The FDA Exposed: An Interview With Dr. David Graham, the Vioxx® WhistleblowerOctober 2012
MANETTE: It's estimated that over 200,000 people a year die from prescription drugs. Do you see this as a serious problem and do you think many of these treatments are more dangerous than the disease itself?
DR. GRAHAM: Death from adverse drug reactions is one of the leading causes of death in the United States. It turns out that most of these adverse reactions are actually what are expected in the sense that they are an extension of the drug's action. For example, we know that drugs for diabetes can lower your blood sugar. If you're more sensitive to the drug than the normal person and it lowers your blood sugar too much, causing you to have a seizure while driving your car and you get killed, well, you died from an adverse drug reaction, but it wasn't something unexpected.
The blood thinner Coumadin® is another example. That drug provides a benefit, but it is also responsible for probably more deaths than any single drug currently marketed. But it has a recognized benefit and there aren't other drugs to do what it does or to do what it does well. So physicians accept that there are patients who are in a serious situation and who might die without the drug, so they take it.
Yes, drugs cause a lot of harm. Unfortunately, we haven't quantified the benefits. For most of these drugs it's more belief. It's faith. We have faith that they'll confer a benefit, but the FDA hasn't demonstrated that they confer a benefit. We're getting much better at quantitating the risks. In the future what we need to do is just take the risks and look hard and dispassionately at what the real benefits are. If the benefits aren't there we shouldn't be having discussions about labeling the drug. You need to weed the garden patch of drugs that aren't doing what they're supposed to do. The FDA has not been very good about that; it likes to cultivate all these weeds.
MANETTE: In a perfect world what role do you see the FDA playing in our nation's health?
DR. GRAHAM: In a perfect world, I think the FDA would need to be restructured. If it were restructured properly, I think that it could actually provide a great benefit to the public health. I would recommend several changes. First, I would separate safety and post-marketing from the pre-marketing. I would create a separate center for product safety. Actually, Senator Grassley and Dodd have recently introduced legislation to create an independent center for post-marketing safety that would serve to protect the American people from unsafe drugs. This isn't happening now.
On the pre-marketing side, the FDA needs to pay greater attention to safety. They need to have larger clinical trials. They need to compare drug products against other drugs that treat the same indication rather than comparing a drug against a sugar pill. What we want in the end are drugs that actually have better benefit.
The FDA also needs to determine the post-marketing benefits of a drug. I've done that for several drugs. How many people are actually benefiting? How many people are living longer versus those who are having their lives shortened? Only when you have that kind of information can you make rational decisions about a medication. The times when I've done the benefit analysis, I've been chastised, criticized and suppressed by the FDA. These benefit analyses should be done as a matter of routine.
There is a lot that the FDA could do to improve, but the changes aren't going to happen on their own. Congress is going to have to make them happen. There's an expression, "the zebra doesn't change its stripes nor the leopard its spots." The FDA isn't going to change the way it does business; changes will have to be imposed from outside.
MANETTE: How do you feel about direct-to-consumer advertising?
DR. GRAHAM: Direct-to-consumer advertising in general is a great disservice to the American people. We see wonderful ads of people demonstrating their health, whether they're skating across the ice or doing their Tai chi. Madison Avenue knows that a picture is worth a thousand words, so they convey an image, a message, and it makes an impression on patients and on physicians. It creates needs or desires where there really isn't a need or a desire.
There was a recent study in The Journal of The American Medical Association that showed that if patients mentioned a drug that they've seen on television to their physician they were much more likely to be prescribed that drug by the doctor. Drug companies know this. That's why they do it. Would the Vioxx® disaster have been as great and as large in the absence of direct-to-consumer advertising? I submit that the numbers would have been far lower than what they were. Direct-to-consumer advertising is part of what made Vioxx® a blockbuster drug. It helped to rev the market up to get people to want to use the drug.
Clearly, direct-to-consumer advertising does not serve the American people well. Madison Avenue is smarter than the most intelligent American. That's why they make so much money and that's why the drug companies go to them to sell their products. We're not living in a neutral world where the information we're getting is objective and unbiased. It might be that the average American, given all the data, all the facts, and all the information in an objective way could make an intelligent, rational decision. But we don't live in that kind of world. We live in a world where what we're seeing is a visual image of these people being vital and healthy and cured of their illnesses. And it's all because of this little pill that they're taking. A patient with that condition says, "I want to be just like that person." So they go to the doctor and say, "I want that pill." Are their lives changed? Maybe some people's lives are changed, but I think most aren't.
