales of Seroquel rose 15 percent.

“There’s something very unique about this compound that has been proven through clinical studies to work across a wide range of mental illnesses,” Schoenberg said.

Today, atypicals account for about 19 of every 20 prescriptions written for antipsychotic drugs in the U.S., according to data from health care research firm IMS Health. Their popularity has helped make antipsychotics the third best-selling class of drugs in the country.

Yet some psychiatrists question whether the cost of atypicals is balanced by the benefit they provide over the older class of antipsychotics. In 2005, the federally funded Clinical Antipsychotic Trials of Intervention Effectiveness, or CATIE, compared four atypicals with an older antipsychotic drug, perphenazine.

The 18-month study, conducted on more than 1,400 participants with schizophrenia, found that the atypicals were no more effective than the older, cheaper drug. A 60-day supply of the recommended dosage of Seroquel costs $605.88 on Drugstore.com; a 60-day supply of perphenazine costs $24.99.

The CATIE trials also found that nearly 75 percent of patients switched medications before the end of the trials, either because the drugs were ineffective or patients couldn’t tolerate them.

Only 18 percent of patients on Seroquel stayed on the drug for the full course of the trial, the worst rate among the five drugs. Zyprexa performed better than the other drugs, but caused the greatest amount of weight gain and metabolic changes.

For AstraZeneca, the CATIE results showed the need for choice in antipsychotic therapies and “demonstrated very clearly that no one agent is perfect,” said Mark Scott, executive director of development for Seroquel.

Robert Rosenheck, a psychiatry professor at Yale and a co-investigator in the CATIE trials, said he’s seen no attitude change among psychiatrists toward the atypicals, in spite of CATIE and other studies that show similar results. Doctors, he said, have been swayed by drug company marketing programs and industry-sponsored research.

“You had 10 to 15 years of marketing in which the companies controlled the journal publications, controlled the speakers bureaus, controlled the dinners, controlled the patient advocacy groups, all of which communicated these drugs were a breakthrough,” Rosenheck said. “But there was little independent research.”

As a result of the demographics of psychiatric patients, about 80 percent of antipsychotic prescriptions in the U.S. are paid for by government programs, according to the National Institute of Mental Health.

It’s against this backdrop that three states — Pennsylvania, Montana and Arkansas — have sued AstraZeneca over Seroquel.

The Pennsylvania suit, which also targets Eli Lilly and Janssen, details the drug makers’ alleged strategy of peddling their medications for unapproved uses while downplaying or concealing the risks of the drugs.

The suit alleges, among other things, that the drug makers manipulated their clinical trials to avoid detection of diabetes and movement disorders; paid doctors to write or attach their names to ghostwritten journal articles about non-FDA approved uses; set up separate sales operations to target medical centers for children and the elderly; and defrauded Medicaid and a state-supported prescription program for seniors through their actions.

“From the outset, Defendants recognized the need to promote nonmedically accepted indications and nonmedically necessary uses as the key to blockbuster success for their respective antipsychotic drugs,” the lawsuit reads.

The allegations are echoed in other lawsuits brought by third-party payers against AstraZeneca.

“AstraZeneca strenuously denies the allegations in these lawsuits, most of which have been brought by private personal injury lawyers, and will defend itself in these lawsuits,” the company said in a statement.

Off-label marketing prohibited
Although doctors may prescribe medicines as they see fit, drug companies are forbidden to promote their drugs for non-FDA approved uses — so-called off-label marketing — under the federal Food, Drug, and Cosmetic Act.

But there are loopholes: Drug company representatives may provide information to doctors on off-label uses if asked, and doctors may freely discuss off-label uses with other doctors at continuing medical education events, which are often sponsored by drug makers.

In addition, a recent report by the Government Accountability Office found that when the FDA finds a drug company promoting an off-label use, it takes the agency an average of seven months to issue a warning, followed by four more months for the company to fix the problem.

One example of off-label prescribing is the use of antipsychotic drugs in children, a rising trend prompted by the recommendation of a few influential child psychiatrists who receive funding from the makers of atypicals.

Congressional investigators recently found that Joseph Biederman, a child psychiatrist at Harvard Medical School, earned at least $1.6 million in consulting fees from drug makers from 2000 to 2007. Biederman’s work has contributed to an increase in the diagnosis of pediatric bipolar disorder, along with a rise in the use of antipsychotics in children.

Biederman is the principal investigator in a study currently recruiting participants to test Seroquel in children age 4 to 6 with bipolar disorder.

According to Medco Health Solutions, a pharmacy benefit manager, the use of antipsychotics in girls age 10 to 19 has more than doubled since 2001; in boys of the same age, antipsychotic use has risen more than 70 percent.

AstraZeneca said its policy is to promote its products only for FDA-approved uses.

“FDA and the courts have recognized that off-label prescribing by doctors is not only lawful but may be essential to giving patients optimal medical care,” the company said. “The decision to treat a patient using a medicine outside the scope of the labeling is a medical judgment made by the physician.”

A number of states, including Delaware, are conducting inquiries into Seroquel.

“We can acknowledge that we are part of a multistate investigation of the drug,” said Delaware Department of Justice spokesman Jason Miller, who would not provide any details.

