How good is America's drug safety system? Since 1997, more than a dozen prescription drugs have been taken off the market due to serious side effects -- in some cases after hundreds of injuries and even deaths have occurred. Is the Food and Drug Administration, which is responsible for approving and monitoring the safety of the medications we take, up to the task? FRONTLINE asked several experts, including senior officials at the FDA, to weigh in. Here are excerpts from our interviews with the FDA's Steven Galson and Paul Seligman, Public Citizen's Sidney Wolfe, and Raymond Woosley of the University of Arizona.

Acting director of the FDA's Center for Drug Evaluation and Research.

What does "FDA approved" mean? Does it mean that a drug is safe and effective, and that we shouldn't be concerned about taking it?

What it means when a drug is approved is that the risks are outweighed by the benefits for the indication and under the conditions that are in the label. That just means if the drug is used in the right patients, in the right way, at the right dose, and there aren't drugs that are contraindicated taken with it, that the benefits outweigh the risks. There's a lot that can go wrong that doesn't fit under that definition. But the benefits outweigh the risks for the indication and under the conditions of use that we specify when we approve drugs, and the public should feel very comfortable with the review process.

So we should feel comfortable with that phrase "FDA approved," that it really means something?

Absolutely. A tremendous amount of expertise has been built up here. We apply the most up-to-date scientific knowledge and tools to the data that we get from responsive companies. The public should feel very comfortable. But they also need to keep in mind that one, the system isn't foolproof, and two, there's no such thing as a totally safe drug. All drugs have risks, even over-the-counter drugs that are taken very commonly, like acetaminophen and aspirin. A lot of people don't understand that, and they need to [understand] that all drugs, over-the-counter [and] prescription, have risks. ...

How adequate is the system that we have in the United States for monitoring drugs once they've been approved and they're on the market?

The system that we currently have has a lot of strengths, and it has a lot of weaknesses. The agency is working over the next few years to get more resources and to improve the system for detecting problems after drugs are approved. Some of the main strengths are that we do get a lot of reports, and hundreds of thousands are in the system. We get a lot every year.

The weaknesses of the system are that the quality of the reports aren't that great. They come from many different sources. They may have a lot of detail. They may have a little detail. Sometimes we can't get back to the reporter to get the details that we need to really fill in the cases. The other problem is that the actual reporting rate is low, which means [that of] a lot of the cases of adverse events that happen, we really only see a fairly small proportion of them.

So there are strengths and weaknesses. We think that there are improvements that should be made, and we will make them.

We understand that the Food and Drug Administration only gets about 1 to 10 percent ... of adverse event reports reflecting what actually occurs out there. Isn't that a dangerous situation ... to not really have a good picture of what's occurring?

Right. I think that, first of all, the estimates for the proportion of cases that we get is a little bit broader than that. Some people think it's more than 10 percent. But nonetheless, the general point is correct -- that we get a small proportion. We'd like to get more. But the system is imperfect. Without being able to require people to make those reports, if we don't have the authority to do that, it's hard to increase it beyond that. Again, we could do better if we had more case reports. But we're trying to do the best with the system that we have.

How much would it help if it were mandatory that doctors reported the adverse events that they picked up out in the real world?

In theory, it sounds like a great idea. The problem that we've got is that the medical profession really would not like that. They have a lot of paperwork requirements. It probably isn't real practical to expect that to happen. Of course, if it were mandatory, we'd get more case reports, and we'd probably be able to detect things a little bit earlier. I just don't think it's really practical to expect that to happen with our current medical care system. ...

How is the Safety Monitoring Group doing, in terms of personnel, the number of people? Does it need more people? Is it adequate?

We think it needs more people. In estimates in our budget requests, and in the president's budget for the upcoming 2004 budget, we will get more people, assuming Congress gives it to us. As well, Congress passed the Prescription Drug User Fee Act in the last session. What that will do is give us many tens of more employees in this part of the agency. So we've got a plan, and we actually see where the resources are going to come from to beef up that part of the agency. ...

