The MacNeil/Lehrer Report; Oraflex Controversy

[Tease]

ROBERT MacNEIL [voice-over]: The painful disease of arthritis affects one American in five. There is no cure. And to add to their suffering arthritis victims are now caught in a media war over a new drug called Oraflex.

[Titles]

MacNEIL: Good evening. Ralph Nader's Public Citizen consumer group today renewed its demand that the federal government ban the arthritis drug Oraflex. In a letter to Health and Human Services Secretary Richard Schweiker, the public citizen group said it had obtained new information since it first asked for a ban last month, citing 12 deaths associated with the drug in England. Today's letter said there were now reports of 45 deaths in England and one in the United States. The drug, benoxaprophen, marketed as Oraflex in the United States, was approved by the Food and Drug Administration in April and introduced in this country in May. Its makers, Eli Lilly & Company, mounted a heavy campaign of media publicity, presenting Oraflex as a new direction in arthritis treatment. Some 400,000 Americans are now taking the drug but many are perplexed over the contradictory publicity. Tonight, should Oraflex be banned or have the dangers been overblown? Jim?

LEHRER: Robin, 31 million Americans already endure the physical pain and suffering of arthritis. The public fight in the newspapers and on the evening news over Oraflex has added psychic pain and suffering to go with it. The Wall Street Journal in a story today cited the case of a 74-year old Virginia woman who has arthritis so bad she often can't even stand up. She saw the Oraflex announcement in May in her local newspaper and the claims made for it by the Lilly Company. She immediately hounded her doctor into prescribing it for her. But then, a few weeks later, came the stories in her newspaper about the British deaths and the call here to ban the sale of Oraflex. So she immediately quit taking it, telling the Journal, "I hope I didn't take it too long for it to hurt me." The story makes the point that this woman along with thousands of other arthritis sufferers are getting whipsawed in a confusing high-powered publicity fight. There were big stories, critics say too big and too misleading, when Oraflex went on the market, and there were big stories other critics say too big and unfounded when the possible negatives came out. The whipsawing, as we're about to find out, continues. Robin?

MacNEIL: The manufacturer of Oraflex in this country as we've said is Eli Lilly & Company. Its British subsidiary, Dista Limited, has been marketing Oraflex under the name Opren for the past two years. Dr. Lan Shedden oversaw the development of the drug, first in England, then there as vice president of Lilly Research Laboratories. Dr. Shedden, what do you say to the demand today that Oraflex be banned because of the deaths in England?

Dr. IAN SHEDDEN: I say that this is a gross over-reaction to the situation which has developed. Oraflex has been fully evaluated in extensive clinical studies conducted in the United States and in the United Kingdom involving a total of 10,000 patients. It's been rigorously scrutinized by regulatory authorities here in the United States and in other countries too. And it's been found to be safe and effective. What we need to do is to put the new patient's information into the context of Oraflex and into the context of other products. But, our position is that this is an over-reaction to the situation.

MacNEIL: Does Oraflex have side effects that cause deaths?

Dr. SHEDDEN: Oraflex does not cause death but Oraflex in a number of patients, in association with a number of events, including the patient's health, the dose of the drug and other drugs co-administered has been associated with death in a small number of people.

MacNEIL: But that still means that Oraflex is a safe drug to take?

Dr. SHEDDEN: Indeed it does.

MacNEIL: Why is Oraflex a useful drug in treating arthritis?

Dr. SHEDDEN: Oraflex is a useful drug because arthritis is a very difficult disease to treat. There are a number of drugs available for its management but at any point in time approximately 30% of all patients suffering from arthritis are taking no prescription medication at all. No drug suits everybody, each drug provides something for everybody. Some drugs provide a lot for a small number of people. Oraflex clearly is an important introduction in a largely unsatisfied market.

MacNEIL: Well, what does it do that other drugs don't do?

Dr. SHEDDEN: Well, let's talk about what it does -- other drugs do, first of all. It relieves the pain and inflammation associated with arthritis, and a number of drugs do that. In addition, it has an interesting and, we believe, unique pharmacological effect which we've demonstrated in the laboratory and also in experimental animals. We've shown that it inhibits the migration of the monocyte into inflamed sites --

MacNEIL: What is the monocyte?

