Healthy Skepticism Library item: 15563

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Publication type: news

Moore R.
Risperdal, Janssen Pharmaceutica under fire - but not in Wisconsin
The Lakeland Times 2009 May 1
http://www.lakelandtimes.com/main.asp?SectionID=9&SubSectionID=9&ArticleID=9448

Abstract:

States launch lawsuits but Wisconsin freely dispenses controversial drug

Full text:

Janssen Pharmaceutica, a Johnson & Johnson subsidiary that manufactures Risperdal, a highly controversial antipsychotic drug approved to treat schizophrenia, bipolar disorder and irritability associated with autism in children, is facing a spate of lawsuits from states who say the pharmaceutical giant fraudulently marketed what they claim is an inherently dangerous drug.

Wisconsin is not among the protesting states, however. Here, in fact, Risperdal continues to be popular among the medical establishment, sitting on the state’s list of Medicaid preferred drugs and dispensed for a broad range of both approved and nonapproved uses, The Lakeland Times has confirmed in an investigation.

To cite just one example, doctors and nursing homes in the Badger State continue to prescribe Risperdal to elderly patients with dementia, despite a four-year-old warning from the federal government that such treatment is associated with an increased risk of mortality.

Risperdal and its generic formulation is one of a group of so-called new generation atypical antipsychotic drugs – clozapine, Pfizer’s Geodon and AstraZeneca’s Seroquel are other preferred antipsychotics in Wisconsin — the makers of which say are safer and more effective than older first-generation medications.

The drugs are also far more expensive, not to mention lucrative.

In 2007, Risperdal was the world’s tenth best selling drug with $4.7 billion in sales, even though schizophrenia, bipolar disorder, and autism-related behavioral problems – the only approved treatment uses of the drug – affect less than 4 percent of the population combined, according to the National Institute of Mental Health.

Now a growing number of medical professionals and state officials, ranging from Pennsylvania to Texas to South Carolina, say Risperdal’s success is a textbook case of pharmaceutical marketing gone wild.

These officials say few of the company claims are legitimate, that Janssen in particular rigged clinical trials to attain the results it wanted and subsequently misled the medical community as well as various state officials.

What’s more, they say, not only does the drug not reduce side effects associated with older first-generation antipsychotics, it is itself associated with increased risks of Parkinson’s-like symptoms and other movement disorders known as EPS, of cardiovascular disease and of the onset of diabetes.

The drug has been linked to neuroleptic malignant syndrome, a potentially fatal condition involving muscle rigidity, and tardive dyskinesia, a disorder that induces repetitive, involuntary movements such as tongue pumping, lip smacking, and rapid blinking.

What’s more, a 2002 study found an increased risk of stroke among the elderly taking Risperdal. In two of four clinical trials, a higher incidence of stroke was seen among participants taking Risperdal than in those groups taking a placebo, with a stroke rate among those taking Risperdal double that of the placebo groups for all four trials averaged. The four studies included 1,200 subjects.

Health Canada and Janssen-Ortho subsequently warned Canadian physicians of a possible link between Risperdal and stroke in 2002. The federal Food & Drug Administration issued a warning in 2003.

The FDA also issued a black-box warning for Risperdal and other atypicals in 2005 after 15 out of 17 clinical trials showed increased morbidity among elderly patients with dementia after being treated with antipsychotics.

Children, too, have turned out to be a vulnerable population.

According to a November 2008 report in the New York Times, from 1993 through the first three months of 2008, 1,207 children given Risperdal suffered serious problems, and 31 died. The deaths included a nine-year-old with attention deficit troubles; the child had a fatal stroke 12 days after beginning Risperdal, the Times reported.

The pharmaceutical companies, of course, dismiss the claims and say any risks are well labeled.

On the other hand, in a 2005 interview with USA Today, FDA whistleblower Dr. David Graham estimated that off-label use of atypical antipsychotics could cause as many as 62,000 excess deaths a year, and he said the FDA – whose drug safety oversight board he characterized as a “kangaroo court” – had known about the problem for two or three years prior to issuing its 2005 warnings.

