When Is a Medical Product Too Risky? : Part 2

by Food and Drug Administration (FDA)

(Page 2 of 3)

When adverse reactions do show up, we have what's called a spontaneous reporting system to track them. Doctors, pharmacists, even patients can report serious adverse reactions to the agency through our MedWatch system, or they can make a report to the manufacturer, who will send it to us. We have a whole staff that puts these reports into a computer database and analyzes them. It's often hard to tell early whether it's a true signal or not because out in the real world, people who are very sick are getting drugs. So we monitor the reports, and as soon as we get a clear understanding that a new finding exists that isn't in the label, we'll work with the company to add it to the label. The company may send out a Dear Health Professional letter to inform doctors and other providers of a new safety issue. And if it really alters the risk-benefit ratio so the risks of the drug, including the newly found risks, now outweigh the benefits, we'll have the company take the drug off the market.

Among the most widely publicized examples of recent drug withdrawals are the diet drug fenfluramine and the painkiller Duract. Did FDA make a mistake in approving these drugs?

The diet drugs are a very interesting example. Fenfluramine was approved by FDA in 1973 for short-term use in weight reduction. It had been approved in many other countries around the world, and there was an extremely wide experience with the drug.

It was used in a low number of people in the United States for a number of years. But in the early '90s, it became wildly popular in combination with another drug, even though the combination hadn't been studied extensively or approved by the FDA. In this combination, people were taking fenfluramine for a longer period than they had been over the previous 20 years.

A report from the Mayo Clinic raised red flags when it showed that some patients had heart valve disease who had been taking this combination. Heart valve disease is not known, in general, to be a side effect of pharmaceuticals, and it's not something that we test for in the clinical trials. You'd have to test every patient's heart function with an echocardiogram to detect it.

So, did FDA make a mistake? Certainly for the 20 years after approval, no one thought a 'mistake' had been made because it took that long for the heart valve problem to be found. I think the entire medical community was surprised by the finding, and the association with heart valve disease wasn't really accepted by much of the medical community for awhile.

But it became clear to FDA, based on our postmarketing system for picking up adverse reactions and from epidemiologic studies that we did, that this was a true association between fenfluramine and heart valve disease. For that reason, we pulled fenfluramine off the market, as well as the recently approved diet product Redux. We'd received a few adverse reaction reports about Redux, or dexfenfluramine, which is a component of fenfluramine and was approved partly on the basis of fenfluramine's long safety record.

In the case of Duract, we knew before the drug was approved that there was what we call 'chemical hepatitis' associated with it because that had been seen in the clinical trials. A number of drugs cause chemical hepatitis; in other words, the doctor knows you have a bit of liver disturbance but you don't.

Was it a mistake to approve Duract? We didn't know that Duract would cause serious liver disease because it was not seen in the clinical trials. If we had thought that, we wouldn't have approved it.

Naturally, a newly approved drug has more uncertainty about it than a drug that's been on the market for 10 years. There's just no way we can get around that. Even if you required 250,000 people to be studied — of course, a drug would never get out on the market, then — when you get it to 10 million people, say, who are taking all these other medicines and might take it longer, you will still find out new things. We're still learning about digitalis, a drug that's been around for 100 years. New papers are still being published: Does it work in heart failure? Should it be given long-term?

Have we learned from the withdrawal of Duract and the other recent withdrawals? Yes, I think the FDA has gained some information, particularly about liver toxicity. And we've held a big scientific workshop for our staff. We're going to be taking more steps to look into liver toxicity to see if it can't be better predicted. That's really the issue. You probably won't see liver failure in the trials. But can you predict that this is a drug that's going to cause liver failure once many more people are exposed? Right now, there's no way to do that.

Based on the risk evaluation that FDA undertook for its recent report to the commissioner, is FDA adequately protecting the public from the risks presented by medical products?

What we found was that our system of premarket review, as well as postmarket surveillance, are performing the way they were set up to.

Of the products now approved, fewer have to be withdrawn from the market. So we see progress in drug review. Is it perfect? Are we the best we could be? Well, we think there are some additional steps that could be taken.

On the premarket side, we need to find better ways to detect liver toxicity, and we're starting to work on that. We think we need a quality assurance unit within each center, and we're going to do that.

On the postmarket side, we feel we need to finish our adverse event reporting system, or AERS. In addition to enhancing the AERS system, we also want to have access to outside databases and have ways of finding adverse events other than just the voluntary reporting. We need more money, though, for these improvements, and we've asked for some money in the president's budget for this year.

Is there more that can be done? FDA, we think, is enforcing the standards and approach called for in our statute, the Food, Drug, and Cosmetic Act. But the question is, is the balance correct, according to society? That's really a general consensus rather than our call.

One important conclusion in our risk management report is that we need to incorporate the views of patients into our risk management decisions much more extensively. After all, consumers are the ones who are assuming the risk. And we know that individuals weigh risk differently. Some people would rather live shorter and have a better quality of life, for example. Other people just want to live, and their quality of life is less important than simply surviving.

If I say to you, "you have a 1 in 100 chance of dying from this drug, but it will do wonderful things for you," that might mean something totally different to you than it would to me. So we need to bring patients, as well as those who treat patients, in much more and ask them, "What is an acceptable risk?"

Beyond FDA's role, are there other steps that you think could reduce medical product-related injuries and deaths in the United States?

Yes. FDA makes the original risk-benefit decision. We look at the population that would be using the drug and ask, "do the benefits to this population outweigh the risks?" If yes, we go ahead and approve the drug.

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.