However, many of the causes of past drug withdrawals are now being caught in preclinical trials, Drs. Robert J. Temple and Martin H. Himmel, of the FDA, comment in a journal editorial.

Investigators led by Dr. Karen E. Lasser, of Cambridge Hospital and Harvard Medical School in Massachusetts, identified 56 new drugs--representing 10.2% of those approved by the FDA between 1975 and 1999--that were given a new black box warning in the Physicians' Desk Reference or were withdrawn from the market. Half of the withdrawals occurred within 2 years after the drug's introduction, while half of new black box warnings were issued within 7 years.

Dr. Lasser's group proposes that the FDA raise its threshold for approving new drugs when safe and effective alternatives exist or if the targeted condition is benign. They also recommend that physicians avoid using newly approved drugs when possible, and when that is not feasible, that patients be monitored for hepatic, hematologic and cardiac toxicity.

In an interview with Reuters Health, Dr. Lasser expounded on this theme. "More studies have to be done before drugs are released and millions of patients are exposed," she said.

She reminded physicians that patients in clinical trials are not representative of the population that may ultimately be exposed to the drug, such as elderly individuals, children and those with comorbid conditions. "The testing needs to be superior to what is out there now," she emphasized.

Drs. Temple and Himmel, based in Rockville, Maryland, defend the FDA's handling of new drugs. For example, they point out, rare adverse effects are unlikely to be uncovered in premarketing trials. In addition, many labeling changes are associated with antineoplastic agents and antiviral drugs, all of which are expected to have substantial toxicity.

They note that the FDA has updated its requirements of manufacturers in light of past adverse events. Drugs are now evaluated thoroughly for their effect on cardiac repolarization, hepatotoxicity, and ability to inhibit hepatic enzymes that interact with other drugs.

"If there is sound reason to use a recently approved drug, the physician need not deny the patient this treatment," they write.

JAMA 2002;287:2215-2220,2273-2275.

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