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One-Quarter of Biologic Drugs Have Had Safety Issues

International analysis finds 11% issued 'black box' warnings by FDA

TUESDAY, Oct. 21, 2008 (HealthDay News) -- New research shows that almost one-quarter of biologic therapies approved in the United States and Europe since 1995 have been the subject of at least one safety-related regulatory action in the decade since they were approved.

Eleven percent, including Remicade (infliximab), used to treat Crohn's disease and rheumatoid arthritis, and Avastin (bevacizumab), used to treat cancer, have been issued a "black box" warning.

The findings, from Dutch scientists, are published in the Oct. 22/29 issue of the Journal of the American Medical Association, a themed issue on the Health of the Nation.

"This suggests the need for more in-depth investigation before approval and highlights the importance of vigilance in post-marketing surveillance for adverse effects," Dr. Phil B. Fontanarosa, the journal's executive deputy editor, said during a a Tuesday teleconference on the themed issue.

"[Adverse effects] generally occurred in general disorders, like serious allergic reaction or cardiac arrest, administration site problems, infections and infestations," said Fontanarosa. "A lot of these drugs act on the immune system, so infections are common complications of these products."

"We've always known that because biologics were going to modulate the immune system, there would be this risk," said Lisa Saubermann, associate director of clinical pharmacy services at the University of Rochester Medical Center. "Any time we modulate the immune system, that's the problem, because we know that the immune system is preventing other things from happening, like cancers."

"It's alarming," she added.

The first biologic treatment, recombinant insulin, was approved in the United States in 1982. Since then, more than 250 biologics have flooded the pharmaceutical market, representing roughly one-quarter of all new drugs approved by U.S. and European Union authorities.

Although all drugs carry risks, biologics are in a special class, because they are derived from biological sources, including antibodies, enzymes and hormones.

Enbrel (etanercept), for instance, is a tumor necrosis factor, a protein made by the body's immune system. The drug, used to treat various forms of arthritis as well as psoriasis, was also the recipient of a black box warning (for infections and central nervous system disorders).

The authors of this paper, from Utrecht University, reviewed 174 biologics approved in the United States and/or the European Union between January 1995 and June 2007.

Between January 1995 and June 2008, 82 safety-related regulatory actions were issued for 41 of the medications, or almost 24 percent of the total.

Of these 82 actions, 63 were advisory letters to health-care professionals in the United States and Europe, and 19 were black box warnings. None of the drugs were withdrawn from the market.

Most of the actions (70.7 percent) were taken within the first five years after approval, with 3.7 years being the average time until a regulatory action was issued.

By way of comparison, a 2002 paper in JAMA showed that, of 548 new non-biologic drugs approved over a 25-year span, 1975-2000, 10 percent had new black box warnings or were withdrawn from the market and about half of those warnings or withdrawals occurred within two years after the product had been on the market.

Biologic medications that were the first to be developed in their class were more likely to have safety-related actions, compared to later contenders, the new study found.

"Patients who are on these medications must be appropriately selected to receive them and monitored appropriately," Saubermann said. "We have to screen appropriately before the drugs are started, make sure the patient hasn't tried other options, then follow up."

More information

Visit the U.S. Food and Drug Administration for more on these drugs.

SOURCES: Lisa Saubermann, Pharm.D., associate director, clinical pharmacy services, University of Rochester Medical Center, New York; Phil B. Fontanarosa, M.D., executive deputy editor, Journal of the American Medical Association; Oct. 22/29, 2008, Journal of the American Medical Association
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