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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

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.

On November 18, 2008, a panel of federal drug experts said powerful antipsychotic medicines are being used far too cavalierly in children, and regulators must do more to warn doctors of their substantial risks.

More than 389,000 children and teenagers were treated last year with Risperdal, one of five popular medicines known as atypical antipsychotics. Of those patients, 240,000 were 12 or younger, according to data presented to the committee. In many cases, the drug was prescribed to treat attention deficit disorders.

But Risperdal is not approved for attention deficit problems, and its risks which include substantial weight gain, metabolic disorders and muscular tics that can be permanent are too profound to justify its use in treating such disorders, panel members said.

“This committee is frustrated,” said Dr. Leon Dure, a pediatric neurologist from the University of Alabama School of Medicine who was on the panel. “And we need to find a way to accommodate this concern of ours.”

The November 18 meeting was scheduled to be a routine review of the pediatric safety of Risperdal and Zyprexa, popular antipsychotic medicines made, respectively, by Johnson & Johnson and Eli Lilly & Company. FDA officials proposed that the committee endorse the agency’s routine monitoring of the safety of the medicines in children and support its previous efforts to highlight the drugs’ risks.

But committee members unanimously rejected the agency’s proposals, saying that far more needed to be done to discourage the medicines’ growing use in children, particularly to treat conditions for which the medicines have not been approved.

“The data show there is a substantial amount of prescribing for attention deficit disorder, and I wonder if we have given enough weight to the adverse-event profile of the drug in light of this,” Dr. Daniel Notterman, a senior health policy analyst at Princeton University and a panel member, said when speaking about Risperdal.

Drug agency officials responded that they had already placed strongly worded warnings on the drugs’ labels.

“I’m a little puzzled about the statement that the label is inadequate,” said Dr. Thomas Laughren, director of the agency’s division of psychiatry products. “I’m anxious to hear what more we can do in the labeling.”

Kara Russell, a spokeswoman for Johnson & Johnson, said, “Adverse drug reactions associated with Risperdal use in approved indications are accurately reflected in the label.”

But panelists said the current warnings were not enough.

While panel members spoke at length about Risperdal, they said their concerns applied to the other medicines in its class, including Zyprexa, Seroquel, Abilify and Geodon.

The committee’s concerns are part of a growing chorus of complaints about the increasing use of antipsychotic medicines in children and teenagers. Prescription rates for the drugs have increased more than fivefold for children in the past decade and a half, and doctors now use the drugs to settle outbursts and aggression in children with a wide variety of diagnoses, even though children are especially susceptible to their side effects.

A consortium of state Medicaid directors is evaluating the use of the drugs in children on state Medicaid rolls to ensure that they are being properly prescribed.

The growing use of the medicines has been driven partly by the sudden popularity of the diagnosis of pediatric bipolar disorder.

The leading advocate for the bipolar diagnosis is Dr. Joseph Biederman, a child psychiatrist at Harvard University whose work is under a cloud after a Congressional investigation revealed that he had failed to report to his university at least $1.4 million in outside income from the makers of antipsychotic medicines.

In the past year, Risperdal prescriptions to patients 17 and younger increased 10 percent, while prescriptions among adults declined 5 percent. Most of the pediatric prescriptions were written by psychiatrists.

From 1993 through the first three months of 2008, 1,207 children given Risperdal suffered serious problems, including 31 who died. Among the deaths was a 9-year-old with attention deficit problems who suffered a fatal stroke 12 days after starting therapy with Risperdal.

At least 11 of the deaths were children whose treatment with Risperdal was unapproved by the F.D.A. Once the agency approves a medicine for a particular condition, doctors are free to prescribe it for other problems.

Panel members said they had for years been concerned about the effects of Risperdal and similar medicines, but F.D.A. officials said no studies had been done to test the drugs’ long-term safety.

Dr. Dure said he was concerned that doctors often failed to recognize the movement disorders, including tardive dyskinesia and dystonia, that can result from using these medicines.

“I have a bias that extra-pyramidal side effects are being under-recognized with these agents,” Dr. Dure said.

Dr. Laughren of the F.D.A. said the agency could do little to fix the problem. Instead, he said, medical specialty societies must do a better job educating doctors about the drugs’ side effects.