MANETTE: What do you think people hear when they're watching the ad and after the ad they list all the possible side effects?
DR. GRAHAM: I don't think it registers. You have the visual image that conveys one message. Then you have the voice that's speaking over this pictorial being shown telling you what this drug is good for. Then at the end the auctioneer gets on and says, "You know this drug could cause…," and they rattle off 25 different things in three seconds. You're lucky if you hear anything. I don't think that people come away with it and they certainly don't come away with any sense of how likely it is to happen because the visual image overpowers anything that gets said.
It's the same with the ads that appear in magazines. Companies are required to put some of the labeling in the ad. You have the ad on the one side - that's the picture. It shows this person being healthy because they take this pill. The fine print is all on the next page. People aren't going to read the fine print. It's the same thing with labeling for physicians. Physicians don't read product labels. Where do they learn about drugs? They learn about drugs from the detail person from the drug company or from other colleagues who have used the drug. They're not learning it from the labeling.
MANETTE: Do you think there is a criminal cover-up going on between the FDA and Big Pharma to approve dangerous drugs that sicken and kill Americans?
DR. GRAHAM: I have no knowledge of criminal activity and I'm sure there are legal standards for what's criminal and what's not. I do think that there is an institutional bias at the FDA that says we will look for a way to say "yes" to the approval of any drug that comes down the pipe. If a drug is so bad that they can't find a reason to approve it, they won't. But, if there is any way that they can approve the drug, they will. The way this is done is by what's called the "indication." Why is it that you're going to take the drug? Maybe you're going to take it because you have high blood pressure. Maybe you'll take it because you have high cholesterol. That's the indication. A company may come in with a drug and want to get it approved for five different indications. One of them is a really insignificant indication that affects a very small number of people. The main indication might affect millions of people. The drug doesn't show efficacy for that major indication, but they're able to somehow or another approve the small indication.
So the drug gets approved for this narrow indication, but the FDA and the drug company both know that it's going to be used for that other indication. It's going to be used "off-label." Then, the FDA turns around and says that they don't regulate the "off- label" use of drugs. No. But, they aid and abet it. They allow it to happen and in many instances "off-label" use of a drug product is a public health threat. The FDA has a responsibility to protect the public health. The FDA should be intervening, but they don't. In my own experience I have seen multiple examples where I've heard people say, "We can't ask a company to put that in the labeling because the company will say no." Or, "We can't do that because that will decrease their marketing. We've got to try to approve this drug. Let's see if we can give them this small indication. At least it's giving them something. You've got to find a way to say yes."
That is the typical attitude of the FDA culture. I think Congress is partially responsible for that because when they issued the PDUFA, the Prescription Drug User Fee Act, what they were really saying was, "We want you to review these drug applications more quickly because you're keeping lifesaving medicines from the American people." That's the line they were fed by Big Pharma. So they pressure the FDA and the FDA gets the message. It's a really pernicious system. I think it's unfortunate. There are many people from the FDA who have examples that they unfortunately can't talk about. They'd lose their job and maybe get thrown in prison because you can't discuss confidential and trade secret information. But the fact is these things happen at the FDA and there have been multiple examples in the past where one could see evidence of that.
MANETTE: Did your faith as a devout Roman Catholic play any role in the decisions you made to put your career on the line to report the truth?
DR. GRAHAM: It did in so far as my faith forms my conscience. It's sort of my sense of what's right and what's wrong and what I am and am not responsible for. I was in a situation here with Vioxx® where I was invited by Senator Grassley's office to testify. I could have told them no, but then they would have subpoenaed me. So of course I went peaceably. I was faced with this dilemma. Should I lay it on the line and tell them the way it really is or do I kind of downplay it? There are ways of doing that.
What I concluded was that I'm now being given the opportunity to tell the truth to the people who are in a position to actually make a difference. I can't make a difference. I can't change the FDA, but Congress can. If I don't tell them the truth, then I'm now responsible, in part, for future deaths. I don't want to become a co-conspirator with the FDA in what happens with Vioxx® because tens of thousands of people were injured or killed because of the FDA's disregard for safety. If I keep quiet about that, now I'm part of the problem. I'm one of them, and at that point then my conscience asks me, "You know what the truth is, are you going to speak it or aren't you?"