Dr. SHEDDEN: The monocyte is a cell which is involved in chronic inflammation. Now, a part of the problem in rheumatoid arthritis --

MacNEIL: And this drug stops those cells from going to the area --

Dr. SHEDDEN: Yes, that's right, and it brings under control the over-exuberant repair processes of the body which are responsible for much of the bone destruction which takes place in arthritis and which produces the infirmities associated with that disease. Now, we've demonstrated this in laboratory animals and in lab tests, we've got some very preliminary clinical experiments done to show that we're on the right track. We've mounted a very large study to follow this out in clinic, and in two or three years' time we'll know whether Oraflex does or does not modify the course of the disease.But that is what Oraflex does -- the things that other drugs do and the things that are peculiar to Oraflex itself.

MacNEIL: Does Oraflex have side effects that other drugs do not have?

Dr. SHEDDEN: Yes. Oraflex causes an increased susceptibility to sunlight and that's not found in other drugs in this chemical class. It is found in other drugs which are commonly used in medicine, however --

MacNEIL: Is that a dangerous --

Dr. SHEDDEN: It's not a dangerous side effect. It's entirely preventable. It occurs quite commonly in patients taking the drug but it can be prevented by either acquiring a sun tan before going on the drug, first of all, or by using appropriate sun screens while taking the drug or by modifying one's approach to sunlight.

MacNEIL: So you would maintain that it is a safe and effective drug and does not need to be banned.

Dr. SHEDDEN: Emphatically.

MacNEIL: Thank you. Jim?

LEHRER: The organization leading the fight against Oraflex is the Public Citizen Health Research Group originally founded by Ralph Nader and headed by Dr. Sidney Wolfe. It was Dr. Wolfe who wrote the original letter to Secretary Schweiker in June asking that Oraflex be taken off the market and today's follow-up letter as well. Dr. Wolfe, you heard what Dr. Shedden says, Oraflex does not cause death. What do you say?

Dr. SIDNEY WOLFE: The Eli Lilly Company has just put out a public statement saying that "No reports have clearly identified Oraflex as a causal agent of death." I think that's a reckless, irresponsible kind of statement that will surely go against them when an increasing number of lawsuits are brought against them. I think that the number of case reports that have been published in Britain -- now a total of 45 deaths reported in the UK. This usually means, probably several hundred deaths have actually occurred. The particular increased amount of deaths from liver damage which are not seen with any of these other kinds of drugs all point in the direction of Oraflex being the cause of death in a large number of people.

LEHRER: You're saying, "point in the direction," but it's not conclusive in your mind?

Dr. WOLFE: I think it's as conclusive as one will ever get. With a drug that doesn't kill people, if you rechallenge them with the drug and they get worse, that's conclusive. If it kills people, it is really difficult. For Eli Lilly to say that there's no evidence that Oraflex causes death, no causal relationship is like the Tobacco Institute saying, as they do today, that there's no evidence of a causal relationship linking cigarettes with lung cancer. It's as strong a relationship as one can get and I think that the sooner the drug is taken off the market the more we will benefit from the British experience instead of repeating it. In addition to killing people because of liver damage and other problems, there are a whole variety of other side effects. Now, I think that if you --

LEHRER: Not just the skin effect that Dr. Shedden mentioned?

Dr. WOLFE: Well, in addition to the skin effect which occurs in 100% of Caucasian, white people who are exposed to sunlight who take the drug, there are also separation of the nails. In addition to that, there are liver and kidney problems and overall --

LEHRER: That would mean among how many, what percentage? I mean everybody that takes Oraflex, their fingernails separate and they have liver problems?

Dr. WOLFE: No, fingernail separation is probably somewhere in the several percent range. The light sensitivity is in 100% of the people who have been given the drug and challenged with sunlight. So that if you ask the question, would you take a drug for which there's no evidence it's better than aspirin but for which there's evidence that it causes a number of side effects and kills people apparently much more than these other drugs, I don't think many people would take it. And that's exactly the opposite way that the drug was promoted. It was promoted as being really as safe or safer than other drugs and more effective. Neither is true.