States seek reimbursement

Meanwhile, lawsuits, both individual and state-sponsored, continue to grind on. This past February, Janssen lost one of those cases, in West Virginia, where attorney general Darrell McGraw brought the suit under the West Virginia Consumer Protection Act, citing the company for making false or misleading statements to West Virginia physicians about Risperdal and another of its products, Duragesic, a narcotic pain patch.

The attorney general’s office found 4,450 violations. In particular, for Risperdal, judge Martin Gaughan ruled that the company sent out false and misleading warnings after the FDA had required drug makers to warn doctors that atypical antipsychotics were associated with an increased risk of diabetes.

“The wording of [the defendants’] November 2003 Risperdal letter was intentionally constructed to modify the FDA’s warning language and mislead healthcare professionals, who rely on this information when prescribing medication for their patients,” the judge wrote in his decision.

Gaughan ordered Johnson & Johnson and Janssen to pay civil penalties totaling $4.475 million for the violations.

“If the FDA has approved a drug for limited purposes and drug manufacturers, in pursuit of profit, market the drug for other purposes, it is false advertising that could put the health and lives of ordinary West Virginians at risk,” McGraw said after the verdict.

Other even more serious cases are pending.

In Texas, for instance, the state’s preferred drug list required doctors to prescribe atypicals rather than the older, less expensive antipsychotics – a scheme the state claims Janssen manipulated by showering policy makers with a cornucopia of gifts and trips and speaking fees.

In 2005 alone, according to the Texas Health and Human Services Commission, Texas paid for approximately 308,000 Risperdal prescriptions at a cost of $73.5 million.

In February 2007, the state of Pennsylvania sued Johnson & Johnson, Eli Lilly, and AstraZeneca to recover money paid through Medicaid and other public-health programs to purchase Zyprexa, Risperdal, and Seroquel, as well as for the costs of medical care for the people injured by those drugs.

As in the West Virginia lawsuit, the Pennsylvania case says Janssen urged doctors to prescribe the drugs for dementia and other non-FDA approved disorders.

That latter charge, if true, is patently illegal. Doctors may prescribe a drug approved for one condition for other non-approved conditions – known as off-label uses – but pharmaceutical companies are not allowed to promote the drugs for uses not listed on the drugs’ labels.

Perhaps the sharpest claims made against the company’s conduct, and the efficacy and safety of its product, is contained in a complaint filed May 25, 2007, by South Carolina attorney general Henry McMaster.

The case is pending, but the language of the complaint is blunt.

“Risperdal is inherently, abnormally and unreasonably dangerous,” the complaint states. “The health risks and costs of Risperdal to the citizens of the State and to the State greatly outweigh any claimed utility of Risperdal. Defendants knew or should have known of the dangers inherent in the use of Risperdal, and that the public and the state would be harmed by the intended and foreseeable use of Risperdal.”

The state puts the number of people injured by the drug in the hundreds, “if not thousands,” and says it spends millions of dollars each year to pay the health care costs of those injured by the drug.

Laying out the allegations

South Carolina brought the action on behalf of the state Medicaid program, the South Carolina Department of Mental Health, and the South Carolina state employees health plan. Specifically, the attorney general is seeking to recover funds it spent providing medical treatment to those participants suffering from Risperdal-related illnesses and to recover funds spent in purchasing Risperdal for uses not approved by the government.

Under the federal Medicaid system, reimbursements for drug prescriptions are provided only for so-called “medically accepted indications.” In addition, drug companies are deemed by states to know Medicaid regulations regarding the scope of prescription drug reimbursement, that is to say, they have a duty to prevent nonmedically accepted and nonmedically necessary prescriptions from being submitted to Medicaid for reimbursement.

Janssen Pharmaceutica, the complaint states, violated that tenet, and did so willfully.

“Upon information and belief, defendants breached this duty by knowingly causing prescriptions for nonmedically accepted and nonmedically necessary uses of Risperdal to be submitted to Medicaid for reimbursement,” the complaint states.

To do so, the complaint continues, Janssen aggressively exploited a loophole in South Carolina law.

