Earlier this month, the US Food and Drug Administration (FDA) cautioned Americans that two classes of drugs in widespread use have serious and sometimes life-threatening side effects that warrant new label warnings.

On 9 March, the agency announced that three erythropoietin-type drugs for treating anaemia increase the risk of death, blood clots, strokes and heart attacks, and accelerate the growth of some cancers. Then on 14 March, it asked makers of 13 widely prescribed sedative-hypnotic sleeping pills to toughen label warnings because of reported severe allergic reactions and “complex sleep-related behaviours”, including falling asleep while driving.

These warnings, for blockbuster drugs that have been on the market for years, highlight an increasing challenge that confronts the FDA. Side effects may not emerge until new drugs are taken by huge numbers of people. This lesson was driven home by the anti-inflammatory drug Vioxx, which was withdrawn in 2004 after five years on the market, for causing heart attacks and strokes. As a greying America consumes an ever-expanding smorgasbord of medicines, the agency is fighting an uphill battle to catch the next Vioxx before it turns into a fully fledged disaster.

So experts are calling for the FDA to move beyond its current passive system for monitoring the safety of marketed drugs. The Adverse Event Reporting System relies on doctors — if and when it occurs to them — to report suspected side effects to the agency. But doctors filed fewer than 25,000 such reports in 2005, suggesting that the system is capturing only a small fraction of the actual side effects.

Side effects often don't emerge until a drug has been on the market for some time. Credit: R. FRIEDMAN/CORBIS

“The system in this country for identifying drug safety signals is not nearly as robust as it could be,” says Scott Gottlieb, resident fellow at the American Enterprise Institute, a conservative Washington think-tank, and a former deputy commissioner for medical and scientific affairs at the FDA.

Last week, Mark McClellan, a former FDA commissioner, told a Senate committee considering new drug-safety legislation that the system “needs to do better than just seeing the tip of the iceberg of a safety problem after it has already hit us”. Health-information technology for drug safety is “an idea whose time has come”, he added.

McClellan and others are pushing the idea of data mining of existing health-record databases as an active surveillance system to pick up early warnings of adverse side effects. By pooling existing databases run by private insurance plans, government agencies and industry, information on well over 100 million people could be studied in something much closer to real time, he says. The FDA could then identify priority questions and the mechanisms for answering them. If such a system had been in place when Vioxx came on the market in 1999, that drug's dangers could have been detected in months rather than years, McClellan contends.

The same thinking is gaining currency in Europe. “There is great potential in the use of these healthcare databases,” says Panos Tsintis, who oversees the safety of marketed drugs for the European Medicines Agency (EMEA) in London.

Drug makers are also backing the idea of a centralized active surveillance system, which they see as preferable to a duplication of effort in which each insurer, government agency and company invents its own scheme. Such a system “would provide information we crucially currently don't have”, said Ron Krall, senior vice-president and chief medical officer for GlaxoSmithKline at an Institute of Medicine (IOM) forum on 12 March in Washington DC. The FDA is testing active surveillance in a pilot programme tracking the side effects of four unnamed, newly approved medicines. “In general, safety information trickles in and the FDA is passive in analysing it,” said Ellis Unger, an official from the agency's drug-review centre, at the IOM forum. “In this programme we grab each new product by the horns. It's very resource-intensive.”

Those costs present a major problem to the cash-strapped agency, which has no funds even to upgrade its existing surveillance system. But advocates of active surveillance say the country cannot afford not to invest what would probably be tens of millions of dollars. That kind of money, says Garret FitzGerald, head of pharmacology at the University of Pennsylvania in Philadelphia, “is peanuts when you think about the public health”.