Why Drugs Get Pulled Off the Market

by Food and Drug Administration (FDA)

"But aren't drugs supposed to be safe?"

According to Janet Woodcock, M.D., director of the Food and Drug Administration's Center for Drug Evaluation and Research (CDER), people tend to ask that question a lot when a drug is taken off the market. The FDA's mission is making sure that drugs are "safe and effective." So what does "safe" really mean?

When it comes to any drug, "safe" means that the benefits of the drug outweigh the risks for the population the drug is intended to treat and for its intended use. "Safe does not mean harmless," Woodcock says. "Every drug comes with risks, and our tolerance for risk is higher for drugs that treat serious and life-threatening illnesses. There is no question that cancer drugs can be highly toxic. But they also save lives."

If the FDA decides that a drug's benefits outweigh its risks, the agency approves the drug for marketing. Approved drugs continue to be evaluated through postmarketing surveillance — a system that monitors a drug's safety on an ongoing basis. Postmarketing surveillance seeks to identify problems that weren't observed or recognized before approval and any problems that might arise because a product isn't being used as anticipated.

The goal is to catch any bad news right away so that the FDA and drug companies can act quickly and communicate new risk information to consumers and doctors. CDER evaluates required reports from drug companies, which must promptly pass on any report they receive of a serious adverse reaction that isn't already described in the drug's labeling. CDER also relies on MedWatch, the system through which consumers and health professionals voluntarily report adverse events associated with all products the FDA regulates.

When the FDA receives reports of significant new adverse events, the agency evaluates them for their seriousness and the likelihood that they were caused by the drug. To the extent possible, the agency also considers how the toxicity compares with other treatments for the same disease. Ultimately, of course, the critical question is: Do the benefits of this drug still outweigh its risks for the population described in the labeling? In many cases, that question cannot be answered immediately, and more reports must be considered. Sometimes, the impact of labeling revisions needs to be assessed.

Usually, when important new risks are uncovered, the risks are added to the drug's labeling and doctors are informed of the new information through letters and other education. It's only rarely that the approval decision on a drug needs to be reassessed and changed. A conclusion that a drug should no longer be marketed is based on the nature and frequency of the adverse effect and how the drug compares with treatment alternatives.

When the FDA believes it is clear that a drug no longer has a place in treatment, it will ask the manufacturer to withdraw the drug voluntarily.(See "Safety-Based Drug Withdrawals (1997 - 2001).") Companies have agreed to withdraw the drug in all cases except one — the case of an antidiabetic drug called phenformin, which was taken off the market in 1976 as an imminent hazard, despite the company's objections. If a company does not agree, the FDA can bring formal procedures to require withdrawal.

At first glance, one might assume that every time a drug comes off the market, it means that somewhere along the way somebody made a horrible mistake — that the drug never should have been on the market in the first place. But FDA experts say that would not be correct. Most often, the withdrawal occurs because of adverse effects that were not seen prior to marketing. Sometimes, there was no clue at all. In other cases, one can see hints of the problem in retrospect, but not the serious events that eventually led to the withdrawal.

Many complex factors go into making judgments about benefits and risks, and into ultimately deciding whether a drug should be taken off the market. Here are some major issues, often overlapping, that weigh into the decision-making process.

Rare, Unpredictable Problems

Most drugs on the market are well-tolerated and their adverse effects are known. Known side effects cause more injuries and deaths than unrecognized side effects. But some problems happen so infrequently that they can't be seen or predicted before a drug gets on the market. Serious drug-induced liver disease, for example, is the leading single reason drugs have been pulled from the market. But it is rare, occurring at a rate of 1 in 5,000 to 1 in 10,000 exposures or less. This will not show up in clinical trials, which will pick up relatively common problems.

"If we want reasonably rapid access to needed drugs, it's not practical to require that they be tested in 15,000 to 30,000 people, which is what you'd need to be reasonably sure you saw even one case that occurs at a rate of 1 in 5,000 to 10,000," according to Robert Temple, M.D., director of the FDA's office of medical policy. "And the case would need to be recognized as drug induced," he says. So drugs are typically tested in several thousand subjects, allowing detection of relatively common serious adverse events, such as those affecting 1 in 1,000 people. This practical size of clinical trials means we can't know everything about a drug when it gets on the market. Rare events will only surface when the drug is used in larger numbers of people. Temple says, "Sometimes less severe events that are seen in trials can be used to predict the occurrence of rare, more serious events, but that is not always the case, and such predictions have considerable uncertainty."

The number of subjects in clinical trials is increasing in some areas of drug development, says Peter Honig, M.D., director of the FDA's office of drug safety. "But the numbers will never be large enough to eliminate the need for postmarketing surveillance." The FDA is working on ways to better predict rare events, especially those related to the liver and heart. But some uncertainties will always be there, including the possibility of rare characteristics that make some people particularly susceptible to an adverse reaction.

About the Author

www.fda.gov
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.