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During the week of November 24, 2008, medical investigators acknowledged 14 medications commonly prescribed for purposes other than those approved by the FDA, and are calling for additional research on so-called off-label uses to determine safety for patients.

For decades, doctors have relied on anecdotal evidence and their own knowledge of disease beyond findings in clinical trials to provide therapy for conditions that are difficult to treat. Following the Hippocratic edict of “first do no harm,” off-label prescribing has rescued countless people from the brink of death, and made bearable many rare disorders for which there are no approved drugs, experts say.

But new research suggests some doctors are taking leaps of faith in risky prescribing practices that are sometimes backed by pharmaceutical companies with interests in finding new markets for established blockbuster medications. Most of the 14 drugs listed in an analysis to be published next month in the journal Pharmacotherapy are anti-psychotics and anti-depressants.

Both drug classes have come under scrutiny in recent years for unexpected side effects, even when they were being prescribed according to guidelines approved by the FDA.

Samuel Packer, chairman of the ethics committee at North Shore University Hospital in Manhasset, New York, said he’s not surprised that doctors are calling for research on off-label prescribing, but he emphasized the issue is a two-headed coin because off-label prescribing can benefit some patients.

“This is a very, very complicated area, and in and of itself off-label use is not a bad thing,” Packer said.

But he said he finds it disturbing when pharmaceutical companies sponsor medical meetings and pay renowned physicians large sums of money to push specific medications for off-label uses.

Last year, widely reported research revealed psychiatrists are the most likely group of physicians to receive remuneration from drug companies and to prescribe a new class of drugs to children known as atypical anti-psychotics, which not only can be dangerous for youngsters but are unapproved for pediatric ages.

Randall Stafford and colleagues at Stanford University compiled the list of drugs most often prescribed off-label. The roster is led by Seroquel, the schizophrenia drug. Stafford said his research found Seroquel not only topped the list, it raised other concerns.

The drug costs $207 per prescription, is the subject of expensive marketing and carries a “black box” warning, the FDA’s highest level of caution for potentially harmful side effects.

The drugs that investigators say often are prescribed for purposes other than those approved by regulators

Drugs Prescribed the Most For Off-Label Use

• Seroquel Schizophrenia Bipolar disorder
• Coumadin Atrial fibrillation (irregular heartbeat) Hypertensive heart disease
• Lexapro Depression Bipolar disorder
• Risperdal Schizophrenia Bipolar disorder
• Singulair Asthma Chronic obstructive pulmonary disease
• Wellbutrin Depression Bipolar disorder
• Zoloft Depression Bipolar disorder
• Effexor Depression Bipolar disorder
• Celebrex Pain relief Fibromatosis
• Zestril Hypertension Coronary artery disease
• Cymbalta Depression Anxiety
• Desyrel Depression Sleep disturbance
• Zyprexa Schizophrenia Depression
• Procrit Chronic renal failure Anemia of chronic disease

New data released from on November 25, 2008 reports states that using inhaled corticosteroids to treat chronic obstructive pulmonary disease (COPD) drastically increases the risk of pneumonia in patients. Researchers who reviewed and analyzed 11 randomized controlled trials involving 14,426 participants also found that inhaled corticosteroid (ICS) therapy did not improve survival rates of sufferers of COPD, a smoking-related lung disease.

“ICS therapy was associated with a 34 percent increased risk of pneumonia,” the research team from Johns Hopkins University in the US state of Maryland and the University of Manitoba in Canada wrote in the November 26 edition of the Journal of the American Medical Association (JAMA).

Additionally, the higher the dose of ICS, the greater the risk of pneumonia, the report said.

“Recognizing the adverse events associated with ICS use is especially important since clinicians may increase ICS therapy from moderate to high doses in patients who are not responding,” the researchers wrote.

“Our data suggest that increasing to higher ICS doses may place patients at greater risk of pneumonia,” they wrote.

Patients with low exhalation volume, on combination therapy where corticosteroids are administered along with another treatment and those on short-duration ICS therapy were also at greater risk of contracting pneumonia when using inhaled corticosteroids, according to the report.

The researchers, who were unable to clearly determine why ICS therapy increases pneumonia risk, also found that using inhaled corticosteroids does not improve survival rates for COPD, which is the fourth leading cause of death in the United States.

The only interventions which improve survival rates among COPD patients are quitting smoking and supplemental oxygen, according to the report.

Characterized by bouts of coughing, sputum production and breathlessness, COPD affects 10-15 million people and claims 120,000 lives each year in the United States.