LEHRER: Well, let's go to the more effective. You heard what Dr. Shedden said, that in animal tests -- and as he said, the Lilly Company is now running further tests to see if this in fact bears out -- but animal tests show that it does inhibit the spread of this disease.

Dr. WOLFE: This drug has now been tested in humans, many of whom I would describe as guinea pigs, for three or four years now. And it's really curious that after three or four years of extensive testing, if you want to call it that, there isn't any evidence right now -- and the Food and Drug Administration will confirm that; there is no evidence that this drug is any more effective than any drug on the market, including aspirin. And I seriously doubt whether we'll see evidence in the future. Dr. Shedden said that we may see it in two or three years. If the drug stays on the market that long we'll also see several hundred more deaths.

LEHRER: What about the idea, though, that Oraflex, you only have to take it once a day, where people who have to take aspirin who suffer from arthritis, I've seen them take handfuls, you know, of it at one time?

Dr. WOLFE: Well, between Oraflex once a day and aspirin many times a day, many pills, although aspirin is just as effective, there are a number of other drugs, eight on the market in this country which have to be taken maybe a couple of times a day. So that there already are alternatives, maybe it's twice a day instead of once a day but I think that that in and of itself is hardly enough of an advantage to outweigh the fact that it is killing people.

LEHRER: And finally, what you said a moment ago, that you firmly believe that if you can continue to sell Oraflex and prescribe it in this country that it is going to cause -- it, by itself, is going to cause several hundred people to die?

Dr. WOLFE: That's correct. I think that already in Great Britain there have probably occurred several hundred deaths. Only 45 have been reported because many doctors feel very funny about reporting the fact that a drug they gave patients resulted in their death.

LEHRER: Let's ask Dr. Shedden. Dr. Shedden?

Dr. SHEDDEN: Yes.

LEHRER: That's a very serious condemnation Dr. Wolfe has just made.

Dr. SHEDDEN: Yes, it certainly is. I'm absolutely fascinated by the idea that possibly hundreds of deaths have occurred in the United Kingdom, and as with many of his statements that have just been made, there's absolutely not a shred of truth for that at all.Let's talk about what actually has happened. We talked about the clinical studies that have been done. This is rather like making a jigsaw puzzle: by the time you get approval for the drug you've filled in much of the center of the picture. And then as the drug is marketed -- and very large numbers of patients have received it, a million and a half worldwide -- you suddenly find that you've got one or two pieces for your jigsaw puzzle that you didn't know you had. Well, the first thing you've got to do is try to determine whether these actually belong in your puzzle at all and in the case of Oraflex quite a number of these cases I don't think belong in the puzzle at all in any way whatsoever. The second thing you then have to decide is whether the other cases that you've got left over fit out in the periphery somewhere or whether they fit into the middle. And there's no question about it, that as one looks at the reports which have appeared in the United Kingdom, there are extremely complicated patients. They were all very old, they were all receiving more Oraflex than they should have been in relation to their renal function and they were receiving drugs other than Oraflex concommitantly and they were suffering from diseases other than arthritis which in themselves might have contributed to the events which occurred. How one can possibly make a comment that the deaths were caused by Oraflex in that complex situation I really can't imagine.

Dr. WOLFE: Well, I think a lot of people other than the company do make that comment.I think that one of the most telling things about what's happened in the UK is that one of the people who's reported a number of side effects is said in a published medical journal article, the British Medical Journal, that this drug has an unacceptable incidence of said effects in the elderly. And I think that that really tells you what the attitude toward the drug is in Britain where it has been available for a couple of years.

LEHRER: But what about his point, Dr. Wolfe, that many of these patients, he says in fact, all of them, had other things besides arthritis and there was the dosage problem and all these other --

Dr. WOLFE: And I think that's why it's important to look at the number of deaths with this drug as opposed to the number of deaths with the other. If one assumes that the kinds of people who have arthritis are more elderly than not and have other kinds of disease, why is it that this drug, as opposed to other arthritis drugs also being used in the elderly, seems to be causing many more deaths. I think the answer is that this drug has unique toxicity which has killed many people.

LEHRER: Dr. Shedden, why is that?

Dr. SHEDDEN: I'd like to respond to that. First of all, it's not true that other drugs don't cause deaths. They often do.

