Report Backs Up Warnings About Drug Avandia

By GARDINER HARRIS
Published: July 27, 2007
WASHINGTON, July 26 — Patients who take Avandia, a popular diabetes medicine, face an increased risk of heart attacks while those who take Actos, a similar drug, do not, federal drug reviewers conclude in a new report.
Avandia, made by GlaxoSmithKline, is particularly dangerous to patients who take insulin, the review found, a risk not found with Actos, made by Takeda.
The drugs, which increase the body’s sensitivity to insulin, were each taken by about one million patients last year.
The Food and Drug Administration should issue strict warnings about Avandia’s heart attack risk, the reviewers concluded. On Monday, the agency is planning to ask an independent panel of experts whether they agree with stronger warnings or want the drug removed from the market.
“A critical question to be resolved in determining appropriate regulatory action is whether the anticipated therapeutic benefit of rosiglitazone outweighs the demonstrated cardiovascular risk,” one agency reviewer concluded, referring to Avandia by its generic name.
Patients with heart disease and those taking insulin should not take Avandia, one review concluded.
The medicine’s global sales for 2006 were nearly $3.4 billion.
Mary Anne Rhyne, a spokeswoman for GlaxoSmithKline, said the company continued to believe Avandia was safe, noting that various reviewers at the agency had reached a range of conclusions.
“Across the extensive data we have, the science shows no increase in cardiovascular death, and does not support a difference in heart attack rates between Avandia and the other most commonly prescribed oral antidiabetics,” Ms. Rhyne said.
Barbara Ryan, an analyst for Deutsche Bank Securities, said that the agency’s report ensures that “there are going to be a lot of lawsuits.” She noted that some firms were already advertising for clients.
GlaxoSmithKline has been accused of trying to intimidate a doctor who raised questions about Avandia in 1999. And agency reviewers were sharply critical of some studies that GlaxoSmithKline has undertaken to test Avandia’s safety, dismissing results from a continuing 4,000-patient trial as unreliable and invalid.
The report also provides ammunition to critics on Capitol Hill and elsewhere who say that top drug agency officials had been slow to acknowledge Avandia’s risks.
A year ago, GlaxoSmithKline provided the agency with most of the data underlying the report and even suggested that a note be added to Avandia’s label discussing the drug’s potential to increase heart attacks.
The agency did not add the note, but European drug regulators did.
“Why has it taken the F.D.A. a year to do this?” asked Dr. Bruce M. Psaty, a drug safety expert from the University of Washington.
One safety reviewer, David Graham, concluded in part of the report that top agency officials falsely reassured the public at a May 21 news conference that at least one large Avandia study had shown it was safe.
That study, Dr. Graham concluded, provided no such reassurance.
The new, 436-page report is a compendium of reviews released in advance of an advisory panel hearing to be held on Monday. The report largely confirms concerns first raised in May by a study written by Dr. Steven Nissen, a renowned cardiologist from the Cleveland Clinic, and published in The New England Journal of Medicine. Dr. Nissen and the Journal were criticized by Republicans on Capitol Hill and others for rushing to print a study they said was flawed.
In 2000, the drug administration removed Rezulin, made by Pfizer, from the market because that drug caused more liver problems than Actos or Avandia, both of which provided similar benefits to Rezulin.
Avandia increases the risks of heart attacks by as much as 40 percent in most patients. In those taking insulin or nitrates, the risks are higher, according to the drug agency’s analysis. That means that the drug’s heart risks likely injure far more patients than Rezulin’s liver risks did. Most diabetics die of heart disease.
Indeed, a main reason for prescribing Avandia is to stave off the effects that high blood sugar levels can have on the cardiovascular system. That Avandia actually worsens patients’ heart status “denotes a serious limitation of anticipated therapeutic benefit,” the report concluded.
Dr. Richard Hellman, president of the American Association of Clinical Endocrinologists, said that he thought it unlikely that the drug agency would ban Avandia, but he predicted that the drug’s sales would plunge, and he said that he would not prescribe it. Patients taking the drug should consult their doctors, who will probably seek other treatment options for them, he said.
Dr. Psaty said he saw no reason to prescribe Avandia.
The drug agency has been severely criticized for its handling of Avandia concerns. In February 2006, Dr. Rosemary Johann-Liang, a drug safety supervisor, recommended that the labels of both Avandia and Actos receive the agency’s most severe safety warning — called a “black box” — for their tendencies to worsen the risks of heart failure, a problem distinct from the heart attack risks seen only in Avandia.
Her recommendation was ignored and she was punished for it, Dr. Johann-Liang said in an interview last month. In June, the agency announced that it had decided to follow Dr. Johann-Liang’s advice. By then, she had tendered her resignation.
The drug agency’s oversight of Avandia has helped garner support on Capitol Hill for legislation to give the agency more resources and authority to police drug safety issues. Presently, the agency has no power after a drug is approved to require drug makers to conduct further safety assessments, and drug makers rarely finish safety assessments they have promised to do.
Senator Charles E. Grassley, Republican of Iowa, who has championed efforts to change the way the agency polices drug risks, said Avandia was proof that changes are needed.
“The F.D.A. betrays the public trust with its delayed response in this case and others,” Mr. Grassley said. “If F.D.A. leaders are asleep at the switch, it’s a dereliction of duty. But if they’re knowingly suppressing information about risks to public safety, then it’s morally corrupt.”
Jean-Pierre Garnier, GlaxoSmithKline’s chief executive, said this week that the company stands by Avandia.
“Whilst some uncertainty remains around Avandia, we stand firm in our belief that it is an effective and valuable treatment for patients with diabetes,” Mr. Garnier said.