Healthy Skepticism Library item: 686

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Publication type: news

Carlisle W.
What Went Wrong with Vioxx?
Radio National (Australian Broadcasting Commission) 2005 Apr 10
http://www.abc.net.au/rn/talks/bbing/stories/s1343699.htm

Full text:

Program Transcript
Wendy Carlisle: In the United States it’s been called the worst drug disaster in history, with evidence given to a Congressional hearing that up to 40,000 Americans have died from heart attacks after taking the blockbuster arthritis drug, Vioxx.

In Australia the damage is unknown, but hundreds of thousands have taken Vioxx and scientists are arguing over the fallout, asking whether our drug regulator, the Therapeutic Goods Administration, acted fast enough to protect us.

Hello, I’m Wendy Carlisle and on ABC Radio National’s Background Briefing today: What went wrong with Vioxx, a drug that cost Australians over $300-million, and which has now been yanked off the market.

ABC TV News – Sophie Scott:
It’s the sort of announcement which sends a chill through those people dependent on medications. Today drug company Merck Sharpe and Dome ordered the immediate worldwide recall of the popular arthritis drug, Vioxx.

Company Spokesperson: We ask that anyone who is taking Vioxx stop doing so immediately and contact their doctor.

Sophie Scott: New data found a small percentage …

Wendy Carlisle: It was the biggest drug recall in Australia’s history. By the time Vioxx was pulled off the shelves in September last year, there were up to 300,000 Australians taking it. Background Briefing didn’t have to look far to find one of them.

Tim, can we do this interview?

Tim Ritchie: Yes, just let me finish this email.

Wendy Carlisle: O.K.

A few doors up from my office at Radio National is broadcaster Tim Ritchie. Tim Ritchie’s been a colleague of mine for years, but I had no idea that such a cocktail of drugs kept him walking.

Tim Ritchie: I have a condition where my spine, one of the vertebrae slips forward and all the ones above it follow that path, and so my spinal cord does an S-bend, which is fine, or relatively fine, when I’m all warmed up, but overnight all the muscles contract and try and hold it in place because it’s sort of gimpy, and when I wake up in the morning, I can’t get out of bed, or go for a walk, it’s hard to even get to the bathroom. So they gave me these drugs, first of all Celebrex, and that didn’t agree with my stomach and so they gave me Vioxx and it was like a miracle drug. I could get up of a morning, and I could go for a walk with the dogs, and as an anti-inflammatory it made the muscles relax, my hips didn’t ache, and so it was like a wonder drug.

Wendy Carlisle: And what were you told by your doctors about the risks and benefits of these drugs?

Tim Ritchie: Benefits: that I’d be able to get up of a morning most probably. I had a particularly nice GP and she said the dangers of it are to do with your stomach, kidneys in the long-term, but certainly nothing about anything to do with heart attack or anything like that, that was never talked about. Vioxx just seemed to fix everything and I was not told to look out for anything really.

Wendy Carlisle: Any history of cardiovascular problems in your family? Strokes?

Tim Ritchie: Yes, my father’s two brothers both died of strokes, so yes, there is a history of it.

Wendy Carlisle: Do you trust your doctor now?

Tim Ritchie: I trust that she makes the best call she can on the knowledge she has at that time.

Wendy Carlisle: So did you talk to her about Why didn’t you say to me that Vioxx has an increased risk associated with heart attack and stroke? Did you say to her, ‘Why didn’t you tell me?’

Tim Ritchie: Yes, and she said she didn’t know.

Wendy Carlisle: Tim’s now switched to another arthritis painkiller on the market, Mobic, which is in the same class of drugs, a Cox-2 inhibitor, as Vioxx and Celebrex.

The drug companies claimed that these drugs, while not shown to be any more effective as painkillers, were much safer, and would help a small group of patients who were most at risk of suffering severe gastro-intestinal bleeds, a potentially fatal side effect of the older arthritis drugs.

