http://www.reutershealth.com/archive/2002/04/30/eline/links/20020430elin020.html

Up to 20% of drugs may cause unexpected problems

By Alison McCook

NEW YORK, Apr 30 (Reuters Health) - Up to one fifth of all new prescription drugs may ultimately be recalled or produce potentially harmful side effects, a new study concludes.

"The safety of new agents cannot be known with certainty until a drug has been on the market for many years," according to Dr. Karen E. Lasser of Cambridge Hospital and Harvard Medical School in Massachusetts and colleagues.

Their study results, published in the May 1st issue of The Journal of the American Medical Association, are based on an evaluation of the 548 drugs that were first marketed between 1975 and 1999. Lasser and her colleagues looked up all drug recalls and scanned the Physician's Desk Reference, a commonly used source of drug information, for new warnings on side effects.

During the study period, 10% of new drugs either received new warnings or were withdrawn, with half of those developments occurring within 7 years after the drug first appeared on the market. Based on these results, Lasser and her colleagues, who included Dr. Sidney Wolfe of the advocacy group Public Citizen, calculated that a new drug has a 20% chance of being withdrawn or producing previously unknown side effects over a 25-year period.

Side effects from new drugs can have a widespread impact. Almost 20 million Americans took one or more of the five drugs that were withdrawn between September 1997 and September 1998.

They found that 56 of 548 new drugs approved by the agency during the 25-year period were later subjected to so-called "black box" safety warnings or banned from the market altogether. FDA uses "black box" warnings on drug labels to warn physicians of potentially dangerous side effects or drug interactions.

In some cases, those side effects can be deadly: Since 1993, seven drugs that were approved, then later withdrawn, may have contributed to over 1,000 deaths.

A total of 81 major label changes or drug withdrawals occurred during the study period, half of them within the first 7 years of marketing, according to the paper.

Several high-profile drugs have been pulled from the market by regulators over the last few years. One drug, the antihistamine terfenadine, also known as Seldane, spent nearly 13 years on the market before being banned in 1998. Another, the gastrointestinal drug cisapride, was available for over 6 years. Both drugs were pulled because researchers discovered high rates of heart toxicity associated with their use.

In an interview with Reuters Health, Lasser said that fewer than 1 in 10 adverse drug reactions are reported to the US Food and Drug Administration (FDA). As such, she said she suspects that new drugs may be causing more harm than this study illustrates.

"So our study is definitely an underestimate of what is going on," she said.

Drugs that are withdrawn or cause previously unknown side effects after being approved were clearly not properly evaluated, and Lasser said there are many reasons why this discrepancy can occur.

Pre-approval studies to evaluate the safety and effectiveness of drugs may not use enough patients to detect all possible adverse effects, she noted. The studies may also exclude some patients, such as children or those with other diseases, who will ultimately receive the drug, thereby potentially failing to identify their specific risks.

In their report, Lasser's team recommends that doctors substitute older and equally effective agents, if available, for newer drugs.

However, in an accompanying editorial, Drs. Robert J. Temple and Martin H. Himmel of the FDA in Rockville, Maryland, argue that Lasser and colleagues are perhaps exaggerating the risks associated with new drugs.

Researchers are getting better at evaluating new drugs, the editorialists note, and most of the side effects that result from new drugs are relatively mild.

SOURCE: The Journal of the American Medical Association 2002;287:2215-2220, 2273-2275.

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