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What countries do it better now than the United States? What is it that they're doing?
The caution that used to be exerted by the FDA at the front end before a drug was approved has weakened. I think that countries such as the United Kingdom, probably France, are doing a better job.
Once the drug is on the market, there's a system in France called Pharmacovigilance, which is really vigilance on a drug once it comes on the market. It's a very carefully, cleverly set up system, so that every patient who gets a drug in certain parts of the country is known. Any medical problem that arises with these patients is also known.
In other words, you get a full accounting of what goes wrong for those patients. Whereas, in this country, anywhere between 1 percent and 10 percent, at most, of the adverse reactions that occur are reported. That's very important. If we had a better system, a more complete system of reporting adverse reactions, it would take maybe six months instead of a year, or a year instead of two years before we got enough information to allow us to make a decision this drug should come off the market, or this drug should have a black box warning.
We published a paper several months ago in the Journal of the American Medical Association, showing that one out of every five drugs that came on the market in the United States in a 25-year period ending in 2000 -- one out of every five -- had to either be taken off the market or was subject to a black box warning.
Now, those decisions to remove from the market or to put a black box warning on could be made sooner -- thereby sparing large numbers of lives and bad health that are caused by the drugs -- if we had a more effective system of reporting. FDA funded an experiment in Rhode Island back 10-15 years ago, which showed that with an intervention, they could increase 17-fold the amount of reports that were submitted -- adverse reaction reports submitted by doctors. It worked well, but then they stopped the intervention, and the reporting rate went back down. There's no reason why we can't use this kind of knowledge to greatly stimulate the amount of reports. But that's just the first step.
The second step is in analyzing the reports and making a decision as to what to do. For too long, the analyses that are done in the post-market surveillance part of the FDA fall on deaf or hostile ears. The people who are running the FDA, the people who are wedded to the idea that when they approved a drug, it must have been OK or we wouldn't have approved it, tend to take very, very negatively the criticism that comes from those people that do the post-market surveillance.
Often, usually, the battle is won by the people that want to leave it on the market, the people who don't want to put a black box warning. So within the FDA, there's a very dangerous, unhealthy tension that results in drugs being approved that shouldn't be approved, and drugs staying on the market much longer than they should.
It seems like, at the FDA, there's not room for people who say there might be a problem with a drug. Is that the case? And if so, how do you explain why that's the attitude there?
In the context of the large number of drugs that had to come off the market in the late 1990s, we did a study of physicians at the FDA who are in the drug approval division. We found that between them, they had identified 27 drugs that they thought were too dangerous to come on the market. But those drugs were approved over their objection. They eventually signed off on the drugs, but they told us anonymously in a survey that they thought the drugs should not be on the market.
Many of them also told us in the survey that they were silenced; they were gagged; they were not allowed to speak out at a public FDA advisory committee meeting to voice their concerns about the safety of drugs, if it would interfere with the possibility that the drug might get approved. ...
The FDA frequently reminds people that the decisions are based on the best medicine and the best science. You have to have an open atmosphere of scientific discussion and dispute if that's going to happen. Despite saying that, FDA scientists have their views overturned, even when they are saying a drug shouldn't be approved. FDA scientists are silenced when they would otherwise like to speak up at a public advisory committee meeting.
So the reality, as opposed to the rhetoric, is really squelching dissension, putting down people who speak up.
As a result of this, a number of people have been killed or injured because of decisions that went the wrong way. They went the nonscientific way. They went the way that the industry would have preferred. Unfortunately, as the British Medical Journal said in a recent article, asking the question, "Who owns the FDA?" I think the answer is too much of the FDA is owned by the views and attitudes and what's good for the pharmaceutical industry.
How does that happen? How is the pharmaceutical industry making its inroads into the FDA? Where is it exerting its influence?
The pharmaceutical industry's influence gets exerted in a number of ways. One, starting 10 years ago [with the Prescription Drug User Fee Act of 1992], the influence was exerted by their directly funding, paying cash right up front for FDA review. So in many ways, the FDA started looking upon the industry as their client, instead of the public and the public health, which should be the client.
A second way in which the industry influence occurs is by having leaders in the drug division who are spineless and gutless, and who don't like controversy. I have heard over and over again, directly from these people, "Why can't this be settled on a scientific and medical basis?" They don't like to take on the very awesome forces of the drug industry and a lot of its indentured servants, so to speak, in academic medicine. So the attitude by the leaders there [is], "Avoid conflict" -- and avoiding conflict means doing what the industry wants.
