When Is a Medical Product Too Risky?

by Food and Drug Administration (FDA)

Five drugs were pulled from pharmacy shelves in a recent one-year period, considered to be too risky by the Food and Drug Administration. Perhaps the most notorious among them was fenfluramine (Pondimin), the "fen" half of the popular weight-loss combination known as "fen-phen." Fenfluramine was removed from the market after being linked with potentially fatal heart valve disease in some patients. The same concerns prompted the withdrawal of the chemically related dexfenfluramine (Redux).

The other drugs removed from the market during the same period: the prescription antihistamine Seldane (terfenadine), the calcium channel blocker Posicor (mibefradil), and the pain medicine Duract (bromfenac sodium).

The string of five withdrawals has led some critics to contend that FDA is rushing to approve drugs that ultimately may prove dangerous to patients.

Is FDA cutting corners when it comes to drug safety? FDA Consumer asked that of Janet Woodcock, M.D., director of the agency's Center for Drug Evaluation and Research, which regulates all drugs marketed in the United States. She and other top FDA officials have just completed a report to FDA Commissioner Jane Henney, M.D., on the agency's approach to evaluating risk, in new drugs as well as other medical products.

Much has been made in the media recently about what one USA Today editorial referred to as a "record spate of drug withdrawals." Has the agency compromised its standards of safety and effectiveness to speed up drug approvals, as some critics charge?

First of all, you have to look at the data. The rate of drug withdrawal in the United States is actually lower than it's been over the past couple of decades. The rate was running about 3 percent of drugs approved that had to be withdrawn in the '80s, and that came down a little bit in the early '90s, and now it is even lower than that, a little over 1 percent at the moment. So the idea that things are getting worse — that more drugs have to be pulled off the market today — just isn't the case.

FDA is reviewing drugs more quickly, overall, than in the past. It used to be that the review period — after the pharmaceutical company studies the drug, writes up its reports, and sends a gigantic package of information to FDA — took about two to three years to complete. We have that down to about 12 months.

The drop in drug review time has had nothing to do with the legal standards for drug approval, which haven't changed. We're able to review drugs more quickly because we have about 400 more people here in the Center for Drugs to review drugs than we did before the Prescription Drug User Fee Act. Under the PDUFA program, started in 1992, drug companies pay fees that allow FDA to add reviewers and scientific equipment — computers and so forth — to speed up drug review.

But shorter review time doesn't mean that the clinical testing of drugs is any shorter. Actually, it's taking longer now for a company to study a drug than it used to. Partly, that has to do with greater scientific knowledge about studying drugs. Over the last decade, FDA has asked for more studies in different populations — women, elderly patients, people with kidney failure, and so forth. On the other hand, companies are studying drugs more for marketing reasons, too, to help sell their drug. And these types of studies also contribute to the safety database for the drug.

What FDA needs is enough time to do a good, thorough review of an application. We think we have enough time now to do that. But uncertainty is a constant with drugs, and it's an issue that we need to separate from FDA review time.

Why doesn't FDA hold off on approving a drug until the agency is sure the product won't have any dangerous side effects?

What we're really talking about here is, what are the standards? How extensively should drugs be studied in people to uncover adverse reactions? Clearly, if you study a drug in 500 people, you have much more uncertainty about the drug than if you study it in 5,000 people, or 150,000. But, as you start to increase the number of people studied, you bring the cost up so much that the development of other drugs waiting back here isn't moving along.

If we made sure that any drug we approved had no side effects, we wouldn't approve any drugs. We'd have a really easy job. Every single drug that has an effect on the body will also have side effects. Sometimes these will be rare, and sometimes these won't be that serious. But for every drug that we approve, we have to balance the benefits of the drug against its risks.

People know about risks, and they're used to them in their everyday lives. "Should I get on this airplane?" "Should I let my child go skiing?" For the benefit you're getting from a medicine, too, you are buying some risk. The FDA can't make that go away, and we shouldn't represent that we do. All we do is try to make clear what the risks are.

There are some risks that we won't know about from the clinical trials. Partly, it's because some risks are very rare. For a risk, say, that would occur in 1 in 50,000 patients, you'd have to study 150,000 people before the drug was approved to give you a good chance of that risk even showing up — although you still aren't guaranteed to find it. To study 150,000 people with each disease would be a prohibitive barrier to getting drugs on the market, especially those for rare diseases.

Also, you might have to follow a person on a drug for quite a long time before the side effect would occur, making it harder to detect.

Another reason some risks do not show themselves during clinical studies has to do with how drugs are used in the real world. In clinical trials, drugs are studied only for the use the company is pursuing. They're studied in patients who are enrolled in trials and are carefully monitored. After a drug is out on the market, all kinds of different patients will be treated with the drug, some of whom will not have the condition the drug was approved for. In addition, they'll be taking all sorts of different medications, and maybe dietary supplements and other products that could interact with the drug to cause problems.

We have to balance our requirements for drug approval versus the need to have the drugs out on the market. There is a continuum of uncertainty that is tolerated, depending on how serious the illness is. For drugs that are for serious or life-threatening diseases that don't have any good treatments, we tolerate a lot more uncertainty. On the other end of the continuum, for a drug that's going to be sold over-the-counter for consumers to use, there has to be a very high certainty that the drug is very safe.

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.