In addition to the state lawsuits, AstraZeneca is facing more than 8,500 personal-injury lawsuits from Seroquel patients who say they developed diabetes or related injuries from the drug. The lawsuits include 680 cases in Delaware Superior Court.

Plaintiffs’ attorneys say they believe the evidence at trial will prove that AstraZeneca hid the risks that Seroquel could cause high blood sugar levels, weight gain and diabetes. The drug maker, along with the other manufacturers of the atypicals, added a warning about the risk of hyperglycemia, or high blood sugar, and diabetes to Seroquel’s label in 2004 at the FDA’s urging — almost seven years after it was approved.

AstraZeneca said most of the personal-injury cases contain little or no information about the plaintiffs’ alleged injuries.

“AstraZeneca intends to litigate these cases on the merits and will defend the cases vigorously,” the company said.

According to AstraZeneca’s own data on the Seroquel label, patients on the drug saw higher cholesterol, triglycerides and weight levels than patients taking a placebo in clinical trials.

In two long-term clinical trials, AstraZeneca said 10.7 percent of patients on Seroquel tested positive for blood sugar levels that indicate diabetes, compared to 4.6 percent of patients on a placebo.

AstraZeneca says the relationship between atypicals and diabetes is complicated by a possible increased risk of diabetes in schizophrenics and the growing incidence of diabetes in the general population.

Other companies sued
The legal issues surrounding Seroquel are by no means unique to AstraZeneca. Last year, Bristol-Myers Squibb agreed to pay more than $515 million to settle federal claims over the company’s marketing practices, including allegations that it was promoting its atypical, Abilify, for use in children and seniors with dementia.

Eli Lilly has paid at least $1.2 billion to settle similar product liability claims with more than 31,000 people over Zyprexa, which has been targeted with the most litigation of any of the atypicals. In a scathing statement issued last month in a consolidated federal case, U.S. District Judge Jack Weinstein suggested that few parties are blameless in the Lilly litigation.

Because of its alleged failure to disclose side effects and its encouragement of off-label use, Weinstein said Lilly could be found liable under the Racketeer Influenced and Corrupt Organizations Act, a law originally designed to target organized crime.

But many of the third-party payers suing Lilly for overcharging for Zyprexa continue to pay for the drug, Weinstein noted. He said the states that sued Lilly have already received substantial payments in the form of liens or hold-backs from personal injury settlements of those covered by Medicaid.

As for the federal government, Weinstein said the FDA has arguably failed consumers and physicians by relying on drug companies for research, yielding to industry pressure on drug labels, failing to curb off-label marketing and not requiring doctors to be adequately informed.

“A large part of the legal problems attributed to Zyprexa, if they exist, are arguably due to the failure of the responsible federal agencies to prevent abuse,” Weinstein wrote.

There’s no question that Seroquel has been a vital treatment for many mentally ill patients. Liz Spikol, a senior contributing editor at Philadelphia Weekly, has taken Seroquel for about 10 years as part of a treatment regimen for bipolar disorder. She said she has seen few side effects from the drug.

“Because of my particular experience with my illness, it was absolutely a miracle drug, and I’ve been on it ever since,” Spikol said. “It’s been basically the cornerstone of my treatment.”

Yet Spikol, who writes the mental illness blog The Trouble With Spikol, said her experience is not typical of bipolar patients, since her illness includes psychotic features.

Some see weight gain
Other patients report a rougher experience with the drug. Bernal, the Claymont woman who takes Seroquel as a sleeping aid, an off-label use, said the drug gives her strong cravings for food and sometimes knocks her out for days at a time. Her weight, she said, has ballooned.

“I’ve never been this big, and I’ve had four kids,” said Bernal, who has not decided whether to pursue legal action.

Bernal’s situation illustrates how off-label prescriptions of atypicals have expanded their use beyond just schizophrenics and bipolar patients. Insomnia has been an especially popular use for Seroquel, said Daniel Carlat, a Massachusetts psychiatrist who publishes a medical-education newsletter.

Seroquel is thought to promote sleep by blocking transmission of histamines in the brain. Carlat, a critic of the drug industry’s role in continuing education for doctors, said he thought the use of Seroquel for insomnia arose naturally, as psychiatrists discovered that a low dose of the drug could help patients sleep.

“That particular use of it, I don’t think was marketed heavily as an off-label indication by the company,” Carlat said.

AstraZeneca is seeking FDA approval for Seroquel XR, its extended-release version of the drug, for the treatment of anxiety and depression. It would be the first atypical approved to treat those conditions, a prospect that baffles some patients who have taken the drug.

Philip Dawdy, a Seattle journalist who has chronicled the issues surrounding the atypicals on the blog Furious Seasons, said it would “open a floodgate of problems” if AstraZeneca is allowed to market Seroquel for depression.

Dawdy, who was diagnosed with bipolar disorder in 1989, said he took Seroquel for a little more than a year for agitation and sleep problems, but he quit taking it when he developed symptoms of tardive dyskinesia, an involuntary movement disorder that is a potential side effect of antipsychotic drugs.

Although Dawdy said Seroquel is appropriate for some patients, he thinks the drug has been prescribed too widely with too little information about what it does to patients over time.

“Docs have got to be judicious in using this, and really look at how it works in the long term,” Dawdy said.

Contact Andrew Eder at 324-2789 or aeder@delawareonline.com.