dangerous prescription
homethe fdainterviewsdiscussion
interview: leo lutwak, m.d.

What were Pondimin and Redux? What were they approved for?

Pondimin was approved many years ago, many decades ago, as a drug to assist in weight loss -- an appetite suppressant. It was a chemical compound that had the ability to change appetite, decrease appetite. Then, years later, presumably because the patent was expiring on Pondimin, a version of it was synthesized, which was essentially the active half of the product. Pondimin was fenfluramine, and they synthesized the dexfenfluramine, which was a portion [of] the Pondimin molecule. This was called Redux as a trade name, with the same properties: the ability to suppress appetite, decrease food intake, and therefore lead to weight loss.

The FDA is wholly dependent on trust  on trusting [that] the company is providing all the truth all the time.

Back when Pondimin was approved, the FDA required proof that it worked for a short period of time, about three months. Over the course of the years, it became evident that obesity, weight gain, was a lifetime proposition, and that drugs would have to be taken continuously. So the companies that were developing dexfenfluramine or Redux did some studies extending the observation period out to about a year.

When Redux was being studied and being prepared for a presentation to regulatory agencies, longer-term studies were carried out up to about a year.

The drugs really are not very different. Pondimin, as I said, is a combination of two chemical molecules that are mirror images of each other -- one of which is active, the other is not. Redux is the active moiety of it, the active portion.

photo of lutwak

Leo Lutwak is a retired FDA drug reviewer. An endocrinologist specializing in obesity, Dr. Lutwak taught at Cornell University before joining the FDA in 1989. While with the FDA, he was the chief medical reviewer for weight-loss drugs and was at the center of the Fen Phen controversy. In this interview, Dr. Lutwak recalls the role he played in the review of Redux and provides insight into the sequence of events that lead to the recall of this drug. This interview was conducted on Nov. 3, 2002. Lutwak has since been retained by plaintiff's counsel in the ongoing litigation surrounding these drugs.

When did you get involved with these drugs?

I got involved with these drugs when I first came to the FDA about 10 years ago. My past experience had been as an endocrinologist and as a physician, doing research and teaching and patient care, and one of my areas of 40-50 years' expertise was obesity. So I was assigned the drugs that were being used for management of weight gain, weight loss -- the anti-obesity drugs.

Pondimin was one of the many drugs that were on the market that had been approved for short-term use. Redux had originally come to the FDA -- I believe in the Neurology Division, because it was supposedly acting on the brain -- and was transferred to the Endocrine Metabolic Disease Division as an aid to management of excess body weight.

So I was assigned that drug. I guess it was about 1993. I started looking at the data that were available in the FDA, both for Redux, which I was reviewing as a medical reviewer, and Pondimin, which was the precursor for Redux, which I was also monitoring for long-term safety, because the process of the FDA is that, even after a drug is approved, safety issues continue to be monitored.

That's when my first contact with drugs as a regulator came about. I knew Pondimin from all the many years that I was in practice. Frankly, I had never used it, because I wasn't particularly impressed by either its efficacy or its safety.

What was your role with regard to Pondimin and Redux?

At the FDA, I was employed as a medical reviewer. A medical reviewer's role is to evaluate the clinical data that the company submits to support the claims for safety and efficacy. We do critical analyses of the material that's sent by the company. We come up with opinions, but not decisions. We come up with evaluations, such as, "This drug does what the company claims it does," or "This drug doesn't do it quite as well, or it does it partially," [or], "This drug is very safe/moderately safe/not safe."

As clinicians, we come up with opinions. Does the efficacy of the drug, the ability to do what it's supposed to do, outweigh the safety issues? [What] we do is factual and some educated expert opinion, based on our own experience and our own knowledge. We don't make the decision. Decisions are made at a much higher level, because these involve regulatory law as well as other aspects of decision-making.

What was known about Pondimin and Redux when you started working on those drugs, in terms of how effective they were and what kind of safety problems they might have had, or--

Well, the safety problems were those that had been reported by the company and by patients to the FDA. It was known that there was a possibility -- which we were told was very, very rare -- of pulmonary hypertension.

We knew that the drugs could produce changes in mood. Some people had problems with excessive sleepiness. Some people had problems of insomnia. These were listed as minor side effects.