A third way in which the industry's influence has been allowed to grow considerably is the absence of congressional oversight. Up until 12 years ago, whenever the FDA would make a mistake -- such as the series of mistakes they've made in the late 1990s -- there would be a congressional hearing. They would have to explain to the legislative branch of the government what went wrong. They would be -- properly, and in the best public health sense -- on the defensive to try and explain what went wrong.
No one is there in the Congress [now]. There have been essentially one or two days of oversight hearings in 12 years, as opposed to maybe the previous 12 years with dozens and dozens of oversights. So they're getting away with no congressional oversight.
Those are some of the reasons. And the culture at the FDA has become, "Please the industry. Avoid conflict. Look upon our role as getting out as many drugs as possible."
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 ten 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.
The reason that we advise people not to use any new drug for seven years, until it's been on the market for seven years unless it's a breakthrough drug, is that the more recent drugs are much more likely to have to get taken off the market or to have box warnings. The drugs that have been on the market for a while, we know more about. They're more reliable. Often, they're generically available and much less expensive.
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."...
Why is it that these similar or "me-too" drugs -- the third or fourth or tenth drug in a category -- why is it going to get into more trouble? Why is it not going to get as serious a review? Why are those drugs coming up with more problems?
Once the industry realizes that painkillers or diabetes drugs or high blood pressure drugs are a lucrative market -- which they've known for a long time -- they try and slice out another piece of it. If you're a company that doesn't have a drug in that category -- "Hey, it's a $1 billion or $2 billion or $3 billion market, if we can just get a drug in there" -- they obviously have to introduce something that is new. Therefore, they have to develop a molecule that is at least slightly different -- different enough to get a patent -- from the existing drugs. In terms of effectiveness, it may well be that the drug is no more effective. But just changing one or two little molecules may impose a safety risk that wasn't present in the other drugs.
So one reason why some of these newer drugs in the me-too category are more dangerous is the companies were manipulating the basic molecular structure, and adding something that turned out to be more dangerous, even though no more effective. ...
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.
Maybe this is going to come as a surprise to people. But 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. You don't have to show, head to head, that it's as effective or more effective. And you don't have to show head to head that it's as safe or more safe.
Therefore, FDA doesn't have the legislative authority to say no to me-too drugs just because, as it turns out, it isn't any better than an existing drug, which is most often the case. Of course, it's going to be worse statistically, because we don't know as much about it as we should. The older drugs have been around for a longer time. We have not only the experience prior to approval, but we have thousands or millions of people who've used them. We have a much better idea of what to expect. That's not the case with a drug that is just coming on the market.
Just to follow up on that -- I was told this morning at the Food and Drug Administration that it's good that we have choices, that new drugs open up the possibility that they're going to be the best thing for some people. It's responsible to approve them, it's better to approve them, and allow doctors to choose.
The party line from the pharmaceutical industry has been, "Doctors should have as many choices as possible. New drugs, even if in the same category, may be of benefit." It is interesting that to support the British Medical Journal's contention that maybe the pharmaceutical industry owns the FDA, the FDA itself is now spouting the same kind of rhetoric.
If this were true, it should be able to be demonstrated in some kinds of clinical studies. If it's just left to a fantasy, to a possibility, that's not good enough. You need to have some kind of evidence that the tenth drug in a category is actually going to be better than -- not just as good or worse than -- an existing drug. If the FDA doesn't have the authority to demand these head-to-head studies, we're not going to find that out until it's too late, until the drug has come on the market.
So for an FDA official to say it's OK to keep approving more and more and more me-too drugs in various categories because they may benefit someone, that's not good enough. That's an anti-scientific, anti-intellectual kind of statement to make. ...
Imagine being a physician or a reviewer at the FDA and hearing, as someone will, their boss say, "Well, it's OK to approve these drugs, because they may benefit someone." It's very demoralizing.
I mean, the morale at the FDA is the lowest I've seen in 31 years now. The turnovers -- the FDA did its own study, which you probably have seen, the summer of 2001, trying to find out why so many people were leaving. Like the results of our study, they found that a number of people are complaining about having their opinions overturned. These are scientists, pharmacologists, physicians, and so forth.
What evidence is there that it's the pharmaceutical industry influence that is changing these attitudes in the upper levels of management at the FDA, that's overruling the scientists, that's putting the business interests first?
The FDA is an agency of the Public Health Service. Its primary mission is to improve the public health. You have to be very cautious when -- through a combination of being funded directly by the industry, as opposed to through the U.S. Treasury, and congressional influences which are pro-industry, as opposed to pro-consumer -- it starts moving in a way that is very favorable to the industry.
