For the first four years that Zyprexa was sold in the US, the promotion of the drug for any use other than adult schizophrenia was illegal. When the FDA approves a drug for a specific use, it can only be marketed for that use. Eli Lilly gained approval for schizophrenia in 1996 and the drug was not approved to treat bipolar disorder until 2000.
Zyprexa belongs to a class of drugs known as "atypical" antipsychotics, which arrived on the market in the US beginning in 1993. Other drugs in this class include Seroquel, sold by AstraZeneca, Risperdal marketed by Johnson & Johnson subsidiary Janssen, Geodon, sold by Pfizer, Abilify, from Bristol-Myers Squibb and Clozaril manufactured by Novartis.
Schizophrenia is considered the most severe of all mental illnesses and is said to occur in only about 1% of the population. The definition of the disorder in the Diagnostic and Statistical Manual of Mental Disorders, IV, reads as follows:
Schizophrenia is a disorder that lasts for at least 6 months and includes at least 1 month of active-phase symptoms (i.e. two [or more] of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms.)
Experts say it would be highly unlikely that a competent psychiatrist could misdiagnosis this condition because the symptoms are so extreme and distinct.
Once a drug is approved to treat one condition, it is legal for doctors to prescribe the drug for other uses. These unapproved uses are referred to as "off-label," and can mean prescribing a drug for a longer duration than specified, at a different dose, in combination with other drugs, or with a different patient population than listed on the label.
The Food, Drug, and Cosmetic Act prohibits companies from promoting a drug for uses other than those approved and the Federal Anti-Kickback Statute prohibits companies from providing remuneration to induce or reward doctors for prescribing products for beneficiaries of Federally funded health care programs such as Medicare and Medicaid.
Accordingly, during the first four years that Zyprexa was sold in the US, Lilly sales representatives were not allowed to discuss any use other than adult schizophrenia and discussions of other uses were not allowed in any company funded event. Lilly itself noted at a July 20, 1995 presentation that the market for Zyprexa was limited the year before it was approved, estimating the total schizophrenia market to be only about $1 billion.
However, the drug was Lilly's best selling product by 2000, with worldwide sales of $2.35 billion, according to Lilly's 2001 Annual Report filed on January 28, 2002.
Zyprexa was approved for adults with bipolar disorder in 2000 and US sales rose 23% over 1999, to $1.69 billion in 2000. The next year, it became Lilly's first product to have sales in excess of $3 billion worldwide, and US sales rose 29% to $2.18 billion, according to the Report.
Experts say there is no way that Zyprexa could have become Lilly's most widely prescribed drug in the US without influencing doctors to prescribe the drug off-label. For instance, even though Zyprexa was approved to treat the manic phase of bipolar disorder only, which is typically brief, patients were kept on the drug for years.
According to Ellen Liversidge, her son was prescribed Zypexa for bipolar disorder and he remained on the drug for two years, during which time he gained about 100 pounds, until he went into a coma and died of profound hyperglycemia on October 5, 2002.
Ms Liversidge says she later learned that other countries had required Lilly to add warnings about the risk of drastic weight gain, hyperglycemia, and diabetes to the label of Zyprexa in the spring of 2002, months before her son died.
On February 12, 2006, due to increased antipsychotic use, the Florida Agency for Health Care Administration announced a plan to study their use by children in the Florida Medicaid program. The agency stated in a press release that close to 18,000 children took antipsychotics in 2005 and more than 475,000 prescriptions were written in the past 5 years.
On October 7, 2007 the AHCA released a report entitled, "The Use of Antipsychotic Medications with Children," that said pediatric use of antipsychotics increased in the late 1990s and early 2000s after a decline in the 1980s and stable use in the early 1990s. The increases were largely attributed to the arrival of the atypicals, starting in 1993.
The report noted that both commercial and Medicaid populations experienced increased use and that one study documented a 75% increase in the commercially insured population of 0-17 years from 1997 to 2001, and another study of use in the commercial managed care population from 1996 to 2001 found a 127% increase among children aged 0 to18.
The study found that antipsychotic use in the Medicaid populations in the late 1990s was already 3-4 times higher than commercial populations but also grew in the early 2000s. In Texas, prescription rates for kids rose 141% between 1996 and 2001 and in another program in the Midwest, usage grew 304% over the same time period, the report stated.
The authors said the analyses reveals that the drugs are used to treat a broad spectrum of disorders, and some of these disorders, such as attention deficit hyperactivity disorder and major depression, "clearly do not call for antipsychotic treatment."
The study found that in the 0 to 5 age group, 53.8% of the antipsychotics were prescribed for ADHD and in the age group 6 to 12, 48% were prescribed for ADHD.
The report noted that the use of antipsychotics with children under 6 is generally not recommended and "should be considered only in very rare circumstances."
The authors pointed out that the risk associated with the increased use would be significant even if the medications were prescribed for indications approved for adults since most would agree that in this context children can not be considered "little adults."