In terms of efficacy, the published information, the known information, the reported information was that these were moderately effective in some people in modifying appetite, in decreasing appetite. Pondimin was not widely used. It just didn't make people feel that good.

Redux initially was reported to us as not having the same side effects or as many side effects as Pondimin, that it was much more efficacious, and that its effects continued even after the patients continued taking it for long periods of time. They didn't develop resistance to it, which is always a problem with mood-altering drugs.

Most of the other drugs that were available at the time are derivatives of Benzedrine, Dexedrine. As we know, all of these drugs produce resistance and dependency and increased requirements, with increased side effects.

The Pondimin and Redux were an entirely different class of chemicals that didn't have those side effects of building up resistance. So this is what we knew at the time.

How effective were these drugs, really? What was known about how effective they were in really making people shed pounds?

In evaluating the data, in looking at the material that the companies had submitted, the drugs weren't very effective. As a clinician, I was not impressed with the effectiveness of them. They led to a decrease of weight of 5 percent to 10 percent, which meant that, in the average individual who was overweight, it would be a weight loss of five to 20 pounds over the course of six months to a year. And many people didn't show any effects.

What led to, I think, the push for it was a very puzzling situation that occurred just about the time Redux was submitted to the FDA for evaluation. There was a sudden flurry of articles in popular magazines, based on a single study that had been reported in the Pharmacology Journal, [about] combining Pondimin with one of the amphetamine-like drugs in the combination that became popularly known as the Fen-Phen. The first "Fen" is for fenfluramine, or Pondimin. The second "Phen" was phentermine, one of the amphetamine-like drugs; that, when you combined the two, you didn't get the same kind of side effects.

It was a sort of push-pull, upper-downer combination. There was a flurry of articles. Clinics [were] set up all around the country, where these drugs were being dispensed by the handfuls to tens of thousands of individuals. The drugs became very popular. So the potential for market for drugs of this nature had increased. Therefore, there was pressure to evaluate Redux, which was a derivative, or similar to this combination.

Why was Pondimin not such a popular drug? What was its big problem?

It had several problems. One, it didn't lead to very much weight loss. Two, it was a downer. It made people very sleepy, uncomfortable, depressed. Patients did not take it. When they were given a prescription, they would take the pills for a few days, and then quit.

When it was combined with phentermine, you had the aspects of the upper, a phenomenon which was very well known to the flower children of the 1960s. If you take the combination of an upper and a downer, you feel better than if you take one alone.

So that combination became much more popular. Probably because of this combination of actions of upper and downer, people did eat less and lost weight a little bit more efficiently.

When did you start getting an inkling that there was something to be concerned about with these drugs?

Well, after I got finished with my first reading of the submission -- again, this is my own way of approaching a drug application -- I would read it very rapidly, and look at all the material that was presented. Then I'd go back and read sections more intensively, and start looking at the numbers more carefully.

In my first go-around with that, I was not impressed with the amount of weight loss. I thought it wasn't really very significant. I was not impressed with the numbers of people that actually did respond.

When I started looking at the reports of adverse events, of complications that came along with the use of drug, I was a little puzzled as a tremendous number of what appeared to be psychiatric events -- mood changes, rage, memory loss.

My first complaints about the drug were that this was going to produce an awful lot of neuropsychiatric type of complications that really were not warranted by the amount of weight [loss] that it did produce.

Then I started looking at other areas of complications of side effects. I noticed reports of pulmonary hypertension. Pulmonary hypertension is a very rare phenomenon. It's when the blood vessels in the lungs start tightening up, and the blood pressure in the lungs goes higher, and there are difficulties breathing.

It's an irreversible disease. It occurs as a result of other conditions. But the form that's seen with some of the weight-loss drugs, which had been reported many years before with other weight-loss drugs, is called primary pulmonary hypertension. It's supposedly very rare.

Now, this was listed as a potential side effect for Pondimin in the initial approved labeling of the drug. But it was listed as an extraordinarily rare phenomenon. When I started looking at the actual reports, it didn't seem that rare. Taking that in consideration of the minimal weight loss seen with it, it seemed to me this was a risk that was not warranted.

