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A November 20, 2008, Philadelphia Inquirer article discusses how a Maryland doctor said she felt “threatened and disappointed” after GlaxoSmithKline P.L.C. urged her to stop discussing her concerns that the company’s diabetes drug, Avandia, caused heart problems.

The doctor’s claim marks the second time that GlaxoSmithKline has been accused of trying to intimidate a researcher who pointed out problems associated with Avandia, which before its side effects became well-known was the top-selling diabetes drug. In 2007, University of North Carolina researcher John Buse testified before Congress that GlaxoSmithKline had called him a liar and suggested it might sue him if his comments about Avandia’s potential safety problems caused the company’s stock to drop.

On November 19, 2008, GlaxoSmithKline, a London company that has large operations in the Philadelphia area, said it had taken appropriate action when Mary Money, an internist in Hagerstown, Md., told the company of repeated instances of congestive heart failure and dangerous fluid retention in patients taking Avandia.

“GSK did not dispute the occurrence of adverse events observed by this physician. In fact, GSK promptly shared the information with the Food and Drug Administration and conducted its own scientific analyses,” the company said in a statement.

The company also said its label at the time Money had raised her concerns included warnings about the risk of congestive heart failure. Those warnings were strengthened in later years as more evidence emerged about heart problems. The drug’s label now includes a black-box warning, the FDA’s strongest.

The new assertions were first reported in the November 19, 2008, Wall Street Journal.

Money and Stephen Lippman, a doctor she worked with who also was head of the diabetes program at the local hospital, Washington County Hospital, said in interviews that the company had failed to take their concerns seriously.

Money said her concerns began in the fall of 1999, after a patient she had put on Avandia developed congestive heart failure and “massive fluid retention. I was just barely able to keep her out of the hospital.”

The patient’s problems disappeared when Money took her off Avandia. Soon, more patients developed the same problems after they started taking Avandia.

She took her concerns to Lippman, who found additional patients with the same side effects after starting Avandia. Together, they collected data on 85 patients, about half of whom had significant edema, or fluid retention and swelling. Edema can indicate heart problems.

In April 2000, Money and Lippman met with GlaxoSmithKline representatives. She said a GlaxoSmithKline physician she identified as Daniel Everitt, who now works for Centocor Inc., of Horsham, attended in person. A Centocor spokesman said yesterday that Everitt declined to comment.

Money also said Martin St. John Sutton, a cardiologist at the University of Pennsylvania, had participated in the meeting by phone. Sutton did not return a call seeking comment.

After the meeting, GlaxoSmithKline asked the hospital’s chief of staff, in a letter, to make sure his doctors did not disseminate “unsubstantiated” information about Avandia.

Money said she expected to hear back directly from GlaxoSmithKline after the meeting, but did not until the hospital’s chief of staff told her about the letter from the company.

Mary Anne Rhyne, a spokeswoman for GlaxoSmithKline, said in a statement that the letter was necessary. “When GSK learns about statements by physicians that are inconsistent with the scientific data on its medicines, we have the responsibility to do what we can to correct these inaccuracies for the benefit of physicians, patients and scientific discourse,” the statement said.

“After first discussing these issues in great detail with Dr. Money, GSK wrote a letter to Washington County Hospital because Dr. Money’s unsubstantiated theory had been shared with all of the departments and medical staff at the hospital.”

Money said she interpreted the letter as an effort to silence her and Lippman.

“I guess I was quite naive,” she said. “I thought that the drug company would want to know that their drug was at risk of harming patients.”

She said she felt vindicated last year when Steven Nissen of the Cleveland Clinic published research in the New England Journal of Medicine saying that Avandia could increase the risk of heart attack 43%.

Nissen said that GlaxoSmithKline had always treated him respectfully, even when it disagreed with him. Nissen has consulted for several drug companies, including GlaxoSmithKline.

Lippman said the meeting with GlaxoSmithKline representatives and subsequent letter had disturbed him.

“The problem with [the] drug system is that if people on the front line feel that they’re going to get humiliated for bringing up questions, they’re not going to report things and they are not going to be the canary in the coal mine,” Lippman said. “The issue is that whatever the 800-pound gorilla thought they were doing, it was intimidating.”

Sen. Charles Grassley (R., Iowa) is expected in the next few weeks to release results of an investigation into GlaxoSmithKline’s handling of Avandia.

Avandia has attracted many critics, including the consumer group Public Citizen, which has asked the FDA to take the drug off the market. This week, John Jenkins, director of the FDA’s Office of New Drugs, told Reuters that his agency was looking more carefully at the rise of heart risks related to drugs, including Avandia, that treat chronic conditions.

Some doctors say they believe Avandia helps some patients and should remain on the market.

Zachary T. Bloomgarden, an endocrinologist at Mount Sinai Medical Center in New York, said Avandia could help reduce serious health problems in diabetic patients who do not respond as well to other treatments. He also has received grants and fees from many drug companies, including GlaxoSmithKline.

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.

On November 18, 2008, Medtronic Inc. said that it received a subpoena from the United States Department of Justice regarding use of its popular bone graft product in ways not approved by federal regulators, a practice that could lead to serious injuries in patients with back problems.

CEO William Hawkins said in a conference call with Wall Street analysts the company is complying with the Justice Department’s request. He attributed the harsh spotlight on the company’s product, called Infuse Bone Graft, to several factors, including a public health notice issued by the FDA in July which warned doctors not to use the product “off-label.”

Hawkins also said “negative stories in the press,” plus a recently filed whistleblower lawsuit, might have piqued the Justice Department’s interest. A lawsuit filed last spring against some of the nation’s top spine surgeons alleged that they used Infuse in off-label ways in return for kickbacks from Medtronic.

Infuse is a genetically engineered product used in spine fusion surgery, which permanently links damaged vertebrae. Before regulators approved the product in 2002, spine fusion required two surgeries, one a painful harvest of bone from the hip, and a second to implant the bone inside thimble-like cages inserted into the spine.

Infuse is approved for a single-level fusion in the lower back and other limited uses. Doctors are free to use medical devices and products beyond the scope of what the FDA approved, but companies may not market the devices for uses beyond those approved.