Dr. WOLFE: Not as many deaths.That's what I said.

Dr. SHEDDEN: Oh? I wouldn't agree with that comment. There have been over 200 deaths reported with indomethacin for example in the United Kingdom. And so it's absolutely untrue to say that other drugs do not cause deaths.

Dr. WOLFE: In how many years, though? You see, a lot of these other drugs have been around for a much longer period of time, as Dr. Shedden knows, and therefore to compare a drug that's been around for 10 or 15 years and say it causes a certain number of deaths with a drug that's been around for less than two years -- already 45 reported deaths and there are a total of 4,000 adverse reactions reported to the British government on this drug alone. It makes up one quarter of all the average reactions for all drugs just with this one drug alone. The last thousand haven't even been processed yet to see how many further deaths there are there.

LEHRER: A final comment on that point, Dr. Shedden, and we have to move on.

Dr. SHEDDEN: Yes. I would like to say this. If the Committee on the Safety of Medicines in the United Kingdom were as concerned about this as some people appear to be by proxy for them, I think they would have taken dramatic action against the drug in the United Kingdom. That, of course, is not the case. We've worked with the Committee on the Safety of Medicines, we've devised labeling to emphasize the need for reduced dosage in the elderly, and as far as I know the Committee on the Safety of Medicines has no intention whatsoever of taking any further action against this drug at this time. I think you have to interpret Dr. Wolfe's comments in the light of that action.

LEHRER: Thank you. Robin?

MacNEIL: When the Lilly Company launched the drug at a press conference in New York on May 19, three prominent rheumatologists talked about its efficacy. One of them was Dr. Israeli Jaffe, professor of clinical medicine at Columbia Univerisity's College of Physicians and Surgeons.Dr. Jaffe is known in the field as the discoverer of the usefulness of another drug in arresting the development of rheumatoid arthritis. He participated in the clinical trials of Oraflex. Dr. Jaffe, are you alarmed by the reports linking Oraflex to this number of deaths in England?

Dr. ISRAELI JAFFE: I'm not alarmed, Mr. MacNeil, but I'm concerned and I'm anxious for more information.

MacNEIL: Should it be banned in view of the uncertainty?

Dr. JAFFE: I have reviewed all of the published literature and based on what I have read, I do not see sufficient evidence for the drug to be banned.

MacNEIL: Are you taking your personal patients off the drug?

Dr. JAFFE: I am not.

MacNEIL: Have any of them asked you to take them off the drug?

Dr. JAFFE: They have.Some have, and those who wish to take themselves off the drug are obviously permitted to do so and we attempt to make an appropriate substitution.

MacNEIL: When your patients ask you, "What should I do, I'm taking the drug and I read all these reports about it?" what do you tell them?

Dr. JAFFE: Very simply I tell them that we have in this country a very responsible, I think, pharmaceutical industry and a very strict regulatory agency in the form of the Food and Drug Administration, probably ane of the strictest in the world, and I abide by their recommendations. And until such time as I have recommendations from the FDA to the contrary, I will continue to use it and continue to watch my patients carefully, which I think any good physician would do.

MacNEIL: You just heard the comment that was quoted from a doctor, a physician in England who said there was an unacceptable incidence of side effects in the elderly. Have you observed anything like that?

Dr. JAFFE: No.

MacNEIL: Is there an incidence of side effects in the elderly that doesn't occur in other age groups?

Dr. JAFFE: There is a higher incidence of side effects in the elderly. And I think that it's quite well understood now that that's because they handle the drug more poorly, and the manufacturer has recommended a significant dosage reduction in older people. This is true for almost all of the drugs of this class and in general one has to be very careful whatever one prescribes for elderly patients because they metabolize and eliminate drugs much, much more slowly.

MacNEIL: Let's turn now to the publicity side of this and what Jim referred to a moment ago as the whipsawing of patients with first the favorable and then the unfavorable publicity.Did your patients come to you and ask for the drug as a result of the publicity that attended its launching?