But the medications are now being used to treat a broad spectrum of disorders never anticipated or approved for adult use and we "therefore lack even the adult analogy in trying to estimate safety, tolerability and effectiveness of antipsychotic agents in the pediatric population," the authors wrote.
A September 2007 study in the Archives of General Psychiatry, reported that the number of children in the US diagnosed with bipolar disorder had increased from about 20,000 in 1994 to roughly 800,000 in 2003.
One of the world's leading experts on psychopharmacology, UK psychiatrist and professor, Dr David Healy, author of, "The Latest Mania: Selling Bipolar Disorder," says bipolar disorder in children is all but unrecognized outside the US and it is unlikely that a significant proportion of these children would actually meet the DSM criteria for the disorder.
A group of researchers that Dr Healy credits with turning American children into profit centers via the pediatric diagnosis of bipolar disorder is led by psychiatrist, Dr Joseph Biederman, at Massachusetts General Hospital in Boston.
According to Dr Healy, Massachusetts General conducted clinical trials with Zyprexa and Risperdal in children as young as four, and recruited participants by running TV ads featuring clinicians and parents informing other parents that difficult and aggressive behavior in children aged four and up might be caused by bipolar disorder.
"This does more than recruit patients with a clear disorder," Dr Healy notes, "it suggests that everyday behavioral difficulties may be better seen in terms of a disorder."
He explains that it would be all but impossible in a short-term trial of sedative drugs in pediatric states characterized by overactivity to not show some behavioral changes that could be regarded as beneficial, so the outcomes of the trials would naturally appear to validate the bipolar diagnosis and increase the prescribing of drugs.
As for the recent claims that child suicide rates have significantly increased since the FDA added warnings about an increased risk of suicide to the labels of the selective serotonin reuptake inhibitor antidepressants (SSRIs), Dr Healy says if suicide rates have increased at all, it is most likely due to doctors switching children from SSRIs to antipsychotics.
In the last two or three years, he explains, drug companies have marketed bipolar disorder by claiming that the problems from SSRIs were the result of patients being misdiagnosed as depressed when they should have been diagnosed as bipolar and given antipsychotics.
However, Dr Healy says, "the antipsychotics have just as great an increase in suicide risk as SSRIs, if not greater."
Many experts are now blaming the Biederman gang for the death of 4-year-old Rebecca Riley, who was diagnosed with bipolar disorder and ADHD at the age of 2-and-a half. Her doctor, Dr Kayoko Kifuji, a psychiatrist at Tufts New England Medical Center in Boston, kept her on a 3-drug cocktail that included an atypical, an anti-seizure medication and a drug approved to treat adults with high blood pressure, until her death in December 2006.
In a June 19, 2007, editorial in the Boston Globe, pediatrician Dr Lawrence Diller wrote, "Biederman and his colleagues at Harvard are the professionals most responsible for developing and promoting those standards of care -- which include diagnosing preschool children as young as 2 with bipolar disorder and treating them with multiple medications."
At the October 13, 2007 conference of the International Center for the Study of Psychiatry and Psychology, Dr Fred Baughman, author of, "The ADHD Fraud," and a well-recognized expert on psychiatric drugs, discussed the death of the 4-year-old in a presentation titled, "Who killed Rebecca Riley?"
The answer, according to Dr Baughman and many other experts in the field of psychiatry and child development at the conference, is the Biederman gang, due to its promotion of a diagnosis for attention deficit and bipolar disorder in children as young as infants.
Dr Baughman says the aim of the "psycho-pharmaceutical cartel" in the 1990s was not to increase the market for psychiatric drugs, "it was to invent a market out of thin air."
About a month before Rebecca's death, on November 23, 2006, Dr Biederman defended the prescribing of multiple drugs to children in the New York Times by comparing it to doctors prescribing multiple drugs to treat heart disease, diabetes, cancer and aids.
"Child psychiatry is not any different," he said. "These drugs have revolutionized how we treat severe psychopathology in children."
A report in the June 17, 2007 Boston Globe by Scott Allen, revealed that Dr Biederman has received research grants from 15 drug makers and serves as a paid speaker or adviser to seven, including Lilly and Risperdal maker Janssen.
Dr Kifuji is apparently a fan of the Biederman gang, judging by Mr Allen's report, in which her attorney, J W Carney Jr, states, "They are by far the leading lights in terms of providing leadership in the treatment of children who have disorders such as bipolar."
The legal filings in Rebecca's case show that Dr Kifuji also diagnosed the other two Riley children, ages 6 and 11, with ADHD and bipolar disorder and placed them on the same drug cocktail, with the cost of all mental health services and drugs covered by Medicaid.
Former Federal fraud investigator, Allan Jones, says the atypical makers were able to turn the schizophrenia drugs into cash cows by influencing the doctors and state officials involved in the approval of formularies that specify the drugs that can be used by persons covered by public health care programs.
