Why Drugs Get Pulled Off the Market : Risk Management Options Fail

by Food and Drug Administration (FDA)

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The day you hear news about a drug coming off the market, it may appear to be a sudden, drastic step. But several other options to manage risks usually have been attempted before that point. The main risk management tools employed by the FDA are education through letters to health-care professionals (known within the FDA as "Dear Doctor" letters) and labeling changes, such as new warnings, sometimes boxed in black for emphasis. Also used are required Medication Guides, labeling specifically for patients that emphasizes significant risks and advises patients how to detect or avoid them. In some cases, a drug is labeled as "second line," meaning it is to be used only in patients for whom other treatments fail. In other cases, a drug that is known to be dangerous is still made available under certain circumstances through what's known as restricted distribution (see box).

Sometimes these risk management techniques are effective, and other times they aren't. "We have our anecdotes, but there is little systematic study on the effect of drug labeling changes on physician behavior," says Temple.

Labeling changes were a partial success with the allergy drug Seldane. Studies showed use of Seldane with inappropriate drugs declined almost 90 percent, but that left considerable exposure to the dangerous combinations, some of which could be lethal.

The label of the heartburn treatment Propulsid (cisapride) was changed several times in 1998. The FDA cosponsored a study to evaluate the effect of various regulatory actions, and found that the percentage of patients inappropriately exposed to the drug was unchanged.

"We know that the farther out we are from the initial approval, the less likely we are to change behavior," Woodcock says. "Once a prescribing pattern has been established, it's hard to change it."

Clearly, the more special care that is required, the more physicians must remember, and the more we need other safeguards like spotting dangerous combination uses at the pharmacy level, the more of a challenge risk management becomes. "We do consider whether we are being unreasonable in our expectations, but sometimes that can't be known beforehand," Temple says.

Currently, the FDA is involved with several drug safety initiatives, including revamping the drug labeling for physicians to create a highlights section, a relatively short section that will describe the most critical information. Better education is a high priority. "We're looking into better ways to educate the public and doctors about changes in risk information, and to get information out faster," says Honig.

But FDA experts say the agency can't do it alone. The FDA judges drug risks for a population, doctors judge risks for individual patients, and patients judge the risks they'll take based on personal values. Ultimately, drug safety requires involvement of all parts of the health system.

Myths About Drug Withdrawals and User Fees

During the 1980s and early 1990s, the FDA was criticized for taking too long to review and approve drugs. Then Congress, the FDA, and the pharmaceutical industry negotiated the Prescription Drug User Fee Act (PDUFA) of 1992. Under PDUFA, drug companies pay fees that allow the FDA to add more resources and speed up drug review time.

The FDA agreed to complete its review of marketing applications within specific times. For example, by 2002, the FDA's reviews of all marketing applications for new drugs were to be completed within 10 months. PDUFA allowed the agency to have a 60 percent increase in staff assigned to review new drug applications. The agency has essentially met all review-time goals. The faster review has led to more rapid approval, with median approval time cut in half — from about 30 months to 15 months. PDUFA was extended through 2002 by the FDA Modernization Act of 1997.

Myth #1: Drug withdrawals have become increasingly common because ever since user fees, the FDA has sped up drug approvals so much that mistakes are slipping through.

The reality is that it's a rare occasion when a drug is taken off the market. The FDA is the consumer watchdog for the more than 10,000 drugs on the market, and the drug withdrawal rate has been essentially constant over the last two decades. And when comparing the time before user fees and after, there has been no change in the rate of drug withdrawals, says Janet Woodcock, M.D., director of the FDA's Center for Drug Evaluation and Research. "There was a cluster of withdrawn drugs in 1997 and 1998, but if you look at the number withdrawn as a percent of those approved for each year, the rate was about 2.7 percent before user fees and is about 2.8 percent after user fees." Some of those drugs withdrawn in 1997 and 1998 had been on the market long before user fees took effect.

Faster reviews to get valuable and life-saving drugs on the market does not translate into safety shortcuts. It isn't that the same number of FDA reviewers are working faster. It also isn't the case that shorter FDA review times mean abbreviated clinical drug trials.

Myth #2: User fees make it difficult for the FDA to stay neutral.

FDA experts say PDUFA has clearly created a situation in which the FDA is responding faster to applications and is having more discussions with drug companies.

The FDA and drug companies share a common interest in getting drugs that are safe and effective to the market and in conducting well-designed trials that are persuasive. "We believe the many meetings and other forms of advice that we give help assure that," says Robert Temple, M.D., director of the FDA's office of medical policy. "Naturally, once they submit an application, the companies want our answer to their drug application to be 'Yes,'" he says, "but we are completely neutral, having no preferred answer except the right one." The FDA's mission is to protect the public health fairly and consistently. Decisions are scientifically-based, not influenced by user fees.

Restricted Distribution

A variety of means have been used to limit distribution of particularly dangerous drugs to be sure they are being used safely, and in some cases, to direct use to the right people.

Propulsid (cisapride) was taken off the market in 2000 because of the risk of heart rhythm abnormalities, but it is still available under a special kind of investigational use. The drug is available to people with severely debilitating conditions for whom the benefits may outweigh the risks and who meet specific clinical eligibility criteria. This limitation assures that it will not be given to people who don't really need it.

In some cases, it is clear that assuring safety will require strict limitations from the outset. Thalidomide was studied in the late 1950s as a sleeping pill and as a treatment for morning sickness in pregnancy, but was not marketed in the United States. The drug is well known for causing severe birth defects. It was approved in 1998, but it is only available under a very restricted distribution system to assure that fetuses are not exposed to it. Thalidomide is labeled for use to treat painful and disfiguring skin sores associated with Hansen's disease (leprosy), but has other potentially important uses under development.

It is absolutely essential that this system work, says Robert Temple, M.D., director of the FDA's office of medical policy. "If people didn't follow the directions while taking thalidomide, the consequences would be terrible," he says. "But it is working and people do follow directions."

In some cases, a drug is marketed generally, but proves to have such a serious effect that it has to be considered for restricted distribution. A critical factor in such cases is whether the FDA and a drug company can agree on the terms. Janet Woodcock, M.D., director of the FDA's Center for Drug Evaluation and Research, says the FDA offered the option of restricted distribution for very severely affected patients in the case of Lotronex (alosetron). Lotronex was approved to treat irritable bowel syndrome in women, but caused ischemic colitis that could be fatal in some cases. After discussions, the manufacturer, GlaxoSmithKline, Research Triangle Park, N.C., decided to voluntarily withdraw the drug from the market in 2000.

About the Author

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FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.