Dr. JAFFE: There certainly was a great deal of that. I would say that for many of us who practice rheumatic diseases alone the phone scarcely stopped ringing for a day or two after that press conference. Not only did they ask for the drug but they were resentful that we hadn't given it to them sooner. And I personally feel very strongly that this is not the way prescription practices should be. Nevertheless physicians reacted to it, a certain number I might add with hostility.

MacNEIL: You participated in the press conference at which the drug was launched. What do you feel about the manner in which this was presented to the public?

Dr. JAFFE: I feel very strongly that the public has a right to know when significant breakthroughs are made in medical research. Firstly, they're vitally concerned and secondly, they've paid for this. They've paid for it at the local pharmacy when they buy the drug and they pay for it with their tax dollars which supports much of the research. And I think that if and when there are breakthroughs -- and we know what a breakthrough drug is -- if and when that occurs it should be made a media event in short order. When a new drug comes along which may be better in certain respects than others and indeed may be worse in other respects, I think the public should be made aware of its existence but in a low-key fashion appropriate to the contribution of the drug at the point in time that it is introduced. I think ethical pharmaceuticals, drugs that are available by prescription, not over the counter, should not be introduced like toothpaste and breakfast cereal. It's far too serious a matter.

MacNEIL: What harm does it do to launch drugs in that way?

Dr. JAFFE: Well, let's take the arthritis story, for example. Arthritis, and we haven't bothered to subdivide it into its hundred categories, but these patients all have inflammation and to varying degrees they are suffering. All of the time: pain, stiffness, progressive deformity. They're always looking for a panacea next door largely because we in this specialty thus far have been failures in terms of really good drug therapy. Our progress has been very slow. So that what happens is it's a yo-yo phenomenon. Their spirits get buoyed up by publicity, they get the drug, they badger the physicians for it, and not invariably, then, there is disappointment among a good many, but not all. Because, as Dr. Shedden indicated, each of these new drugs will capture, will help to control symptoms in a certain number of these people and there's no way of prejudging who will respond. Furthermore, arthritis patients have a remarkable information network. They're better than the KGB and the CIA. If an arthritis patient misses a television announcement, a well-meaning friend or relative will be quick to call and say, "Did you just pick this up on Channel 4?" or "Did you see this in this morning's daily paper?" So that they are buoyed up and then invariably some disillusionment sets in. The difficult part in the Oraflex story is that instead of a gradual lack of enthusiasm among those in whom the drug failed to work, there has been this tremendous engraftment of fear and hysteria so that emotional hardship has been inflicted upon physical pain. And I think that's a very tragic turn of events.

MacNEIL: Thank you.Jim?

LEHRER: First to you on this question, Dr. Wolfe, of how a drug like Oraflexshould be announced to the public. First of all, how do you think the Lilly Company handled it and how do you think it should have been handled?

Dr. WOLFE: Well, I agree with the last statement that when a drug is put on the market, that the information about it should be accurate and people should be informed. I think that if this had been done in the case of Oraflex that people would have been told: there is no evidence this drug is any better than any other similar drug such as aspirin, (a), and they also would have been told that there had been a number of deaths at the time. I think there was too much accentuating the positive, eliminating the negative, as a song in the '40s used to say, and I think that therefore both patients and physicians were misinformed. The fact that 400,000 people used the drug within a couple of months of the time it was put on the market, somewhat unprecedented, really bespeaks the amount of misinformation put out by the company at the time the drug was put out. So I think that accurate information needs to come out. I also have heard of a number of patients who demanded the drug from their doctors. So that the first move was the Lilly move and it was to mislead and manipulate older people, the main group that has arthritis.

LEHRER: Dr. Shedden, do you have any second thoughts about the way your company brought this drug to the public's attention.

Dr. SHEDDEN: Oh, not at all. The public are bombarded with information about drugs and disease from a variety of places, and because of the drug lag in the United States, drugs are marketed abroad here before they're available in this country. Therefore there's a great deal of information coming in from foreign experience which has been promulgated by the financial press and by other places. It's extremely important, I think, that as the patients are receiving this information anyway, that the company should have the opportunity to put forward its point of view. With regard to the assertion that the point of view that we put forward was false and misleading, I would remind you that the information that we produced and distributed to the media was strictly in accordance with the labeling granted to us by the Food and Drug Administration.