Each state has an approved formulary and "before a drug can be prescribed for a patient on Medicaid it has to be on the list," he explains.
Evidence to support this claim came on August 21, 2007, when the Associated Press reported that drug companies had spent a lot of money on two members of the Minnesota panels who helped select the drugs covered by Medicaid. Dr John Simon earned $354,700 from drug makers between 2004 to 2006, and Robert Straka, a University of Minnesota pharmacy professor, was paid $78,000 while he served on the panel, the AP said.
And on August 27, 2007 the Pioneer Press reported that Dr Simon earned the most money from Lilly, "whose antipsychotic drug Zyprexa is the most costly each year for Minnesota's fee-for-service health program for the poor and disabled."
Lilly's financial disclosure records show payments to Dr Simon of $91,854.95 in 2004 alone. On October 17, 2007, the Associated Press reported that he had quite the panel.
The corruption of advisory committees has led to criminal charges against a state official who was fired in Pennsylvania. On November 21, 2006, Steven Fiorello, the Director of the Pharmacy Services, and chairman of the formulary committee, was charged with one count of conflict of interest for accepting money from drug companies and one count of failing to disclose income on Statements of Financial Interests.
"Fiorello served on a committee that decided which drugs would be used for mental health treatment in all state hospitals - decisions which guided more than $9 million in annual drug purchases," the state's Attorney General said in a press release.
While he was helping to guide the purchases, the press release stated, "he was also paid more than $12,000 by drug companies for appearances, speeches and presentations, as well as service on a drug company advisory board."
In October 2006, a state official in Texas, Dr Steven Shon, was fired after the state's attorney general found that Janssen had improperly influenced him to place Risperdal on the state formulary, while he was receiving money from Janssen.
According to Lilly's August 6, 2007 second quarter SEC filing, the California Attorney General's Office has subpoenaed documents related to Lilly's "efforts to obtain and maintain Zyprexa's status on the formulary, the marketing and promotion of Zyprexa, and the remuneration of health care providers."
Lilly's off-label marketing of Zyprexa has come under scrutiny in the past several years, in large part, because lawmakers and law enforcement agencies became suspicious about the skyrocketing costs of a drug approved to treat such limited conditions being prescribed to so many patients in public health care programs.
According to Lilly's SEC report, Medicaid fraud lawsuits filed against Lilly thus far include the states of Alaska, Louisiana, Mississippi, Montana, New Mexico, Pennsylvania, South Carolina, Utah, and West Virginia. Arkansas is the latest state to file a lawsuit.
The Medicaid fraud allegations include that Lilly illegally marketed Zyprexa for off-label uses while concealing the serious health risks associated with the drug, and most specifically high blood sugar levels, extreme weight gain and diabetes.
The lawsuits seek to recover not only the money paid to purchase Zyprexa for patients on Medicaid but also for the medical care of persons injured by the drug. Mississippi alleges that about 10% of the Medicaid patients who took Zyprexa in that state have developed diabetes which will require life-long care.
Montana's lawsuit alleges that Lilly gave kickbacks to doctors, promoted Zyprexa as a sedative in nursing homes, and created a 280-person sales force to promote the drug exclusively for off-label uses, specifically in long-term care facilities.
The West Virginia complaint alleges that Lilly promoted Zyprexa for off-label conditions including anxiety, sleep disruption, mood swings, attention deficit and dementia and "benefited from its misrepresentations and fraudulent conduct by gaining sales of Zyprexa at the expense of other, safe, effective drugs."
In private litigation, since June 2005 Lilly has entered into settlements with approximately 30,200 claimants in the US for about $1.2 billion and there were still about 350 lawsuits covering about 540 claims pending in the US at the time of the August 2007 filing.
However, off-label prescribing has obviously not ceased because in 2006, Zyprexa sales were $4.3 billion and for the second quarter and first half of 2007, US sales of Zyprexa increased 4% and 5%, respectively, and international sales increased 14% during both periods, according to Lilly's SEC filing.
Additional lawsuits are now being filed on behalf of suicide attempt survivors and the family members of suicide victims who died while taking Zyprexa. They allege that Lilly knew about the increased risk of suicide associated with the drug but failed to warn the public while it widely promoted the Zyprexa for off-label uses.
An August 2002 analysis of clinical trial data on drugs approved by the FDA between 1985 and 2000, by Dr Arif Khan of the Northwest Clinical Research Center in Bellevue Washington, found the rate of completed suicides in the antipsychotic trials to be 752 per 100,000, an astronomical number considering that the suicide rate is only 11 per 100,000 for persons in the general population.
Families seeking legal advice regarding Zyprexa related suicide can contact the Baum, Hedlund, Aristei & Goldman Law Firm at: (800) 827-0087; http://www.baumhedlundlaw.com/
(Written as part of the Pharmaceutical Industry Litigation Monthly Round-Up, Sponsored by Baum Hedlund's Pharmaceutical Antidepressant Litigation Department)