According to what I read, and the way I interpreted the Food and Drug Administration's role, we're supposed to evaluate drugs for their safety and efficacy. When the safety is questionable, it requires an awful lot of efficacy for it to be warranted. So I raised that issue, and I was told by the company that, "No. This is a very rare side effect that just doesn't occur in enough individuals make it worth being concerned about."

Then we started hearing reports that this was much [more] common, particularly in Europe, in France. The drugs were originally, I believe, marketed in France. The European authorities were beginning to be concerned about the pulmonary hypertension. There was a large study that had been commissioned in Europe that was headed by Professor Abenhaim.

You were saying you started noticing that there were more reports of pulmonary hypertension associated with Pondimin and Redux than was known, or was in the label of Pondimin. What do you mean by that?

Copies of reports were sent to the company, and copies of the reports were sent to the FDA of side effects. There is this MedWatch program which was -- I don't remember when it was set up at the FDA. It's a voluntary program in this country. Physicians, patients, pharmacists, and other health workers voluntarily report adverse events with drugs.

In some countries in Europe, it's a little less voluntary. They have other methods of following this -- through national health registers, and so on. But still, it's estimated that only about 10 percent of adverse events are actually reported to regulatory authorities anywhere in the world.

When I started seeing reports of pulmonary hypertension, I became a little bit concerned. It could be just a matter of randomness that suddenly several reports came in, or it could be serious.

But apparently there were enough of these reports coming in Europe that the Europeans' commissions got Professor Abenhaim of Montreal to direct a long-term intensive epidemiologic study of the incidence of pulmonary hypertension in people using weight-loss drugs.

We didn't hear from the company. We heard through the contacts with physicians abroad, epidemiologists in this country who knew Professor Abenhaim, that Redux and Pondimin -- Redux had been marketed in Europe for some time by this stage -- that both Redux and Pondimin seemed to have more of these side effects than any of the other weight-loss drugs.

Are we saying that official information that the company was telling the public didn't mesh with the actual number of side effects? What are you saying?

Exactly. What the public was informed of was the material that was in what's called the "official labeling" of the drug. That's the package insert that comes with the drug, or the advertising. All that is considered part of labeling. The labeling stated that pulmonary hypertension was extraordinarily rare, and that didn't quite mesh with what we were hearing. Then, when the Abenhaim report was released, it was very evident that the labeling was not correct -- the incidence of pulmonary hypertension was much, much, much higher than had been listed in the official labeling.

How can there be such a disconnect between what it says in the label and the real experience?

Well, the label is approved when a drug is approved. The experience comes along later. The company can voluntarily request a label change, or, when the FDA becomes aware of increased numbers of reports, the FDA can ask the company to provide a label change.

There hadn't been any recent label change to reflect this new information that pulmonary hypertension was so common -- not so common, but was much more common than originally thought.

So you started getting concerned about the larger numbers of side effects, specifically pulmonary hypertension?

Well, there were others. It wasn't just pulmonary hypertension. Because even with the increase in pulmonary hypertension, considering the millions of doses of pills that were being used, it still was a relatively rare phenomenon. It wasn't as if everybody taking it is going to come down with pulmonary hypertension.

But there were other side effects that were troublesome. To this day, I remain concerned about the neuropsychiatric side effects -- mood changes, memory loss, and so on. I don't think it ever has been fully explored.

Then I kept tabulation on my desk of different systems that were being affected by these drugs. I became aware there were a large number of cardiac events reported that I couldn't understand from the reports. So that was another concern that I had, that this might have some kind of cardiac effect that we didn't understand.

This raises some issues, because the class of drugs that Pondimin and Redux represent[s is] the class known as selective serotonin re-uptake inhibitors -- SSRIs. There were other SSRIs on the market. At that point, the principal one was Prozac. This kind of phenomenon had not been reported with Prozac, which was puzzling. It seemed to be limited to that peculiar molecule that was present in fenfluramine, this slight difference between fenfluramine and Prozac.

The cardiac events had me more concerned. They seemed to be much, more frequent than pulmonary hypertension or the neuropsychiatric. Then the reports we were getting from the company -- there wasn't any adequate explanation.

One explanation that sort of ran through all of the reports was, "Well, these people who are taking these pills are overweight. Overweight people have heart disease. One would expect more cardiac problems in people who take drugs for weight loss, because they're fat to begin with."