Dr. WOLFE: That's not true. The Food and Drug Administration itself has complained about it. That statement is an absolute lie as are many other things you've said.

Dr. SHEDDEN: I'm sorry, I don't agree with that, and I resent the implication that that was a lie

LEHRER: Dr. Jaffe, you were there at the press conference. Did the Lilly Company say anything that was misleading in their announcement?

Dr. JAFFE: I think they said nothing that was misleading in the announcement. What they did do at that press conference, quite frankly, was to show the healing of lesions of experimental arthritis as studied by X-ray in animals. Now, they made it very clear that these were animals and this was experimental arthritis which had no relation to the human disease. But I can well understand how a science reporter, and then trying to translate this into something that might be of immediate value to the patient, could misinterpret and misconstrue some of the animal data and hop, skip and jump to what then could be a false interpretation.

Dr. WOLFE: Might you even understand that that's particularly why Lilly did that, so that these kinds of misinterpretations would occur? I mean it was no accident that they presented this animal data. I think it was a malicious way of promoting the drug.

LEHRER: Dr. Jaffe also indicated a moment ago that you all have also counted the emotional thing and you've scared people strongly around the country and now they're coming back and doing just the opposite.

Dr. WOLFE: Well, the information we have put out is information that we have received from the Food and Drug Administration, which had received much of this data from the government in the United Kingdom. I think that one of the more striking things that's happened, we are told, in the last several weeks is there has been a significant fall in the use of the drug since the information about its dangers came out -- and that's as it should be. My advice to doctors would be not to prescribe the drug because they may be guilty of a malpractice action, and to patients, not to use it. Here's the medical record of a 47-year-old woman who died in Nevada from taking this drug. I'm sure that other people don't want to fall into that category.

LEHRER: Dr. Wolfe, let me ask you this. You heard what Dr. Jaffe said. That the Food and Drug Administration approves prescribing of this drug and that the Food and Drug Administration is a reputable organization that probably has the toughest laws, he said, of any drug agency in the world. And as long as they say it's safe -- and they do -- then why shouldn't he prescribe it?

Dr. WOLFE: At the time that this drug was approved, the FDA, for a variety of reasons, which we're investigating now, were not fully aware of all the dangers of this drug. I would say that if they had been there's a serious question as to whether it would have been approved and I would say the same in the United Kingdom. The United Kingdom doesn't have as strong drug laws as we do; I think there is some question as to why it was approved there. The head of arthritis at the National Institute of Health says he would never use the drug. That is a very powerful statement which I would agree with.

LEHRER: Dr. Jaffe, are you concerned?Are you and your fellow physicians concerned about malpractice suits if you continue to prescribe Oraflex?

Dr. JAFFE: No, that is not a deterrent as far as I'm concerned. And I think that the source of prescribing patterns, just to repeat, Mr. Lehrer, shouldn't be the media and with all due respect it shouldn't in my judgment be Dr. Wolfe. There are responsible bodies to whom we turn for appropriate information.I think a physician does more than write the name of a drug on a piece of paper. He accepts a responsibility. I am very impressed with the caliber of care delivered by most of the physicians in this country, particularly those who deal in this specialty. Now, if a patient, as indicated by Mr. MacNeil, says I would like to be removed from that drug, quite obviously we take them off. No one forces a therapy on a patient, for any reason. But when a patient already in the first month is doing well, a small subset, Mr. Lehrer, who are doing better on this for relief of inflammation than they had ever done before, now say I'm going to stop taking this even though my pain, swelling, and stiffness will return because I'm frightened, I think that's some degree of irresponsibility on Dr. Wolfe's part.

Dr. WOLFE: Well, I think the American Public Health Association, which has 30,000 members, is about to petition the government, the Food and Drug Administration, tomorrow or the next day to take this drug off the market. These are doctors whose main concern is public health not profits as is the case with Lilly.

LEHRER: We have to go. Robin?

MacNEIL: Yes. Dr. Wolfe, thank you for joining us inWashington; Dr. Jaffe, Dr. Shedden in New York.Good night, Jim.

LEHRER: Good night, Robin.

MacNEIL: That's all for tonight. We'll be back tomorrow night. I'm Robert MacNeil. Good night.