dangerous prescription
homethe fdainterviewsdiscussion
interview: stuart rich, m.d.

What was your role in that pulmonary hypertension study, the international study [on pulmonary hypertension and diet drugs]?

I helped write the protocol. I reviewed all of the reports that came in, to make sure that they were accurate and they fit. I helped analyze the results of the study when the study was over. I helped write the paper that got published in The New England Journal of Medicine. So I was a key player in the conduct of all of this.

I had said, Well, you can try. ... The FDA would never permit a drug that had little benefit, terrible risk, on the American marketplace. The FDA is your watchdog that looks out for your safety.'

Part of the complexity is that Servier does not have a marketing force in the United States. So the plan was to license [the diet drug Redux] to an American pharmaceutical company, and let them do the marketing and the sales. That was American Home Products [now Wyeth]. [They] had an enormous marketing force in this country. Their top-selling drug, Premarin, was one of the most prescribed drugs in the United States. So that's how they were, in part, drawn into all of this play.

photo of rich

Stuart Rich is a professor of medicine and director of the Rush Heart Institute Center for Pulmonary Heart Disease in Chicago. In January 2004, he will become the chief medical officer at United Therapeutics Corporation, and will continue at Rush on a part-time basis. In this interview, he recounts his role in the international study of pulmonary hypertension associated with the diet drug Redux, which was published in The New England Journal of Medicine in 1996. The interview was conducted on Nov. 19, 2002.

What was particularly shocking to me was that on the heels of reporting that this drug caused a fatal, incurable disease in Europe, the company was planning to put it on the American marketplace.

When I had heard this, I had said, "Well, you can try. It's never going to get in this country. The FDA would never permit a drug that had little benefit, terrible risk, on the American marketplace. The FDA is your watchdog that looks out for your safety. Their main charge is safety."…

But nonetheless, they submitted to the FDA the paperwork to get this drug approved in the United States, Redux. The sister drug, Pondimin, had already been approved in 1975. It wasn't used very much because of all its side effects. But Redux was going to be their blockbuster [that] they were going to launch.

I was asked by the FDA to be a consultant to them, to testify at the hearing where they decide approval or no approval, share with them my experience of the study in Europe, and my opinions regarding benefits, risks, [and] things like that. I did that. That meeting was in September 1995.

When I agreed to be a consultant to the FDA, they sent me a packet of information that is shared with all of the members of the advisory committee. In the packet of information was all of the efficacy data on the drug. The claim was that this drug makes pounds melt off of you, so it was worth a risk, because there would no longer be obese people in the United States. All of the 300,000 deaths a year they attribute to obesity -- and that number, by the way, is not a solid number -- would end. So you have a life-saving drug with a small risk.

If you looked at the efficacy studies, you found out that its efficacy was minimal, at best. Three percent weight loss after one year. If you weighed 300 pounds, I could say, "End of the year, I'll get you down to 291, with a risk of dying of pulmonary hypertension."

So when I saw all of that, then I really couldn't believe that the FDA would ever give serious consideration to this. Yet, at that hearing that I was at -- can you imagine a lot of lively discussion? The committee voted unsafe. They voted thumbs-down for safety. They were leaning towards "yes" for efficacy. But if you're not safe, you're not going to get approved.

That meeting was suddenly and unusually halted by Jim Bilstead, who was the director of the division. He tabled the vote. He wasn't going to allow a final vote of "yes" or "no." So we're going to table the vote. We're going to meet at another time to finish this at another time; highly unusual. And it was at the other meeting -- where none of the consultants were invited to come back and testify -- that that was approved 6-5 in favor.

Why would somebody at the Food and Drug Administration ask for another meeting after the consultants voted the drug down?

One of the mysteries behind this whole fiasco is what went on behind the scenes of the FDA. I have some suspicions; I don't have proof.

The only thing I can say is that the people at the FDA are human beings like all of us -- like people who work for the CIA, and for the companies. And they're human. There are conflicts of interests, there are motivations, and people sometimes do things that we question why they did that.

But nonetheless, I can tell you that Jim Bilstead resurrected this drug from being denied, and ultimately got it approved. In about April 1996, the drug was approved.