So I went ahead and did that and prayed that it all works out well for me personally. That I have a job and I'll be able to support my family, that I'm protected from retaliation, that maybe some good will come out of that. My faith plays a role, but it wasn't a direct teaching of the church. You have to do x, y and z, but it's the faith as I've internalized it. My conscience is formed by the voice of Christ speaking internally to me. That's what the conscience is; it's the voice of God speaking to each and every one of us about what's right and what's wrong. I knew what was right. If I walked away from that nobody else would have to do anything. I'd be beating myself up because my conscience would condemn me. So yes, faith plays a part in everything that I do. It's not saying I'm a saint, because I'm not. But I can't separate who I am from my religious faith. It's all part of the same person.
MANETTE: Do you think Congress genuinely wants to fix the problems at the FDA or are too many politicians influenced by the pharmaceutical industry?
DR. GRAHAM: I don't know what Congress will do in the end. My hope is that they will act decisively to reform the FDA and make the American people safer by having strong post-marketing. Will that happen or not? I don't know. I think there are many people in Congress who see this as a serious problem and who very much want to see a change. I think at the same time there are other people who don't think it's such a bad problem, and many of those people honestly believe that. For those people I'd say they haven't seen the evidence so they don't really understand how bad the problem is. There are undoubtedly some people who are influenced by industry. Does that influence their judgment in the end? I don't know. They'd probably say no, it doesn't. Maybe at a conscious level it doesn't. But we have the same phenomenon in the scientific world where we look at research studies that are funded by industry and studies that are funded by government, by National Institutes of Health or the Medical Research Council in the United Kingdom. Multiple studies have been done that have shown that if your study is funded by industry you are much likelier - about five times more likely - to come up with the result that's favorable to the drug company than if your study on the same subject is funded by an independent body unrelated to the company.
Now, are the researchers who did this study biased? Are they consciously cheating and manipulating the data and everything else? No. I don't think that's happening at all, but the fact is if the study is funded by industry it's much more likely to be favorable to industry. Without attributing bad motivations to the scientists doing those studies all I can do is point to a strong correlation.
With Congress I would be concerned that there could be a strong correlation there because Pharma is very bright. They fund as many politicians as they can. They get to the Republicans and the Democrats. Look at the funding on the major committees, the Health, Education, Labor and Pension Committee in the Senate or the Oversight and Investigations Subcommittee in the House. The Wall Street Journal reported recently that many people on these committees are funded by industry to a substantial degree. Industry knows how to exercise influence. What we have to do is overcome that influence with evidence, and then rely on the fact that at the end of the day the Congress will do what's best for the American people.
Will that happen? I don't know because then it gets embroiled in politics. You know, Republicans versus Democrats, the left versus the right, conservatives versus liberals. Yet, what we're talking about is public health and public health is nonpartisan. I can say this with certainty. For every member of the House of Representatives somebody in their district died because of Vioxx®. Somebody in their district had a heart attack because of Vioxx®. For every Senator in the Senate, many more people in their state died because of Vioxx® or had a heart attack because of Vioxx®. It doesn't matter whether it's a red state or a blue state. Those are human beings and what we're talking about is public health. What I'm hoping is that Congress will respond. There is a problem and the evidence is overwhelming, but we'll just have to wait and see.
MANETTE: What are your thoughts on former President Bush's attempt to pass tort reform, which would protect most pharmaceutical companies from lawsuits except in the most egregious cases?
DR. GRAHAM: I think it's dangerous and wrong for the following reasons. We already have an FDA that's been neutralized by industry and sees industry as its client. The Center for Drug Evaluation and The Office of New Drugs dominates drug safety so that the drug safety is not independent. Drug safety can't protect the American people. So government now isn't going to protect the average citizen from the consequences of unsafe drugs. The only alternative they have left is the legal system - the tort system. It's not a wonderful system. It would be much better if we had effective post-marketing regulation so that we could get bad drugs off the market before they hurt more people, but that's been neutralized. All that's left to people now is the courts. That's the only way we have of getting companies to change their behavior.
What tort reform will do is remove that threat as well. It's basically giving companies immunity because now the people who are injured by the drugs can't recover damages that might actually mean something to industry. I mean $250,000 for damages; they blow that in one ad campaign. To them that's nothing. But a lawsuit for multiple millions of dollars has more of an impact. Now, is that optimal? No. But the fact is that since we have a regulatory agency that doesn't regulate and we have a public health agency that doesn't protect the public, we have thousands of people who are being injured by products that the FDA knows are unsafe. The FDA knew there was a problem with Vioxx®. They knew it was a big problem back in mid 2000 yet did nothing about it.