“According to the South Carolina legislature, the purpose of the Medicaid Fraud Act is to preserve the integrity of the Medicaid program by providing a statutory deterrent to any person causing submission of inappropriate claims to the program,” the complaint states. “The state of South Carolina, as is true of many states, lacks a practical means of ensuring that each prescription for every drug constitutes a medically necessary use of that drug. The state thus relies on persons receiving payment and benefit to turn square corners in their dealings with the Medicaid (and other health) programs. Nevertheless, this lack of practical ability represents a loophole in the scheme of the Medicaid and other programs.”

Janssen recognized and aggressively exploited that loophole in several ways, the complaint states.

“First, defendants engaged in a direct, illegal, nationwide program of promotion of the use of Risperdal for nonmedically accepted indications and nonmedically necessary uses,” the document declares. “Defendants have conducted this program of promotion knowing that prescriptions for Risperdal are generally reimbursed by the state Medicaid (and other health) programs, even though prescriptions for nonmedically accepted indications and nonmedically necessary uses of Risperdal fall outside the coverage of state programs.”

And it’s not just the nonmedically accepted uses of Risperdal the South Carolina attorney general has a problem with; even the company’s claims about its approved uses don’t stand up to scrutiny, according to the complaint.

“Second, since the inception of their promotion of Risperdal, defendants have falsely represented to the state, and to the public in general, that Risperdal is safer and more effective than less expensive first-generation antipsychotics,” the complaint states.

Indeed, in late 2006, both a major British government study and a United States study funded by the National Institute of Mental Health concluded that atypical antipsychotics were no safer and worked no better than the older, much cheaper generic drugs.

The American researchers pointed out that using the more expensive atypicals cost patients $300 to $600 more a month than if they took first-generation medications.

History

To understand how the states think Janssen fraudulently promoted the atypicals, and, in South Carolina’s case, Risperdal, requires a little history.

The FDA approved the use of Risperdal tablets in 1993 for the management of manifestations of psychotic disorders in adults. In 1996, the FDA approved an oral solution for the same use.

In 2002, the FDA changed both indications to the “treatment of schizophrenia” in adults and, a year later, the drug was approved as either monotherapy or combination therapy for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder, or extreme mood swings.

In 2006, the drug was approved for the use in children 5-17 to treat moderate to severe behavioral problems associated with autistic disorder, though not for the core symptoms of autism.

From the beginning, Janssen touted Risperdal for its enhanced therapeutic properties without fewer side effects such as movement disorders like tardive dyskinesia. Whatever their legality and substantive merits, Janssen’s promotional efforts paid off handsomely.

By 2003, atypical antipsychotics such as Risperdal had grabbed 90 percent of the market of all antipsychotic drugs prescribed for all psychiatric purposes, regardless of whether they were approved for those indications or not. Risperdal itself grabbed the largest United States market share, both for FDA-approved purposes and for unapproved purposes.

But, the South Carolina complaint alleges, that success was achieved through a series of unlawful acts and practices, including the promotion of the drug for multiple nonapproved purposes – attention deficit-hyperactivity disorder (ADHD), depression, anxiety, mood disorder, and aggression associated with late-onset dementia.

Rigging the trials, hiding the facts

The complaint argues that there have always been potentially serious side effects associated with the drug, and that the company knew it, hiding the fact by conducting fake clinical trials.

“Medical literature dating as far back as the 1950s, and defendants’ own pre-clinical studies of Risperdal, demonstrated that Risperdal, like older antipsychotic medications, had the potential to cause diabetes, diabetes-related injuries (e.g., weight gain and hyperglycemia), cardiovascular complications and other severe adverse effects,” the complaint states. “By the time Risperdal was first marketed, the neurochemical bases for the efficacy and side-effects were generally known to defendants, i.e., effects on dopamine, serotonin and histamine systems in the brain. Therefore, prior to marketing, defendants should have been concerned about Risperdal causing neurological problems, weight gain, diabetes, pancreatitis, hyperglycemia, cardiovascular complications and metabolic syndrome. And yet Risperdal’s original label, and all label changes until 2004, did not adequately warn of these adverse side effects.”

Despite all those potential side effects, the complaint alleges, Janssen opted for the bare minimum of clinical trials for the drug, and those were of limited duration, “such that no side effects were likely to be revealed.”