But when I looked at the actual weights of the people taking them -- because that usually is reported in an adverse event report -- none of them were the massively obese. There were overweight people. There were people who weighed 50 percent, 75 percent more than ideal. But they weren't particularly grossly overweight.

The other thing that was troublesome was that these were mostly young people, young women. Now, the fact that they were young women wasn't so surprising, because these pills were being marketed to women primarily. The advertising was to women. The marketing data that are available are that weight-loss pills tend to be taken more by women than by men.

What do you mean that you saw reports of cardiac problems? What does that mean? What were you seeing in adverse event reports?

They were the adverse event reports of a patient having heart attacks. Patients having high blood pressure. One thing that was running through that, which I asked about, was the patients were having heart valve problems, leaking valves. The reports we got back with these leaking valves were the result of other medications the patients were taking, or the results of the pulmonary hypertension. Pulmonary hypertension can produce valvular disease as a secondary phenomenon.

Now, I'm not a cardiologist, so I asked for opinions from cardiologists. I'm not a pulmonologist. I asked for opinions from pulmonary specialists. The reason I was becoming concerned -- as I was saying before -- that these are serotonin-modifying drugs. They modify the behavior of serotonin, which is a hormone that is involved in appetite. It's involved in brain function.

But, as an endocrinologist, I was very much aware of the role of hormones. Hormones don't act just in one place. The word "hormone" comes from the Greek meaning "the messenger." Hormone is a substance the body produces that travels throughout the body, and it has slightly different actions in different organs.

Serotonin is a hormone that we know affects not only brain function, but small blood vessels, the gastrointestinal system, the lungs, the kidneys. So this combination of unusual side effects, as a result of hormone-modifying agent, had me concerned. I wrote interim reports in which I summarized my concerns, and sent those on to people further up the chain in the review process.

How were your concerns received by higher-up administrators at the Food and Drug Administration?

The people in the division of the Food and Drug Administration where I worked were equally concerned. We had many internal conferences within the division at the FDA, discussing these problems. Letters and phone calls were made to the company, requesting additional information.

This was during the review process. This was before any decision had been made. So we had a good deal of concern about it, yes. My concern was reflected by the people to whom I reported. They supported and they recognized that these were legitimate concerns.

At some point, there was a meeting to determine whether or not to approve the new drug, Redux. What went on there?

... Pondimin had already been approved, so Redux was the drug in question. That was presented to an advisory committee. There was a lot of debate. There was a lot of discussion. There was a lot of concern. By the time this had been presented, the information concerning the higher incidence of pulmonary hypertension was public.

The article in which Professor Abenhaim and his group reported their results had not yet been published, but the information in it had been circulated, and it was pretty well known. It was presented at that advisory committee meeting.

The final decision was very, very close. I can't remember the numbers. But the final decision of that advisory committee was that the drug not be approved. But it was by a [5-3] margin.

Some of the members of the advisory committee had to leave before [the meeting] was completely over. They had left their votes. There was some concern that perhaps this wasn't a fully informed advisory committee. It was a rather unusual move. But after the final vote, some of the higher-level managers, administrators at the FDA, announced that a second advisory committee meeting would be held to review this in a few months.

[At] that second advisory committee meeting, the company was going to present some additional material. By that time, the Abenhaim paper had been published. There were some concerns about the neuropsychiatric events, but that wasn't being presented at that second advisory committee meeting.

The vote at the second advisory committee meeting was also sharply divided. But this time, there was one vote more for approval than against approval. ...

What accounted for the change in the recommendation?

Well, I never talked with the individual members of the advisory committee who changed their minds. So I really can't tell you what accounted for it. It was a puzzle.

I don't have any evidence for any reasons for this to have occurred, except perhaps their opinions were changed. I know that my opinion wasn't changed when I heard the second presentation from the drug company, but I'm only talking about one individual -- myself.

I didn't think the company had presented any additional evidence for safety or for efficacy. I was just as puzzled back then as I am now as to why the vote had changed. But it was a margin of one. And that happens.

How did you react, as a scientist? You'd been looking at all this data all the time, and trying to figure out what was best for the American public.

I was very disturbed. Then we talked about it internally, within the division at the FDA. There is one tool that's left, and that's the labeling. So we decided we were going to try to make this as tight a labeling as we could, listing all of the side effects prominently.