There has to be a system in place that reins companies in. If the FDA isn't going to exercise control over companies, then who will? How will it happen? I don't think that working through the courts and lawsuits is a particularly effective way of doing it; but it's the only recourse we have now, and that will be removed as well. You can demonize the trial lawyers but I think that there are patients who are severely injured by drugs. The defense is, "It's on the labels so we're protected." The problem is that nobody reads the labels so how do they protect anyone? The FDA should be making those decisions.
MANETTE: What can you tell us about all the antidepressants on the market that millions of children are taking?
DR. GRAHAM: In early 2004, SSRI antidepressants and suicidal behavior was a big safety issue. The FDA had suppressed a report written by a colleague of mine in drug safety and had prevented him from presenting this information in an advisory committee meeting. That information leaked to the media, embarrassing the FDA because it had been caught suppressing very important information - that most of the antidepressants don't work for treating children. Someone in my supervisory chain initiated a criminal investigation to identify the person who had leaked this information to the media. It turns out that the investigation ordered by these FDA officials was illegal. They broke federal laws - at least two or three federal laws - in ordering this investigation.
I think it's well established that depression is very common in adolescence. With the antidepressants that we have on the market right now only one of them has been shown to work in children and that's Fluoxetine or Prozac®. All the other SSRI antidepressants are no better than sugar pills. However, if you were to read the labeling for these drugs it doesn't point that fact out so patients think one SSRI is as good as another. This is another way that the FDA has betrayed the American public and has betrayed the public health.
With the SSRI and antidepressants what the FDA should have insisted on was a signed informed consent at the time a child was going to be treated. That informed consent would say three things. One, these are the antidepressants that are available. Only Fluoxetine has been shown to work for depression in children. All the other drugs are no better than placebo. That's point two. No better than placebos. No better than sugar pills. Third, all of these drugs appear to have the ability to increase the risk of suicidal behavior. As a parent, if I see that in writing and the psychiatrist or GP is going to write the prescription and put my child on some drug other than Fluoxetine, I can say, "Doc, why are you putting my child on a drug that doesn't work in kids."
The FDA didn't want patients to have that information so they refused to have signed informed consent. The companies didn't want the patients to have that information because all of a sudden the "off-label" use of these drugs would dry up. So whose interest was being served there?
MANETTE: How do you feel about taking the approval process out of the hands of the FDA?
DR. GRAHAM: Well, where would you put it? If you put it somewhere else they're going to eventually become co-opted the way the FDA has been co-opted. I think the most that we could probably hope for is to try to disassociate the industry pressures from the approval decision. You have to change the culture of the organization, and you have to change the incentives in the organization. The culture and the incentives that the FDA operates by would have to be changed, and Congress can do that through legislation and by establishing different standards for how a drug gets approved. Not only do you have to show that the drug is effective, but you've got to show that it works as well or better than other drugs that treat that indication. You've got to prove to me that the drug is safe, not that the drug is harmful because you're never going to prove to me that the drug is harmful. You set up stringent standards of evidence that might lead to the approval of safe drugs that actually have benefits to the population.
Then pair that up with an independent post marketing regulation. Currently, the pre-market people who approve the drug decide what happens after it's on the market. If the drug needs to come off the market, they're the ones who have to say yes at the end of the day. The people at the FDA who approved the drug, the Office of New Drugs, they are the single greatest obstacle when it comes to removing unsafe drugs from the market. I can vouch for that from personal experience. What you have to do is you have to take that responsibility and power away from them and put it with the group who sees their mission as serving the public and protecting the public health from unsafe drugs. I think if you do those two things you'd be a long way towards getting the FDA on the right footing.
Also, it would probably be beneficial not to have the FDA's funding come from industry. He who pays the piper calls the tune, and we now have a captured agency. Industry underwrites more than 50 percent of the Center for Drug Evaluation's budget. When industry yanks the chain whose neck is going to get tugged? The Center for Drug Evaluation! If industry isn't happy with them and the funding dries up what are we going to do? We're going to have to let half our people go. The program is going to shrink. Congress is going to be jumping up and down on our back. So it's a captured agency and America is not well served when industry is calling all the shots. Yes, industry has a right to make a legitimate profit from marketing products that help the American people. But you shouldn't have a situation that just basically leaves the American public defenseless. And that's what we have right now. We're virtually defenseless.
MANETTE: Are there other Vioxx®'s out there? Do you think this will repeat itself at this high profile level?