Not only that, but those trials did not confirm the notion that Risperdal and other atypical antipsychotics were less likely to cause movement disorders and muscle rigidity.

“Upon information and belief, defendants trials were designed to produce similar rates of EPS in patients sorted into placebo groups and those taking Risperdal,” the complaint alleges. “In order to produce their desired result, defendants selected patients for the placebo groups that were already in the course of treatment with high doses of typical antipsychotics.”

That was important because, as the complaint pointed out, the manifestation of EPS in a patient taking antipsychotic drugs is dose dependent – the larger the dose, the more likely EPS will become, and those who develop it generally continue to experience EPS for months, even after discontinuing treatment.

Thus, the patients in the placebo group would continue to show signs of EPS at the same rate as when they were taking the antipsychotic drugs, while those taking Risperdal predictably developed EPS at the rate expected in a population taking antipsychotic drugs, a rate which essentially matched that of the placebo group, the complaint reports.

“Based on the similar levels of EPS in the placebo and Risperdal groups, defendants claimed, in their marketing, that patients taking Risperdal were as likely to develop EPS as patients taking nothing and thus less likely to develop EPS than patients taking traditional antipsychotics,” the complaint states.

Janssen also knew about the drug’s propensity to cause weight gain, thereby significantly increasing a patient’s risk of contracting diabetes, the complaint states.

“Despite such knowledge, defendants failed to include a warning of the potential for weight gain and the possible development of diabetes as a result of the use of Risperdal in its US labeling for years,” the complaint states. “In fact, defendants concealed the true safety profile of Risperdal from 1993 until 2004. Even then, defendants did not warn citizens of the state of the risk of diabetes associated with Risperdal.”

Targeting the elderly

In 1999, according to the complaint, the FDA caught Janssen promoting Risperdal for the nonmedically accepted treatment of the elderly.

“In a letter to Todd McIntyre, director of Janssen’s regulatory affairs department, the agency strongly disagreed with certain promotional materials that it had received as part of its monitoring and surveillance program,” the complaint states. “According to the FDA, Janssen engaged in a false and misleading campaign to promote Risperdal to geriatric patients.”

In those promotions, according to the complaint, Janssen claimed the drug was safe and effective for elderly patients, despite little or no data to support such a claim. The company also asserted that Risperdal had a low incidence of movement disorders, had a low incidence of sedation, and failed to warn that the use of Risperdal by healthy elderly patients created a greater potential for hepatic and renal dysfunction and cardiovascular problems.

Finally, the FDA found, Janssen marketed the drug inappropriately by representing that Risperdal was a safe and effective treatment for hostility in the elderly.

“Upon information and belief, despite studies and data that confirm the lack of efficacy and significant health and safety risks associated with the promotion of Risperdal for the elderly, defendants continue this practice,” the complaint states.

Through all these years, the South Carolina complaint alleges, Janssen bolstered its “research” with support from bogus experts.

“Upon information and belief, defendants sought ghost written research and paid ‘key opinion leaders’ to support defendants’ marketing claims,” the complaint states. “These ‘key opinion leaders’ were nothing more than third-party consultants and researchers who were put on defendant’s payroll to support and lend credibility to defendant’s scientific and marketing goals.”

Allegations

In all the state of South Carolina has filed eight counts against the pharmaceutical giant, including the submission of fraudulent Medicaid claims, recovery for the cost of treatment for injuries caused by Risperdal, violation of the state’s Unfair Trade Practices Act, negligence, fraud and misrepresentation and unjust enrichment.

The state is seeking not only the return of Medicaid reimbursements for nonaccepted uses and not only the differential between the use of Risperdal and traditional antipsychotics, but also payments to cover the cost of treating injuries caused by the drug, and it is seeking a penalty of $5,000 per prescription written and three times the actual damages sustained by the state of South Carolina.

“At all relevant times, defendants knew, or should have known, that Risperdal was, and is, hazardous to human health,” the complaint concluded. “Risperdal is abnormally and unreasonably dangerous as marketed in that the health risks and costs associated with Risperdal greatly outweigh any claimed utility of Risperdal to Medicaid (and other program) participants. As a direct result of the unreasonable marketing practices of defendants, Risperdal was, and is, defective and unreasonably dangerous.”