That's difficult to do. Legally, if it's listed in the side effects, it means the company has informed the patient and the prescriber. Practically, if you've ever looked at one of those package inserts, they're written in very, very tiny print. I don't know how many physicians actually read them all the way through.

So what we started talking about, within our own little group there at the FDA, was that we would see if we could get the company to put these warnings in what's called a "black box." A "black box warning" means that this has to be highlighted prominently at the very beginning. It's in a box with a very dark black border, and it's with larger type than the rest of the label.

The company resisted this black box approach. We had repeated meetings taking place at the FDA offices with representatives of the company. The company came up with legal arguments as to why they should not be required to put a black box on. This protracted the approval process, because the drug is not approved until absolutely every "i" is dotted and every "t" is crossed. That includes the labeling. The labeling has to be completely acceptable. So there [was] a lot of negotiating and discussions, face-to-face, by telephone, by letter, by e-mail with the company, in trying to get appropriate labeling. ...

So we were negotiating the label, and the company dominated in that. As far as I recall, the black box was not placed on the Redux label when the final approval came through.

So companies negotiate labels, and it's not something where the FDA says, "You know, you're going to put this on?" How does that work?

The FDA tells the company what it would like in the label. The company prepares a draft of the label, submits it to the FDA. At the FDA, there's internal discussion of every aspect of the label, because the label covers many, many aspects in addition to safety and efficacy. And we come back with counterproposals.

I recall, when I first came to the FDA, every one of these would be discussed face-to-face with the company. With modern technology, we use video conferencing, teleconferencing, and discuss line by line the entire label, and negotiate with the company. "We would like this." They would not. This goes back and forth. The compromise.

I recognize that the drug companies are in this to make money, and anything that would cut the sales would not be pleasing to their marketing people. There's some type of compromise. We would like to make sure that every drug is 100 percent efficacious, 100 percent safe, and there ain't no such thing. So it's a matter of compromise. Usually the compromise is favorable, both to the company and to the public that's going to be using the medication. In this case, I felt it was not.

Did you ever have the sense that manufacturer of these drugs was not forthcoming about their side effects and adverse events?

Unfortunately, I did have a feeling almost from the very beginning that the company was not being forthright and forthcoming with information. I had a feeling from the very beginning of, when I first started looking at these drugs, that the company was giving us partial truths, half-truths, covering up, trying to change the information.

This had me concerned to the point that I would be reading the material they sent with extra diligence, looking for where the commas were placed, where the words might be right and the meaning not, and so on. This was unfortunate, because I did not like this controversial, confrontational approach. I have a great deal of respect for the scientists who work for the pharmaceutical companies, the clinicians, the chemists, the pharmacologists. Some of the top scientists in the world work for pharmaceutical companies. I was very, very uncomfortable with this particular presentation, this submission.

What can you tell us about how the reports from Fargo and the Mayo Clinic came into the FDA, and the timing of things?

As I said before, I had been making a list of adverse events associated with both drugs since I considered them the same drug.

In April of the year -- this was less than a year after Redux had been approved and went on the market. The following April, I received a group of adverse event reports that had originated in Fargo, North Dakota, of patients with mitral and aortic valve disease who had been taking either Redux or Pondimin.

This puzzled me. A whole stack came in at once. I remember getting a little bit excited by it. I went to a national statistics book to see what the population was of Fargo, and of all of North Dakota. I wrote a memo in which I emphasized that this was extraordinary. It was as if everybody in the state of North Dakota was developing valve disease, because they were all from one specific clinic.

We contacted the company to get some more information on this. I don't remember how long it took it, but it took several days or weeks. Then we were told this was probably was in error, this probably wasn't true, that they were investigating it.

That was April. But then, in June, someone else at the FDA heard that the Mayo Clinic had seen these same patients, and that the people at the Mayo Clinic had prepared an article describing this that was going to be published in July, I believe.

The Mayo Clinic people were invited to come to the FDA. They presented their information. At that point, it was completely out of my hands. At this point, the whole issue of the drug and the valvular disease was bumped upstairs to the upper-level management at the FDA.

I was present at most of the meetings that took place with the company and with Mayo Clinic staff. But I was [a] back-seat auditor. I did not participate in any of these discussions.