DR. GRAHAM: At this current moment I don't think there are other drugs out there that are as bad as Vioxx® in terms of the enormous numbers of people that were hurt. During my Senate testimony I did mention that there were five other drugs that I thought the FDA really needed to reevaluate because in my estimation the benefit to risk was misjudged. After I named those five drugs the FDA was in the media saying that I did junk science and that these drugs were safe and effective and that I was a crackpot. However, recently the FDA announced that they were going to take Bextra® off the market. Well, Bextra® was one of the five I mentioned. They announced that with Acutane® they were going to impose a restricted distribution system. Well, I had recommended a restricted distribution system 15 years ago. The major problem with Acutane® is that it's just so widely overused that it causes an enormous amount of potential harm to pregnancy exposure. If we restricted the use of the drug to the small number of women who really need it each year, the problem would be pretty much resolved. But the FDA didn't want to do that because it would interfere with company profits. If you restrict the distribution and only one-tenth of the people who are getting it now are getting it tomorrow, profit will drop 90 percent. Of course companies aren't going to go along with that and the FDA isn't going to do anything that's going to harm corporate profit.
After my Senate testimony the FDA announced that they can look at other drugs - not only the other three of the five that I mentioned. There are other drugs on the market that I prefer not to talk about that the FDA knows are killing people. Ten or 100 people a year are dying because of the use of a particular drug or being hospitalized. Hundreds or maybe thousands of people are being hospitalized each year. For some of those drugs the benefits do exceed the risks. For others, it's clear that more could and should be done and maybe that means restricting the distribution of the drug's use or maybe it means banning an indication for the drug saying the drug should not be used for particular indications. Maybe it would be something like with the SSRI's where I believe there should be signed informed consent so that parents will know that the drug the doctor is prescribing for their son or daughter actually doesn't work in children.
I think that there are many things that can be done that haven't been done. There are other unsafe drugs out there, and the nature of our business is that a drug could be approved tomorrow that turns out to be the next Vioxx® and we won't know until it happens. Then the question is, how quickly do we identify the problem and how quickly do we take effective action against it? We're pretty good at identifying these problems quickly. Where the FDA falls flat on its face is that there is a long period of time in which it does nothing. Then what it normally does is woefully inadequate and ineffective and as a result the body count mounts and that needs to be changed. Maybe Congress will change that.
MANETTE: Let's talk about incentives. When you say incentives what do you mean? For example, working at the FDA, is their pay somehow based on how many drugs they approve?
DR. GRAHAM: Currently, the performance evaluations for managers at the FDA are built around the drug review. How many reviews did they get done? Did they meet their PDUFA deadlines? It looks bad if you miss your PDUFA deadlines. The unspoken mores—what's the expected—is that you're going to approve as many of these drugs as you can. There has to be an overwhelming reason for you not to approve. Frequently what will happen is that these medical officers in their review will recommend that a drug not be approved and they get overruled by the higher ups because the higher ups are answering to a different set of incentives. You have to change that. A lot of that comes from the leaders. What I want to see is does the drug really make a difference? Is it beneficial?
There are many classes of drugs where we've got 10 or 15 members of that class. They all lower your blood pressure. They all lower your cholesterol. Another one comes along and the FDA feels its obligation to approve it. Why? Maybe the standard should be that for the drugs that come later in a class, they've got to show that they're actually better than the drugs on the market because we've already got these other drugs that work. That would create incentives maybe within industry to develop drugs that are better than the ones that are already there. Currently, the way the incentives are for industry, it's safer to do a "me too" drug, another drug in the same class.
MANETTE: Do you think that the FDA should not be partially funded by industry?
DR. GRAHAM: I think that PDUFA funding for the FDA is a mistake.
MANETTE: Can you explain that a little more clearly because most people don't know what PDUFA funding is?
DR. GRAHAM: The drug companies pay a substantial amount of money to the FDA at the time that they bring a drug application for approval in order for the FDA to review the drug. Basically it's a tax. It's a fee. Industry pays the fee, and the FDA will review the drug application. But the real expectation is from the company: "We've paid our money, now approve our drug." That's basically how the FDA reacts as well. I think that the funding for the FDA should be independent of the industry that it's regulating and I think in the scientific field there's good evidence to support this notion. Industry money is influencing the decisions that get made, and it creates this incentive structure. You have this culture, you have these expectations, you have pressure from Congress. All of them come to a head at the FDA and all of those incentives are in the direction of "approve the drug." That's what happens so I believe that the FDA is unduly influenced by industry and that undue influence is in part the result of industry money funding the FDA operations.
MANETTE: Dr. Graham, thank you for your commitment to your convictions and for sharing insights that drove you to save many lives.
DR. GRAHAM: You're welcome. I hope I've helped.
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