Inhaled corticosteroid therapy is used only to reduce symptoms and complications associated with COPD, according to the report.

An article in the November 25, 2008 edition of the Philadelphia Inquirer illustrates how Johnson & Johnson gave hundreds of thousands of dollars to a research center run by an influential child psychiatrist in order to create data to help expand sales of the company’s antipsychotic drug Risperdal in children.

These documents shed new light on the close relationship Johnson & Johnson had with Joseph Biederman, a Harvard University psychiatrist at the center of a controversy involving the dramatic increase in antipsychotic drugs, including Risperdal, prescribed for children, often for unapproved uses.

Johnson & Johnson spent at least $700,000 to fund the Johnson & Johnson Center for Pediatric Psychopathology at Massachusetts General Hospital. The purpose of the center, according to an internal company e-mail contained in the court documents, was to “generate and disseminate data supporting the use” of Risperdal in children and adolescents.

The e-mails were from 2001 and 2002, long before the FDA approved Risperdal for use in children in 2006. Physicians are allowed to prescribe drugs for unapproved uses or patients, but drugmakers are barred from marketing drugs for such off-label uses and can face civil charges and steep fines.

Officials at Ortho-McNeil-Janssen Pharmaceuticals Inc., the Johnson & Johnson subsidiary in Titusville, New Jersey, that manufacturers Risperdal, said they funded the center “to conduct rigorous clinical trials to clarify appropriate use and dosing of Risperdal in children.”

The company said it promoted its products “only for their FDA-approved indications.”

Biederman did not return a phone call.

The documents were provided by plaintiff lawyers pursuing a class-action suit against Johnson & Johnson, contending that such a powerful drug should not have been widely recommended for children. The court papers show Johnson & Johnson:

• Budgeted $6.4 million to hold “educational summits” and sponsor advisory panels in part to counter negative media reports on the research, diagnosis and treatment of children with mental illness.
• Was actively involved in drafting research that Biederman was to present at a medical conference and asked him how to deal with unfavorable research results suggesting that a placebo worked as well as Risperdal.
• Discussed clinical trials for drugs as “growth opportunities” and tied trial proposals to sales potential.

Biederman is a Harvard researcher and psychiatrist whose work has fueled a rapid rise in diagnoses of bipolar disorder in children. His studies, often on small numbers of children and funded by drug companies, have expanded the use of what are known as atypical antipsychotics in children.

Children are believed to be much more vulnerable to the side effects of these drugs, which include weight gain, breast milk production in both sexes, facial tics and muscle tremors.

On November 18, 2008, a panel of federal drug experts said antipsychotic medicines were overused in children and urged the FDA to do more to warn doctors of their risks.

Besides Risperdal, atypical antipsychotics include Zyprexa, made by Eli Lilly & Co.; Seroquel, made by AstraZeneca P.L.C. and others.

The documents, which resulted from discovery efforts in the lawsuits, portray Biederman as using his influence to get money out of Johnson & Johnson.

In an e-mail from November 1999, for example, Johnson & Johnson marketing executive John Bruins warned his bosses to quickly issue a $3,000 check to Biederman to pay for a lecture.

“Dr. Biederman is not someone to jerk around,” Bruins wrote. “He is a very proud national figure in child psych and has a very short fuse.”

Bruins also suggested that Biederman had taken business away from Johnson & Johnson after the company turned down the doctor’s request for a $280,000 research grant. “I have never seen someone so angry,” Bruins wrote. “Since that time, our business became non-existant (sic) within his area of control.”

In the court documents, e-mails from Johnson & Johnson executives said Biederman had asked the company to fund a pediatric research institute at Massachusetts General Hospital, resulting in a donation of at least $700,000 in 2002. Biederman is listed as the chief of the Johnson & Johnson Center for Pediatric Psychopathology.

Biederman is the subject of investigations by Harvard and by Sen. Charles Grassley (R., Iowa) for failing to disclose to Harvard at least $1.4 million in funds from Johnson & Johnson and other companies. Laws require researchers to disclose such relationships to their employers, to protect the integrity of medical research.

Massachusetts General said on November 24, 2008 that it planned to investigate the allegations raised in the court documents.

Harvard said it was not connected to Massachusetts General Hospital or to the pediatric institute there. A university spokesman said he could not comment on Harvard’s review.

Biederman first told Grassley he had received $3,500 from Johnson & Johnson, but the company told the senator’s office the figure was $58,169 in 2001.