American Home Products was now very actively involved in the packaging and labeling. Their mission was to make sure no black box warning appeared on the package insert, because marketing research showed that if physicians saw a black box warning about its safety, they would not prescribe it as a weight loss pill. If you could eliminate the black box warning, then they would prescribe it. ...

I do not have intimate knowledge as to what transpired between American Home and the FDA for those negotiations. But nonetheless, we now had a drug with minimal efficacy, with terrible safety concerns, and no warning, being put on the marketplace. That drug was launched somewhere in the spring, early summer of 1996.

What was your personal reaction? What was your reaction to the Food and Drug Administration resurrecting this drug that was almost dead?

Do you want the truth? It was despair. My reaction was despair. Why despair? My specialty is I treat patients with pulmonary hypertension. These are the sickest cardiovascular patients that exist. They're young people. They're tragic stories.

We have some treatments -- they are very difficult treatments. It's a death sentence, and it's a slow death, like drowning over months to years, if you can envision what that's like. My heart breaks with every new patient that's referred to me.

So I did the math. They had 10 percent of the women in France on diet pills. OK? Let's assume they're equally successful in the United States. Take all the women. Take 10 percent. We do our projections as to what percent of these will develop pulmonary hypertension. I get a large percent of these referrals around the country. I'm now thinking that I'm going to go from 200 patients a year to 2,000 patients a year, and I despair. I'm not going to be able personally to deal with this epidemic of this horrible disease that I absolutely knew was coming around the corner because of this.

Outrage, shock -- you can name all those emotions. Despair. I was distraught over the notion of what's going to happen as a result of this.

Nonetheless, a part of what we in academia do is we publish our results in the medical literature. We wrote up the results of the study we did in Europe in a paper that we submitted to The New England Journal of Medicine. I don't know how familiar you are, but that's really considered the number one prestigious journal in the world. They like to publish breaking news and breakthroughs, and things like that. They accepted the manuscript right away, and they published it as the lead article in the last week of August 1996.

By agreement, we gave a copy of that manuscript that we submitted to Servier, since Servier originally funded the study. That's very common to do with pharmaceutical studies, even if the results are unfavorable -- to share them with the company that sponsored it, but not allow them to censor it.

They obviously shared that with American Home Products. When it was known that the paper was going to be published, everyone was able to brace themselves. Right on the heels of their launch of this blockbuster drug, there's going to be a paper in The New England Journal of Medicine, saying the drug is not safe. ...

You know, there's a new embargo on the articles in The New England Journal of Medicine. The official [publication] date is on a Thursday, but Wednesday at 5 o'clock is when the embargo is lifted. So you'll see on the evening news on Wednesday the stories in The New England Journal of Medicine.

It just so happened that that was the week of the Democratic convention held in Chicago. The Today show was in Chicago covering the Democratic Convention. Obviously, all of a sudden, this New England Journal of Medicine paper breaks, and this is news. "Blockbuster drug saves lives, lose weight. Not safe. What are we going to do?"

So they called me, and asked if I would be willing to appear on the Today show Thursday morning to talk about the article which I co-authored, which seemed to be at odds with what everyone was being led to believe about this wonderful drug. I agreed. That was the interview that I had with Bryant Gumbel that Thursday morning.

What did you say on the Today show?

Well, I'll be very honest. I couched my statements, in part, because of concern that if I was too inflammatory in this wonderful country of ours, I could end up defending myself in a court of law. Basically, what I said was nothing that was not mentioned in the paper -- that the drug carrier risked a very high risk of developing this fatal disease; that it should not be prescribed lightly; that if, as a physician, you felt that you had a very obese patient who really needed a treatment because of some lifesaving issues, fine. Do not prescribe this as a slimming agent. Do not prescribe it carelessly. Do not assume that there is no serious side effect, because, in fact, it's a potentially serious drug.

So what happened right after your appearance?

Well, interestingly, I got a phone call from [an executive] from American Home Products. ...

When I got back to my office at the medical center earlier that morning, he called me directly. He told me he saw my interview on the Today show, and warned me that it was very dangerous for me to talk to the press about that; that if I had any issues regarding their product that I wanted to publish in a scientific journal, so be it. But if I spoke to the media about their drug, bad things would happen.

What did you understand that to mean, "Bad things would happen?" I mean, those are actually the words he used?