The positive opinions of the pharmaceutical industry of the FDA have never been higher than they were at least from 1997 to 2001. The last year, they've been complaining a little, because there's been a smaller number of drugs approved.
But one way of gauging how favorable the FDA is acting towards the pharmaceutical industry is just to ask the pharmaceutical industry what they think of the new FDA, the FDA from, let's say, 1995-1996 through 2000-2001. They love it. They gave a former FDA commissioner an award for doing a terrific job. You would not have seen these things 10-15 years ago, when the FDA was in an appropriately vigilant and appropriately adversarial attitude with industry.
The FDA, obviously, has to work with the industry, and that's good. But when the FDA starts getting taken over in many ways by the industry, that's not good. In response to the questionnaire that we sent out to the physicians at the FDA, they themselves told us that, many times, they believe that industry influence was operating on the people above them, and getting their bosses to overturn some of the decisions that they had made against approving a drug.
So there are lots of sources of evidence about the fact that the pharmaceutical industry has an almost unprecedented finger or thumb on the FDA in the last few years, compared with any time in the past.
What does your organization do? ... What is it that the Health Research Group does? Why are you in business? ...
I decided to start this group [31 years ago], largely to monitor the Food and Drug Administration and the pharmaceutical industry. That's been about two-thirds of the work we do. We also monitor occupational health, worker health, and OSHA, put out some things on questionable doctors, and so forth.
But the imbalance of power between the pharmaceutical industry and the FDA has always been a problem. It's gotten much worse the last five or six or seven years. But even in the better days, there was a need for someone outside the government -- and, obviously, outside the industry -- to raise questions, collect information, analyze data, and try and get drugs taken off the market.
We've succeeded in getting 12 prescription drugs taken off the market over these 20 or 30 years. We don't often ask the FDA, "Take a drug off the market." When we do, it's only because we think the information is crystal clear. We asked for Rezulin to be taken off the market way before it was taken off the market. We asked for it to be taken off the market, I think, in the summer of 1999. It wasn't taken off the market for another year and a half.
So our job is to collect information free of the influence of the pharmaceutical industry, or free of the often-negative influences of the Congress, which sometimes pushes the FDA in the direction of the industry, and take appropriate action. [That] means filing a formal petition with the FDA asking them to ban a drug, put a warning label on, and if they don't respond, suing them. We have a litigation group which has gone to court many times to ask the FDA to take a drug off the market. In a number of instances, we have succeeded. Usually, the cases are not litigated, because the FDA backs off.
But the question is, why is it necessary for there to be a force outside of the FDA, when the FDA has all the legal authority they need to protect the public health? I think the answer is they aren't using their legal authority. They are a cop with all of the law behind them, but often intimidated by the pharmaceutical industry, and not using the law to protect the public from a series of well-documented health hazards.
Well, is that actually true? ... Does the FDA really have the authority to keep drugs that are maybe marginal off the market? Isn't there a standard? If it's better than a placebo, do they have the capability? Does Congress need to tell them to do a different job?
... Under existing law and regulations, FDA has shown a number of times in the past that if there's a safety question about a drug or a dose of a drug, they can say no to it. The companies may not like it, but they have the authority to do that. If the companies object, the information can possibly be made public, and the side of the FDA will more likely prevail.
Just as in the 1980s and up to the mid-1990s the FDA did, in fact, turn down a number of drugs, because they weren't necessarily any more effective, and there were questions about safety. They could still be doing that. It's a matter of law enforcement. The fact is that, despite advice to the contrary by physicians at the FDA, pharmacologists, advisory committees, they have gone ahead recently and approved a number of drugs.
One of the drugs we're trying to get off the market now is a weight reduction drug called Meridia, sibutramine. The physician in charge of that drug at the FDA said it was too dangerous, [that] it shouldn't be approved. The FDA advisory committee on that drug voted against approving it. It was approved despite that, because there was a big push to replace a recently banned diet drug, Fen-Phen, dexfenfluramine, or Redux, the drug there. The FDA felt, somehow, "Well, we've taken one away. We have to give them another," even though the doctor at the FDA thought it was too dangerous, even though the FDA advisory committee thought it was too dangerous.
The FDA does have the authority to say no much more often than they have in the last five or six or seven years. The FDA would be helped, however, if they did have the authority to impose massive civil penalties on drug companies. There's nothing a drug company can do, no matter how horrendous, that the FDA will fine it, because the FDA doesn't have the legal authority to fine drug companies for anything at all.