What would you do to make the system better, more reliable?

The plans that we're talking about, we think are going to make a big difference over the next period of time. That is, one, increasing the resources that the center spends on adverse event reports. Two, looking at the systems by which we analyze these large data sets, that we have to try to make sure that we're applying the best tools to let us detect things quickly. Third is moving towards technological improvement, such as electronic reporting, such as automatic reporting. Lastly, we want to improve the communication between our post-marketing people and the people that approve the drugs originally, so that they can talk quickly when there's a problem, and we can get to resolution and action more quickly than we can now. ...

Director of Public Citizen's Health Research Group since its founding in 1971.

How well is the safety of the American public assured today by the system we have for approving and monitoring drugs?

In the 31 years that I've been monitoring the Food and Drug Administration, what has gone on in the last five and six years is unprecedented. There have been an unprecedented number and percentage of drugs taken off the market; in many cases, drugs with known problems before they came on the market.

There's an unprecedented turnover of top scientists and physicians at the FDA. We now have three former FDA scientists on our staff. The absence of congressional oversight to sort of hold the FDA accountable has also been devastating. So the outcome of all of this is that we've had more drug safety-related problems in the last four or five years than really almost any comparable period of time.

The sad thing is these were preventable. They could have been avoided. In most, if not all of the cases, there were strong danger signals even before the drug came on the market that there was a problem. In all cases, once they came on the market, there was a very dangerous and reckless slowness to respond to the signals that came after marketing -- signals in the terms of deaths and serious injuries to people who took the drug once it was on the market. So I think the combination of problems in the pre-approval phase, combined with a very defective system for post-market safety surveillance have really been devastating.

At one time, 10 years ago, I would have said -- and did say -- that the FDA was the gold standard, that no country was doing a better job, either in the approval of drugs in the first place, or, secondly, in finding out as quickly as possible once they came on the market. That's no longer the case. Other countries that formerly were looking up to our gold standard are now outperforming us, and protecting people in those countries much more than we are protecting Americans. ...

If the mistakes that the FDA were making were in the area of lifesaving drugs that there wasn't any substitute for, where you would say, "Yes, there's a risk, but you've got a benefit that clearly outweighs it," that would be a whole different thing. It turns out that the FDA's done a very good job with drugs that are truly breakthrough [lifesaving] drugs. They've put them on a faster track, and there really haven't been problems there.

The problems have all been with drugs where we already have 10-20 drugs, painkillers, on the market; where we already have 10 or more drugs, diabetes drugs, on the market. The drug in question, from the start, in many cases, is not really a breakthrough. ...

So the FDA has gotten in trouble and gotten the American public's health in trouble by a series of mistakes involving drugs that we already have many other examples on the market that are just as effective, just as safe or, in fact, as it turns out, safer. ...

So the FDA seems to have made a number of mistakes in the area of drugs that we really didn't need. Twenty years ago, if any of these drugs such as Duract, Posicor, Rezulin, and a number of other of them came on the market or came up for consideration with the kinds of questions they had, the FDA's response would have been, "We're not going to approve this drug. We're going to take a better look at it."...

Twenty years ago, if a question came up about safety, it was much more likely that the FDA would say, "No. Let's wait a minute. Let's get more information." More recently, the scrutiny over drug safety has weakened. In the study that we conducted of FDA physicians, they told us in 1998, compared with several years before, the standards were lower for safety and for effectiveness. In other words, the decision to approve a drug was more lax, more risky in a sense, in the late 1990s than it had been even three or four years before. We focused on those people that had been around long enough to be able to compare what was going on then with what was going on earlier.

So if you relax the standards and don't pay as much attention to early warnings about safety as you should, and if you relax the effectiveness standards and say, "Well, the drug is only this much better. It's statistically significant. Even though it might not be clinically important, we'll still approve it," that's a real relaxing of the effectiveness standards. If you relax both the safety standards and the effectiveness standards, you're looking for trouble. And that's what's happened.