"Bad things would happen" was the exact phrase he used. ... I took the threat very, very seriously. I decided, OK, it's a little unpredictable when you talk to the press anyway -- sometimes you want to say a story, and it comes out a little differently -- so maybe I wouldn't talk to the media. I never did, from that point on, and I was approached by all of the major news stations -- CBS, ABC, NBC. ...

I never talked to the press again. Because I didn't know what they had in mind. They are a very big, a very powerful company. ...

What was the effect on science? What was the effect on distribution of information -- the information that people need?

Let me tell you candidly, I never refused to lecture on the topic. I never held back in telling what I knew was fact. I was very careful to separate out science from speculation, where I could get into trouble. So I only said what I knew I could support with scientific evidence. I published immensely on the topic. So I didn't withhold from the medical community what I knew. But I was careful about what I said, and how I said it.

But you withheld from the public, which is still out there taking these drugs like crazy. ...

No. I really didn't withhold from the public. What I refused to do were special interviews. What I had said was in the public domain. What I was trying to do, after careful thought behind the scenes, was to do everything that I can to protect the public.

Let me tell you exactly. The drug was on the market now, and it's being sold. There are people out there selling them. I could walk around with a placard down in Chicago or in Washington, D.C., and that's just not going to do a whole lot of good [or] save a lot of lives.

But what I did do is use my influence in the medical community. We set up our own independent safety study of this drug in the summer of 1996. The FDA had asked American Home to do it. They didn't. I did it, and my colleagues did it. We paid for it out of our own pockets. We collected this data, implicating the dangers of the drug.

American Home was not happy that we were doing this, especially since they had no control over the collection of the data. That ultimately brought them back to the bargaining table, and it ultimately led to the withdrawal of the drug from the marketplace.

So one could argue that using diplomacy and behind the scenes, I actually accomplished a whole lot more than I could have had I made a public outcry. It wouldn't do any good for my patients for me to be in jail, slapped with a subpoena, filing a lawsuit, defending myself in court, and taking me out of the picture.

So I think, after careful thought, I probably went the route that had the best impact. ...

So when this story's all done, what does this mean about the system that protects the American public, and assures that the drugs that we get are safe and effective?

Well, OK. If you're asking for perfection, the bad news is it doesn't exist anywhere -- my profession, your profession, FDA. The system is evolving. There are weaknesses and flaws.

The drug approval process is a difficult one. I will tell you that I've had a lot of interaction with the FDA. The overall majority of the people are dedicated, hardworking, concerned, caring, wonderful people. But they're human.

There is a very powerful pharmaceutical lobby called PhRMA that, like the other corporations in America, tries to have every legislation done in their best interest. One of the problems with the FDA today is a law where the pharmaceutical companies are actually paying the cost of the FDA. ... There is a conflict there. It's an overt conflict. It's in the FDA's best financial interest to be favorable to the pharmaceutical industry, because that's where their support comes from. I think that was a bad law, and that probably should be changed. But working in those constraints, I think they're doing the best they can.

The pharmaceutical industry is in the business of developing new drugs with the ultimate goal of improving our lives. There are financial interests involved. The amount of money we spend a year on drugs is enormous. There's great profit in this industry.

Personally, my feeling is that if you want to be in the healthcare industry, that you have to make sacrifices -- I don't care whether you are a device company, or a drug company, or a doctor, or a hospital, or what -- that patients' welfare comes first. The public expects that a doctor will do his best, that a drug will be safe, that a hospital will be careful. They have every reason to expect that, and they are betrayed when they're not. Accidents happen, but when it's an intentional betrayal, that's a problem. Hopefully, things will get better.

Whose interests were served in the story of Fen-Phen and Pondimin and Redux?

That's a story of corporate greed. ... Again, not everyone agrees with me. I've said all the way along, and I've just said it here, "If you want to be involved in healthcare, then you have to make some concessions." That is, you will have less profit in the interest of the public. If you want to make tennis shoes, go make your tennis shoes, and sell as many as you can, and charge whatever you want. If you want to make T-shirts, make as many T-shirts, put whatever you want on them, charge whatever you want. That's fine.