Another thing that would improve FDA's authority is if they could actually say, when a new drug came along, "You have to provide us evidence that this drug is safer and/or more effective than the old drug, or we're just going to turn it down." They don't have that authority right now. ...
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.
If there's a drug that has some problems -- if you're seeing some drugs that are coming up with adverse effects that weren't expected that are very serious -- is it a reasonable approach to try to manage that problem, to try to figure out a safer way to use that drug, maybe through warnings of the risk to people who use it, or who prescribe it?
Two answers required. We would prefer the use of risk prevention, if possible, to risk management. Here's why. If there's some evidence of a risk for a drug before it comes on the market, what should be done is not to approve it. Management is not really the concept. It's risk prevention by not approving the drug.
Once a drug -- let's assume a drug that there wasn't any information prior to approval -- comes on the market, problems start arising. The question is, what can you do to "manage the risk," other than just take it off the market? If it's a drug for a life-threatening medical condition, you'd like to keep it on the market. You'd like to do whatever you can to retain it on the market.
The drugs that have gotten in trouble are mainly not lifesaving drugs. They're drugs with lots of other ones around. FDA has an almost unblemished record of failing to use risk management techniques, such as warning labels, letters to doctors, box warnings, to take care of these problems. In instance after instance, after a failed -- and dangerously so -- risk management program, the drug comes off the market. The question is, now that we have so much evidence from drugs like Rezulin, drugs like Duract, drugs like Posicor, of failed FDA-industry risk management attempts -- why bother trying those again, particularly if the drug is not a unique drug?
The answer, again, should be [that] once enough evidence occurs prior to marketing or afterwards that there's a problem, don't even pretend to think that you can manage it by putting warnings out. Both the FDA and our organization did a study showing that fewer than 5 percent of the people who were getting Rezulin were getting the supposedly correct number of liver studies to make sure that they weren't getting toxicity. So it just doesn't work.
The concept of risk management, if it also includes risk prevention by bans either before a drug comes on the market or shortly afterwards, if there were evidence that that worked -- labeling changes, warnings -- it would be one thing. But FDA knows from its own experience -- with failed attempts to manage risk by warning labels and box warnings -- not to go that route, especially if it's a drug that really doesn't offer any unique advantage.
Six or seven years ago, they might have said, "It's worth trying." It's been tried. As a result of trying it and failing to accomplish it, large numbers of people have been killed or injured for drugs that should have been taken off the market sooner rather than later, when they were taken off the market.
So risk management -- it's not good for consumers at all? It's not good to try to figure out how to make a drug that's got some problems, used more safely?
If the drug has unique advantage and is really saving lives, it's definitely worth trying to figure out what you can do to keep it on the market. But if the drug, as is much more often the case, is not a uniquely advantageous drug, when the problem arises, it should be dealt with definitively, and the drug taken off the market, rather than pretending, contrary to all of the evidence of the last five or six years, that you can actually manage the risk without taking it off the market. ...
So how many people are coming from the FDA to work here? Why are they doing that?
In the first 24 or 25 years of this group's existence, no one from the FDA ever called and said, "I'd rather be working with you." Because they thought that at least they could get some things done in the FDA. Sometimes they would give us leads on things that we could follow up on, although most of the efforts to ban drugs really came from our own surveillance.
However, unlike the first 24 or 25 years, [in] the last six or so years, there have been an unprecedented number -- as in more than zero -- of FDA employees who have asked to work here.
I would say that, as of now, there have been about ten physicians or other scientists in the FDA who have called and said, "I really would like to leave the FDA, and work here." We don't have the funds. We have three working, all on a part-time basis. All came from the drug part of the FDA, which is the most demoralized part of the FDA right now, I believe. All of them said, "We aren't able to do what we would like to do at the FDA, because we are being squelched. We're being ridiculed. We're being overturned in terms of our decisions. We would like to come here, because you are free of those kinds of influences."
As a matter of policy, we don't take any money from the government. We don't take any money from industry or any associations at all. So people know, from our record, that we tell it like it is. We do very careful research. A lot of it published in medical journals, and so forth.
So I think that one of the symptoms of the demise, or at least the retrenchment of the FDA from what it used to be, is this large number of people, including one very recently who sent a resume, and said, "Can I come and work here? I'm going to take early retirement from the FDA."
We were just talking about some numbers here. Should we be alarmed at the number of drugs that have been coming off the market in the last few years? Or is it really no different than it's always been?