[What happened at the FDA after the agency recognized that Pondimin and Redux had this second serious side effect, heart valve damage?] ...

After I learned that these were legitimate reports, I went back to some of the previous reports that we had received from the company -- European cases, primarily.

The MedWatch reports that the company submits have a very complex face sheet with boxes to be checked off, and so on, and components to be written. Then, if it's a complex case, there may be anywhere from one to 10 additional pages describing the actual case history.

What I found was that a great many of the reports [where], on the face sheet, specific diagnoses were listed. A diagnosis of pulmonary disease would be listed, or hypertension. Various other specific diseases [were] listed as being the cause for the adverse report. But when I started looking at the material in the subsequent attachments, I found there was valvular disease present in many patients. ...

How was this bad news received by management? Was there a great willingness to take the drug off the market?

Oh, yes. Oh, yes. Once the information came to the upper-level management of the FDA, there was involvement all the way up to the commissioner's office. ...

You ended up in a conference trying to advocate not taking Fen-Phen. How active were you in trying to stop people from taking this drug?

When the reports first started coming in of pulmonary hypertension associated with the use of fenfluramine and, in Europe, with the use of dexfenfluramine with Redux, I became very concerned about this, and advocated, at that point, changes in the label.

I was also concerned with this off-label use for long periods of time of the combination of Pondimin with phentermine, the Fen-Phen combination. I was particularly disturbed about this, because the man who had initially published the use of the combination for weight loss -- who had been working at the University of Rochester at the time he did that work -- was now a middle management official at the FDA. [He] was giving interviews and writing articles, and giving speeches around the country, advocating the use of Fen-Phen in an off-label role.

Now, the FDA has no role in the regulating the use of drugs. That's a state's right, by law. But I thought it was rather peculiar that, while the FDA division that was monitoring these drugs was finding problems, someone in another division was advocating the use of this combination.

Various states around the country were trying to ban these Fen-Phen clinics, or regulate them. The state of Florida was in the process of writing legislation for that, and invited several people to come down to talk to the medical board of Florida.

I was one of those invited. I went to that meeting with the approval and the imprimatur of the FDA, to discuss the problems associated with the use of Pondimin. At that very same meeting, this other individual was advocating the use of these drugs while I, a few minutes before, had completed my presentation of the dangers of this. I found this very, very unusual -- and awkward.

In the table of organization of the FDA, this individual was much higher up than I. On the other hand, I felt that I was much more qualified as a scientist, as a clinician, as a result of my years of experience, to make the statement that the drug was dangerous. And he was advocating its use. ...

Did you ever feel any pressure to lay off this case at all?

No. The pressure was never applied while I was involved with this.

As I said, I received support from the division that I was in at the FDA. I received very strong support from the division director, the deputy director of the division. They supported me, and backed me up on this all the way.

Do you think, in some ways, did the FDA have any kind of failure in this whole Pondimin, Fen-Phen, Redux story? I mean, from the sense that--

Are you asking me for an opinion? ... My opinion is that there must have been a failure along the way. To me, this seemed to be very evident, very obvious that these were dangerous drugs that didn't do very much good and had potential for doing a tremendous amount of harm, because there's a tremendous number of people taking the drugs.

To me, this was evident. I felt at the time -- and I still feel -- that something should have been done about it much, much earlier. So that's one concern. When you ask whether I feel that the FDA fell down on the job, this is one area that I thought it did.

Another area that I thought it fell down on was the fact that an upper-management individual at the FDA was actively advocating the use of the drugs, when all this information about the negative aspect of the drug was readily available to him. And he was supported, he was promoted, while all of this was going on.

That disturbs me. I don't know where it came from. I don't know who the individuals are who were responsible for this lack of oversight or this deliberate oversight. But these are opinions; I have no facts there. ...

Is the FDA in the hands of industry in one way or another?

What is my opinion of what is happening at the FDA? I don't think it's very different from what's happening in other government agencies and other regulatory agencies. But the problem with it happening in the FDA, with changes that are occurring in the FDA, is that the FDA is responsible for about 25 percent to 30 percent of the U.S. economy. So what happens in the FDA affects an awful lot of people. It's also responsible for areas in which 99 percent of the individuals have no expertise, and have to depend on others.

