Doctors Urged to Be Wary of Prescribing New Drugs

Study: Deadly side effects may not show up till long after approval

TUESDAY, April 30, 2002 (HealthDayNews) -- New research warns doctors to put off prescribing new drugs until they're proven safe because dangerous side effects may stay hidden until long after the medicines are approved and on the market.

The scientists say seven drugs approved and then withdrawn by federal regulators since 1993 have been implicated in more than 1,000 deaths. Half of the recalls occurred within two years of the drugs' debut. Meanwhile, 20 million Americans took at least one of the five compounds pulled from the market since 1997.

"Unsafe drugs are being approved," says Dr. Karen Lasser, a Harvard University physician and lead author of the study, which appears in tomorrow's Journal of the American Medical Association. "The whole process has to be much more closely regulated."

Contributing to the problem, the researchers say, is potentially "explosive" sales volume and usage by patients, who are increasingly being wooed with direct-to-consumer advertisements.

However, officials at the U.S. Food and Drug Administration (FDA), which oversees the safety of the nation's medicine chest, denies that its approval process is flawed. On the contrary, agency officials argue, the fact that post-marketing surveillance catches adverse reactions and leads to a relatively small number of withdrawals shows the system works well.

"There clearly is nothing that's going to prevent all recalls," says Dr. Robert Temple, an FDA official and co-author of an editorial accompanying the journal article. However, the agency is "way better" than it ever has been at avoiding them. Temple denies that priority review, in which regulators process a new drug application within six months, puts consumers at increased risk of harm.

Lasser and her colleagues, including consumer advocate Dr. Sidney Wolfe, of Public Citizen, combed through the Physicians' Desk Reference between 1975 and 2000 for new "black box" warnings, the FDA's strictest labeling advisories.

The Physician's Desk Reference (PDR) is the Bible for doctors and other prescribers seeking safety information about drugs. The book, published by Thomson Medical Economics, is updated annually, with information collected by drug makers and approved by the FDA. Subscribers also receive twice-yearly supplements that record any labeling changes or drug recalls that occurred after the most recent edition went to press.

The FDA approved 548 new drug products between 1975 and 1999, according to the researchers. Of those, 56 (about 10 percent) were either withdrawn (16) or required at least one black box change. One drug needed six such revisions. The researchers project that over a 25-year period, any drug has a 20 percent chance of either being withdrawn or receiving a black box warning -- a figure the FDA considers "debatable."

While many of the drugs that ran into trouble were breakthrough or lifesaving remedies, Lasser said many others were not. Four of the 16 that had to be pulled, for example, were nonsteroidal anti-inflammatory drugs (NSAIDs), for which doctors have a wide range of well-established alternatives.

Liver toxicity is the chief reason drugs undergo major label changes or get removed from the market, although other common reasons include their propensity to cause heart problems, kidney failure, or birth defects.

Drug companies must conduct three phases of clinical trials before winning FDA approval for a new product. But these are typically small studies, involving an average of about 3,000 people in total. As a result, they may not be able to pick up rare risks that occur once in every 10,000 or 100,000 patients. On the other hand, Lasser says, many of the labeling changes and recall actions covered side effects that were known to regulators before they approved the products.

"It's true that sometimes an event is relatively rare, and you're not going to pick it up," she says. "But if the condition is benign, and there already is a safe, effective drug [on the market], we think the threshold should be much higher for approving" a newcomer.

Temple called that prescription a "throwaway," and added that one obvious change -- demanding much larger pre-approval clinical trials -- would radically alter the way drugs are approved in this country. Drug makers claim it costs as much as $500 million to bring a drug to market, much of which comes from funding clinical trials.

However, he says, the FDA in the last decade has made two changes that significantly improve patient safety. The agency requires drug makers to analyze how their experimental compounds interact with other medicines, and it assesses how new drugs affect certain heart rhythms. "I don't expect us to be surprised, really ever, at least by the interactions we're familiar with," he says.

Mukesh Mehta, who helps oversee the publication of the PDR, says he has noticed more labeling changes to drugs in the book in recent years. Yet, he couldn't say if that reflected a trend in the pharmaceutical industry of pushing through more dangerous or poorly tested treatments.

Mark Grayson, a spokesman for the Pharmaceutical Research and Manufacturers of America, calls the notion that the FDA was a leaky agency "absolutely specious."

There are always potential risks when a new drug is approved, Grayson says. On the other hand, "many, many people get a great benefit from these medicines."

Grayson points to the recent example of Lotronex, a bowel medication that was pulled from the market in 2000, but which an FDA panel last week recommended reinstating despite its apparent risks to patients.

What To Do: For more on drug safety, try Public Citizen or the Institute for Safe Medication Practices. To learn more about the drug approval process, visit the U.S. Food and Drug Administration.

SOURCES: Karen Lasser, M.D., M.P.H., instructor, medicine, Harvard Medical School, Boston; Mukesh Mehta, Pharm.D., vice president, clinical communications, Thomson Medical Economics, Montvale, N.J.; Robert Temple, M.D., associate director, medical policy, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Md.; Mark Grayson, spokesman, Pharmaceutical Research and Manufacturers of America, Washington, D.C.; May 1, 2002, Journal of the American Medical Association
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