The absolute number of drugs that's come off the market in the last five or six years is really much higher than any period of time. The industry and its increasing friend, the FDA, try and say, "Oh, no. What you really should be looking at is what percentage of the drugs that we approved came off the market." From a public health perspective, what really matters is how much damage is being done. The more drugs that come on the market, and then have to be taken off the market only after a lot of people are killed or injured really is a measure of the total damage. So the total damage is really much higher than it's ever been.
A recent study by the GAO, done at the request of some members of Congress, showed that even more recently, the percentage of drugs that is coming off the market is higher than it's been before.
But whichever way you look at it, the FDA is doing the worst job in the drug safety area than they've done anytime in the past 31 years. You hear this from employees at the FDA, some of whom are coming to work here. Others of whom are just taking early retirement. A much larger number are sort of biting their tongues, staying at the FDA, even though they are not at all satisfied with how weakened the standards for safety and effectiveness have become over the last five or six years.
You mentioned the French system of Pharmacovigilance. ... In the United Kingdom, in Great Britain, is there a better system as well, compared to what we have here? ... What's the system in England?
In the United Kingdom, they have a system called the Yellow Card system, where physicians who have patients who they believe have had adverse drug reactions will fill out a yellow card, and send it in to the government.
An interesting contrast between the British system and the American system is that most of the adverse drug reactions that get reported to the FDA come from the industry. They are required by law to report these. We believe that the completeness or accuracy of a lot of these reports is tainted, because they come from the industry. In Britain, the overwhelming proportion of the adverse reaction reports come directly from physicians, who do not have the financial incentives to tilt the data in a way to make it look more favorable to the drug company.
But even in the United States, experiments that have been tried to increase the amount of adverse drug reaction reporting have worked -- and then they've been abandoned. When I was a resident back 35 years ago, the Residents' Fund would get $20 or something like that every time an adverse reaction was reported. It encouraged a lot of young residents to report things, when they might not have otherwise. ...
A number of things that have been tried and worked, but then they've been abandoned. So the United States knows exactly what to do if they want to increase the number or rate of adverse reaction reports.
But equally important is, what do you do when you get those reports in there? Do you take them seriously? Do you take the obvious and legally mandated action to take a drug off the market? Or warn about it once those reports come in there? That's what is going wrong as much as anything at the FDA. Once all the work is done on these reports, they don't go anywhere too often, and people suffer.
Can you just give me a basic description of the user fees? What's that concept? How does it work?
For the first 86 years of FDA's existence, from 1906-1992, all of FDA's funding came through the U.S. Treasury. In other words, everyone -- industry-- People paid their taxes and FDA got appropriations out of the budget.
Starting in 1992, unfortunately, a law was passed that said, for a large proportion of the work done by the FDA on looking on new drug applications, the money's going to come directly, quid pro quo, from the industry. If they want a drug reviewed, they pay directly to the FDA to have the drug reviewed.
This system has created a very unhealthy relationship -- even more unhealthy than it used to be -- between the industry and the FDA, where the FDA says, "We have to be nice to these people, because they are paying our bills." It's developed an unhealthy sort of client relationship between the government and the industry which, I think, has resulted in some drugs getting approved that shouldn't; drugs being put on a faster track than they should have.
I think that, in general, it's been a very bad idea. We strongly favor ending this experiment, which has had, in the10 years that it's been in existence, some of the worst things happen in terms of drug safety we've ever seen. I think that's not the only explanation. But direct cash funding from the pharmaceutical industry to the FDA turns out to be a very bad idea.
This may be a personal thing, but I've heard a lot of people say, "Sid Wolfe never saw a drug that he liked. He's just too negative to evaluate drugs." What do you say to that?
For anyone to say that we are just totally negative about drugs, and that we've never met a drug that we actually do like, is ridiculous. They are essentially ignoring a large proportion of the work that we've done over the last 31 years. Because the thing that most people know us for, other than our work at the FDA to try and get drugs taken off the market, are books called "Worse Pills, Best Pills." Now three editions, 2.2 million copies sold, where for every drug that we say, "This is the worst pill. It's dangerous," we say, "But here is a safer alternative." So that book and a newsletter we put out accompanying the book in between editions clearly says we have a long list of drugs that we think are good, effective, and safer. They're often older kinds of drugs.
So we have a much longer list of safer alternatives than we do of dangerous drugs. That's not surprising. That's why we try and guide people, if they'd need to take a drug, to take one that has more benefits and fewer risks, rather than the worst pill that has fewer benefits and more risks.
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