The FDA's mission, [its] role in society, has been to safeguard the safety and efficacy of drugs, devices, and foods for the sake of public health. ...

I think what we've seen in recent years is that the regulatees have more and more power. One of the reasons is we have this swinging-door policy. People come into the agency from the industry, because that's where the expertise people [are]. People leave the agency after they reach their retirement pay scale, and go back into the industries they had been regulating before.

So there is a conflict of interest. Whether it's real or whether it's a psychological one, I think there is a tendency to try not to irk the people you're regulating, because you may need them someday, or they can reward you.

Now, there's supposed to be more layers of protection, particularly in the FDA. We have the advisory committees that are supposedly independent of government. You can't serve on the advisory committee if you work for a federal agency. You can't serve on advisory committee if you work for industry.

But advisory committee members are composed primarily of people from the academic world. Academicians gets their promotions, get their reputations, based on their research. Research takes money. Money comes from industry.

So again, there's either a conscious or a subconscious desire not to irritate the "golden goose," the goose that lays the golden eggs, because you're going to need them to pay for your research.

So you've got conflict of interest at many, many levels. I don't know what the solution is. Other countries have somewhat different approaches. In some countries, the actual review process is by established, retired researchers who no longer have any need to keep going, or getting promoted, or getting funding.

That may be one solution. But I think you need the young people and the younger minds, more in-tune people, to serve on advisory committees and to serve in these agencies.

When you think about the whole story of Fen-Phen and Redux, or Pondimin and Redux, where's the guilty party in this story?

I think there are many guilty parties in the Pondimin-Redux story. The company is, to me, the principal villain. The company had the information. The company did not transmit the information. ... The company fought actions.

I think probably there is some complicity within the FDA. But I couldn't tell you where or how, because there was a lot of foot-dragging taking place.

I mean, eventually, the system worked, and the drugs were removed. But in the meantime, many people did get hurt. It may very well be that this is part of the protection that an individual reviewer's point of view may be wrong, and you do need management individuals to weigh the plusses and minuses.

I've been too close to this to be completely free of conflict of interest, also. I mean, my conflict here is that I felt very strongly about my opinion and my expertise. My expertise may not be as great as I think it is. My opinion may not be as valuable as I thought it was at that time.

Perhaps the higher-level management people who elected to postpone a decision until they had harder evidence may be ultimately right in the long run. In the bigger picture, this may be the proper way to go. ...

When a new drug is approved by the Food and Drug Administration, do we know that it's safe and effective, really, at the time it's approved? What do we know?

When a new drug is approved by the FDA, we know that the evidence submitted to that point, the evidence available to that point, shows that the drug has efficacy to do what the company claims that it will do, and that it is relatively safe. Nothing is absolutely safe. But it's relatively safe, if used as proposed.

However, we have to recognize that even with the most extensive testing, only a small proportion of the human population that would be taking the drug has actually been looked at, and the drug has only been used for a relatively short period of time.

So what we as consumers -- I as a patient, you as a patient -- have to know and have to recognize is that this is a still a relative unknown. Once the drug gets out there and starts being administered to millions of people with different genetic backgrounds, different abilities to metabolize the drug, new things are going to appear.

The drug may turn out to be less safe than we thought. It may turn out to be safer than we thought. It may turn out to be more or less efficacious. It may have effects that are surprisingly good. It may have effects that are surprisingly bad, and we don't know it.

There have been many people who have said that the safest thing when a new drug appears is to recognize that you are still part of the testing process if you take the drug. You're still a guinea pig. Wait two to five years before you -- this is true for the physician; it's true for the patient -- wait two to five years before you're really comfortable about using it.

So there's no guarantee. When you get the fact that something says, "FDA approved," is not a guarantee; it's an opinion. It's an expert opinion. It's based on evidence that's available at that point. But it's not an absolute fact yet.

The FDA, of course, is very dependent on the honesty of the company, too.

Yes. The FDA is wholly dependent on trust -- on trusting the company is providing all the truth all the time, that the company is not hiding information, not covering up information, not changing information. This is part of the trust.

There are penalties prescribed by law for lying to the FDA. They are infrequently evoked. We see that periodically. But generally speaking, I think most pharmaceutical companies are run by competent, honest scientists. Most of the studies that are done are done by honest, competent scientists.