In dealing with healthcare, people's lives, there are rules. The rules are everything that you do has to be in the best interest of the public, or you can't do it. Now, is that rule broken? All the time. But that's my kind of Pollyanna vision of the world. "If you want to join us in the healthcare industry, you have to make some concessions." ...

As a result of Fen-Phen becoming a craze, and Redux coming on the market and getting approved, what actually happened, in terms of the damage you've seen?

I have had many patients who have pulmonary hypertension from the diet pills, and who've died. So I lived through part of the tragedy.

The good news -- if you can call it good -- is that the drug was withdrawn very quickly. It was withdrawn almost within a year of being approved, and the irony is, it was withdrawn for another reason. It was withdrawn over the scare that it was damaging heart valves, which many people thought was overstated, and the risk was not as great as it was.

Nonetheless, good things happened here rather than bad things. The good thing was that because I think the people at the FDA regretted the fact that this drug got approved, and they were happy to take any opportunity to get it back off the marketplace. When this scare came out about valve disease, they didn't really insist on what we would call sophisticated epidemiologic studies to prove it. They just went back and said, "This drug has to come off. It's just too unsafe."

What does this whole tale say about the system we have for monitoring drugs once they're on the market?

Well, that system -- it's called MedWatch -- is flawed, and that's nothing new. ...

To put it in perspective, when I do a clinical trial to test a new drug, and I want to see if it's safe and effective, we might give it to 1,000 people. It sounds like a lot of people. In the results of 1,000 people, we see most of them got better, and there was no serious risk, side effects. The drug is safe and effective. Let's get it approved.

If a drug causes a serious reaction in one in 10,000 people, that's very dangerous, because drugs are given to millions of people. ... We never really know about the safety of a drug until it's actually on the market, because one in 10,000 is a high-risk drug. Very few trials give drugs to 10,000 people.

So the FDA initiated what's called a MedWatch program many years ago. They ask physicians to report any time that they see an adverse reaction to a drug that they think might be related. You don't have to prove it was related. You don't have to fill out tons of paperwork. You don't have to do any studies. "You took drug A. Your hair fell out. I'm going to report it to the FDA."

If the FDA keeps getting report after report after report, they're going to say, "This was not a coincidence. There's something going on here," and they can investigate. They collect this data, and they can say that the drug appears to be risky, because we're seeing an increase of this disease or that reaction. That's when the labeling gets changed and updated, or the drug is pulled from the marketplace.

The problem with MedWatch is that there's no enforcement of it. It's purely voluntary. As a physician, with the thousands of forms that I have to fill out every week for every patient and every procedure, I don't want to fill out some more forms. That's what this is. "More forms. Don't have to do it. 'Do it if you have spare time.' I have no spare time." Doctors don't fill out the MedWatch forms.

So it's understood that typically only 1 percent of all of the adverse reactions that exist get reported voluntarily after the drug is approved. It's a flawed system.

How do you enforce it? Do you penalize people? Do you fine them if they don't fill out the form? Do you tax them? Do you audit them? I don't think that I have the right answer. I think what you do is educate people, and tell them how important it is, that it really is important. The FDA relies very heavily on the volunteer reporting system after drugs are approved to find out not about efficacy, but about safety.

In what sense then does the Fen-Phen disaster reflect a problem with that voluntary system? In some sense, you're at the mercy of the company, too?

Well, always. Look at-- I don't care whether it's the pharmaceutical industry, or whether it's the oil industry, or an accounting firm. There's an assumption of truthful business practices here -- that when I give you a report, it's going to be a truthful report; that if I publish my earnings at the end of the year, when I submit my tax forms at the IRS, it's assumed that I'm being honest. If I'm not, and they decide to investigate, I'll get into trouble.

The pharmaceutical company supplies annual reports to the FDA on every drug that they sell. They are required to periodically report updates and any serious reactions to the FDA to keep them appraised. ... But we assume that these companies are being honest and truthful, and doing the best that they can. As I said, it's not a perfect world.

Anything else you want to say about your whole experience with Fen-Phen?

Well, you know, it's a sad story in so many ways. It's sad to victims. It's sad to the FDA, to The New England Journal, and to the pharmaceutical industry as an industry, because it's another black mark against them. A lot of good companies [are] doing a lot of good work, and a lot of lives [are] being saved. So it's a sad story in every way.

 

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posted november 13, 2003

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