I would imagine, as most people do, that if a new drug is coming on the market, it's got to be better and safer than other things that are already there.

For close to 30 years, we have supported legislation that would say a new drug cannot be approved unless there's evidence that it's either safer and/or more effective than an existing drug. Such legislation was strongly fought by the industry, and it's never passed. So right now, if you want to bring a new drug to the market, you don't have to even do a study to compare it to the state-of-the-art drug. ...

So although FDA doesn't have the authority to require head-to-head safety and efficacy studies on a drug, if it turns out that there is some evidence, prior to approval, that the drug is more dangerous, they can -- and have in the past -- say no. They just aren't saying no often enough in the present.

Director of the Office of Drug Safety in the FDA's Center for Drug Evaluation and Research.

What don't we know about a drug at the time it's approved?

There are a lot of things that we don't know about a drug at the time that it's approved. First of all, because of the limited number of people who were studied during the clinical trial phase, rare adverse events are often difficult to pick up during that phase.

For example, for a serious side effect that occurs once in every 10,000 prescriptions, if you have a clinical trial that only studies 350 individuals in three separate arms, it may be very difficult to understand or to pick out that piece of critical information.

Once a drug is marketed and used in tens [of thousands], hundreds of thousands, or even millions of individuals, it's more likely for that rare adverse event to occur.

There are also lots of other things that we don't know at the time a drug is approved. For example, it's hard to fully characterize the entire range of use of a particular medication, once it is on the market.

The general population is a complex one. People have many underlying illnesses. They use many different kinds of drugs. They have many different kinds of diets. They use different kinds of dietary supplements or herbal medicines. All of the potential interactions, underlying illnesses -- co-morbidities, as they are called -- can contribute to the underlying risk profile of the drug, and can result in an unintended or unpredicted adverse event. ...

How do serious adverse events reports rise to the level of, "Hey, we're really concerned about this drug"? Does it take one case? Does it take 10? Does it [take] 50? How does that work?

We look at every serious adverse event report with a tremendous deal of care. There are a couple of things that we look at. First of all, was this a serious adverse event that we knew about at the time of marketing? Given that no drug is safe, and given that each drug has a different adverse event or toxic profile, there are certain situations where we might expect serious events, adverse events. ...

So an unanticipated adverse event, [or] an adverse event that's occurring far more frequently than we had anticipated are two signals that tell us that we need to pursue more information and greater investigation. ...

Is one event serious enough to take a drug off the market? Or is there something you have to see -- a certain pattern, a certain percentage of people who were using something?

I think there's no easy answer to that question, because each drug, and its indication, and its use is specific. ... So we evaluate each drug on its own merits, if you will. How is it being used in the population? What is it indicated for? What do we know about its toxic profile, both prior to marketing and subsequent to marketing? What other alternatives for medications are there out there? Are there substitutes that have equal benefit, but lower risk?

We look at every drug and every circumstance individually. Is the drug being utilized appropriately by the medical community? Is it being utilized appropriately by consumers? Are there ways that we can change those utilization patterns in order to improve, not only the benefit, but also to lower the risks of that medication? These are all the kinds of factors that we consider. ...

How alarmed should the public be that a number of drugs have been taken off the market fairly recently? ...

If you look historically at the rate at which drugs have been removed from the market, you'll find that it has been fairly steady. Although it may appear that the rate is higher, because there have been a series of high-profile removals, the reality is that very few drugs get removed from the market. This rate hasn't changed over time.

The consumer needs to understand that the FDA's mission is to ensure that drugs are safe and effective before they are approved for marketing; that the vast majority of medications meet that very high standard prior to their approval; that we are dedicated, once a drug has been approved for marketing, to keep a close eye on what's happening in the post-marketing environment; and [we] respond quickly and aggressively when we find that there are problems with a particular medication. ...

What, if anything, would you do to improve the system? ... How could we feel even safer?