The information sometimes gets filtered through the company, but most of the information we have, I think, can be relied on. If we couldn't rely on it, we couldn't do our job. The American public would be in real trouble if we had to suspect everything that came [out]. ...

What do you think about this new development of the user fees, the fact that industry pays for the FDA approval?

I can't say anything about whether the institution of user fees has changed anything at the FDA, because the user fees came into effect about the same time I came to the FDA. So I have nothing to compare it with.

I'm not happy with the concept, because he who pays the piper, calls the tune. I think that a regulatory agency should be independent of the industry it's regulating, whether it's drugs, or airlines, or stocks and bonds.

To be completely independent, it should be funded by the taxpayer, not by the industry. I think the proper use of the tax dollar is to fund these activities, rather than having the taxpayer pay it indirectly through increased costs of medication. The user fee factors into the cost of the medications that you buy.

So how have you seen, or how do you imagine the user fee is influencing things at the Food and Drug Administration?

I think that the user fee probably influences the process of review, because the other side of the coin, the industry pays the user fee. The FDA, in turn, promises to expedite the reviews.

When you expedite a review, this is being done in two ways. One is by throwing more reviewers into the review process. Sometimes that does speed up the process. But it cuts down on the ability to reflect and to change.

The other way is to have the individual reviewer just do a more rapid job. That, again, cuts back on the ability to reflect on implications and to read every line in an application, and to evaluate every number.

I don't like the user fee for that reason. I think that the concept that the FDA should do an expeditious job is a very good concept. But when the FDA's budget depends, to some extent, on the industry paying for it, then the industry is going to call the tune. Philosophically, I don't like that. But I don't make that decision. That was a congressional decision. ...

You referred to yourself as a whistleblower and as a dissident. How so?

My dissidence, my whistleblowing is not, I guess, in the common accepted use of those words. It's that I've objected to how things have been done. I think that there's something wrong with the process. I don't know what it is. I don't know how to correct it. But I think it's wrong.

... I thought it was wrong that the company was allowed to have a second chance at the advisory committee.

I thought there were wrong decisions made. When I expressed that, I started feeling enough heat to make me recognize that my opinions were not only not respected, but they would be disregarded and pushed out of the picture.

So perhaps it was weak on my part not to have resigned from the FDA, and started waving flags and shouting from rooftops. But, frankly, I couldn't afford to. I have self interest as well.

So in other words, was there room or not for your--

There was no room for my kind of complaints after this whole situation. There was no room for my complaints because, after this situation was over, after the Redux and Pondimin were removed from the markets, I found myself trivialized within the FDA.

I came to the FDA to work on drugs in two specific areas where I felt I had unusual experience, expertise, and knowledge. And I was reassigned to areas that I found very dull, unrewarding. ...

You'd expect people would be out there saying, "Good job, Leo. You solved this case."

There's an element of adolescence in all of us. We like to be patted on the back. We like to be told, "You did a marvelous job. You won the game for us. You're the hero." I suppose part of me felt that I was playing that role in what I did with Redux and Pondimin.

Part of me refused to accept the fact that I was essentially a voice crying in the wilderness here, and couldn't expect to be rewarded for it. But it would have been nice to have been rewarded.

I didn't expect the Congressional Medal of Honor for this. I didn't even expect a $50 bonus for it. But it would have been nice if somebody had said, "Hey, you did a good job."

And the opposite happened. So I suppose that leaves a little bit of bitter, a quinine taste in my mouth. ...

When you started getting these reports, noticing the side effects, looking at the efficacy data, did you make a decision in your mind, about what you wanted to see happen to those drugs?

When I first started getting the information on Redux and on Pondimin, I was extremely disturbed. As the information flowed in, and I saw that it was confirmatory, I felt it was an open-shut case.

This was a dangerous group of drugs with very little, if any, benefit, and that they should be immediately removed from the market, removed from use, discontinued, disappeared.

When that didn't happen, I became disturbed. I became very concerned. I became concerned about the system. I became concerned about the drug company's role in this.

I was particularly concerned with the potential effect on the thousands or millions of people who would be using the drug. This sort of drove me to do this very intensive accumulation of information. At times, I lost my temper. I'd go so far as to say that there are times that I got angry about this. ...

 

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posted november 13, 2003

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