I think we have just reached an historic agreement with the pharmaceutical industry that was codified by Congress in the third round of the Prescription Drug User Fee Act, which, for the first time, gives us prescription drug fees for use in post-marketing surveillance.

There's always room for improvement. A number of areas that we're going to focus on in the coming years is understanding more thoroughly how drugs are utilized once a product is marketed, and the degree to which utilization can change the risk profile of a drug once it has been marketed. That's one area that we can certainly focus on. ...

The other is, for lack of a better term, what I would call "applied research." Understanding how physicians receive information and make decisions about therapeutics has always been an important issue in safe pharmacotherapy.

Understanding how consumers make decisions, and how to influence their behaviors to ensure safe medication use is another area of great interest of mine, and I think an area that the FDA will be continuing to place greater emphasis on.

So I think understanding drug utilization, and understanding how physicians and consumers use medications to ensure their greatest benefit and to limit those risks are two areas where we could improve FDA's processes. ...

I think consumers have an important role in the safe use of medications. They are ultimately the individuals who make the decision about what they take. ... Consumers need to actively read the label, understand what they're taking, look at the information that is provided to them by the pharmacy, listen carefully to what the physician is saying, ask questions of the physician. Whenever they receive a new medication, ask the physician, "Will this be a problem, because I'm taking the following medications?" or, "I use the following herbals," or, "I'm taking the following over-the-counter medication."

Frequently, in the course of a clinical encounter with the physician, the doctor won't have all that information. So it's really incumbent upon the consumer to take charge a little bit; make sure that they are reading the label, because those labels are there for them; reading the patient information, and talking to their physicians about other products that they may be taking could potentially interact with the prescription that they're currently receiving. ...

Vice President for Health Sciences at the University of Arizona, he was a top candidate to become FDA commissioner in 2002.

Are Americans as safe and protected as [they should be by our drug safety system]?

I think Americans need to recognize that every time they put a pill in their mouth, especially a new pill that they've never taken before, it's an experiment. How big an experiment depends on the pill and how well it's been studied. Unfortunately, many of the pills we take have not been studied adequately. Even the old ones that we think we know a lot about, we're learning every day that we missed something along the way.

At the same time, I have to say we know more about a new medicine today when it goes on the market than we've ever known before. But we've also learned from the science that there's an awful lot out there that we need to learn. We assume that a medicine is going to have the same effect on one person as the next. Now we know, with better data and more time, that there's huge variability between the response of one individual and another. The average medicine only works and has the right effect in only about 60 percent of people. Many people have side effects. We didn't know how many until we started looking carefully, and some of those side effects are deadly.

Why don't we know everything we need to know about drugs at the time they come on the market?

We don't know everything we need to know about medications because we've relied upon the market. The market is going to find out what's good about medicines. It's never going to ask all the questions about what could be wrong with it. As long as we mostly depend upon the marketplace to study the medications, we're never going to know all the warts. I mean, why, if I'm a stockholder in a company, I don't want my company looking for bad news. I want them to find the good news and invest in finding that. That's what we have.

But when we're dealing with health and we're dealing with medications, we have a responsibility to find out all about these medicines. So it's society's responsibility. It's the National Institutes of Health, it's the FDA, it's the [Department of] Health and Human Services' responsibility to provide that other half that the free market isn't going to provide us, to tell us the downside, because the marketplace will push these and tell us all the great things about them. ...

The toughest part of this is, when do you put a drug on the market? Do you wait until all the answers are in? Well, a lot of people can suffer, waiting for those medications. So that's the hard job that the FDA has to deal with. How much evidence do we need to be fairly certain that there's going to be more benefit than harm? That's the risk-benefit ratio.

When a drug goes on the market, only about 3,000 patients have ever been given that drug. We will never know all the toxicity that can occur, especially the one in 10,000 or the one in 20,000 that can be seriously harmed. Our detection of that will only happen after the drug is on the market and exposed to huge numbers of patients. ...

I get the sense that sometimes there's not a great deal of intellectual honesty in this whole industry, including among the regulators. Is this a problem?

It is. It's a serious problem, not having independent thought, even in the regulatory side. We have regulators who recommend a drug go on the market, and then they're the same ones who have to make the decision to take it off. That means they've got to say, "I made a mistake, I let this on the market and there's some problem I missed," and that puts them in a terrible situation. ...

We need for the pharmaceutical industry something analogous to the National Transportation Safety Board, so that when a plane goes down they go in and analyze what happened. They may find that the plane was the problem and the manufacturer, or they may find that the regulations were inadequate. But they're independent. When a drug comes off the market, we have no analysis to say, "Should it have ever gone on the market? Was it a mistake at the agency? Was it a mistake at the industry? Was it something that was totally unpreventable? Did the system work?"

I think it's important for people to know that drugs will always have to be taken off the market. That's not a signal that there's a problem. Medications will never be tested completely in our system, and that's OK. But we have to find the problem and we have to see could we have done it better, could we have done it differently. We don't ask the drug company, "Did you make a mistake in developing this drug?" or the FDA, "Did you make a mistake in approving this drug?" It should be another body to make that determination. So independence is not going to be there; we have to add it. ...

Is the balance of the FDA out of whack, in your opinion?

I think the FDA is so grossly underfunded for its mission that it is out of balance because of user fees. User fees enable the agency to hire people to work for the industry. The other budget has been so limited and so cut -- the other budget being that which is there for safety -- the number of people hired at the agency to protect, to analyze data and drug safety, is criminal. The number of people required to study 3,000 drugs that are on the market is far more than the 17 or 20 -- however many they have now. The teams that are needed to do drug safety are infinitely more than what they've got right now.

We don't have a safety system in this country. We've got a good voluntary report system, but it is not a full system. We need other tools, like other countries. In France, a very small country, they've got 30 sites where they've trained people to go and look at the medical records, talk to patients to find out what happens when you take a medication. So if it looks like there's a problem, they can actually pick it up very quickly.

In the United Kingdom, they have a network of general practitioners who report their findings on every new drug they use, so that you can not only pick up signals, but you have an estimate of how large is the signal. You know that 100,000 people took the drug and one or two people were hurt, 10 people, whatever. You have the ability to quantify the problem.

We don't have that. We know that for every adverse event that is reported to the FDA, about 100 never get sent in. We only get 1 percent of serious reports sent in, and many of those are sketchy. That's why it takes a while, too long a while, to detect these problems. ... The system works, it's just too slow. It's too cumbersome. We have to do too much else to verify that a signal is real, because we don't have the other tools. ...

What would be an ideal drug safety system?

The ideal drug safety system would be one that had the ability to look at drugs throughout their lifespan, as soon as they go on the market, to have studies designed to look for problems that could not have been detected before marketing. It would involve spontaneous reports for those rare reactions. It would involve a French-type system, where you go in and look at subsets to see what happens.

And then even think long-term toxicities -- I mean, there is a possibility that there are side effects with medicines that will take 10, 20 years. We're now in an era where we're taking drugs for 20, 30 years. We're taking drugs to lower cholesterol. We're starting them in our 20s and 30s. That's never happened before. No one in our society really has taken medications for that long a time before. There's no way we will be able to pick up toxicities unless we have controlled trials where we have groups to compare, and that means we need the ability to do randomized, long-term safety trials. Those are very expensive to do.

We need community-based studies. We need to look in subsets of the population. Those aren't being done now. We don't look at women. ... We need to be doing targeted studies in Hispanics, in Native Americans, because there will be toxicities unique to those populations that will be totally missed if we just look at everybody in the country.

There are many things we need to do. There needs to be a team of people independently funded.

By not doing these things, what's the cost?

The cost of not having this kind of a safety system is we take drugs off the market that shouldn't be taken off the market. ... We lose 100,000 lives every year. We lose $137 billion because we don't have an adequate safety system.

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posted november 13, 2003

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