But the market blitz that accompanied their arrival on the market was unprecedented. Vioxx and its sister drug, Celebrex, were massively over-prescribed, so that instead of being for a small group, doctors wrote scrips for just about everybody with muscular skeletal pain. The message that Vioxx and Celebrex were safer hit the mark, and the became the drug of first choice, even though they were no better at relieving pain that Paracetamol or the older, cheaper arthritis painkillers.

The financial impact on the Pharmaceutical Benefits Scheme, the PBS, was immediate and extreme. And by the end of last year, 25-million prescriptions had been written for Vioxx and Celebrex. These two drugs cost the taxpayer over $800-million and between them they helped blow out the PBS budget and force up the price of prescription drugs for patients.

In the United States where direct marketing of drugs to the public is legal, Merck Sharpe and Dome, the maker of Vioxx, spent $160-million on TV, radio and magazine ads.

This is audio from part of an ad promoting Vioxx.

Voiceover:
Vioxx is here. A prescription medicine for the most common type of arthritis pain, osteoarthritis. One little pill, taken just once a day, can provide 24-hour relief. For more information, ask your doctor or pharmacist about once-daily Vioxx for the relief of osteoarthritis pain, and you may be able to plan your day around your life, instead of your pain. Vioxx, for everyday victories.

Wendy Carlisle: In September last year, Merck suddenly announced it was voluntarily withdrawing Vioxx from the market in Australia and the United States. The reason? A study to see if Vioxx would be any good at slowing cancer suddenly backfired when it was discovered Vioxx increased the risk of heart attack and stroke.

Four years earlier, another study had found similar problems, but the drug had stayed on the market. That study was called Vigor. Merck funded it and its aim was to prove that Vioxx was safer on the stomach than the older and much cheaper non-steroidal anti-inflammatories available.

The Vigor study came up with good news for Merck: Vioxx was safer on the tummy, but there was also some seriously unwelcome news. Patients taking Vioxx were four times more at risk of heart attack and stroke than those taking the comparator drug Naproxen, in the study.

The drug company and the scientists who did the Vigor study said that Vioxx wasn’t to blame for these heart attacks. They said that Naproxen actually prevented them, and this made the heart attack findings open to question.

In the aftermath of the Vioxx recall, the US Congress held special hearings last November into whether the US drug regulator, the FDA, had acted quickly enough over Vioxx.

Dr Gurkipal Singh, one of America’s leading rheumatologists and expert on these Cox-2 drugs, was one of the witnesses. He thought the argument that Vioxx wasn’t to blame for the increased heart attacks was implausible.

Gurkipal Singh: Well I believed the Vigor result, that was the problem, and the Vigor result showed a fivefold or a fourfold, depending on which study you believed at that point in time, increase in risk of heart attacks with Vioxx versus Naproxen, so that was the Vigor result, that’s what caused me to have a lot of concern about what was going on with the drug. What I did not believe completely was the explanation that was given for the result, that it’s not Vioxx that is causing these problems. That to me appeared to be an unreasonable explanation.

Wendy Carlisle: I would have thought though that as a specialist consultant to Merck on Vioxx that your concerns would have been heart by the company.

Gurkipal Singh: Well many people, I mean I wasn’t the only one, many people expressed their concerns to the company, when people who were experts in the platelet anti-thrombotic areas including guys like Dr Carlo Petronio and many other international scientists, expressed their opinion.

Wendy Carlisle: And so what did you do to try and get more information our of Merck to alleviate your concerns about Vioxx?

Gurkipal Singh: Well we tried our best to get more data. I was quite concerned and I wanted some relational data on hypertension and congestive heart failure and a few other complications that could conceivably be related to heart attacks, but I was unable to get that data at that point in time, it was very difficult.

Wendy Carlisle: Why couldn’t you get that data from Merck if you were already a consultant?

Gurkipal Singh: Well I don’t know, I don’t know the answer to that question, but I was not able to get the information.

Wendy Carlisle: At the US Congressional hearing, Dr Singh was asked to review internal Merck emails that had been subpoenaed by the Congress. These emails were between Merck scientists discussing how best to design a study into Vioxx which did not show the drug’s increased risk of heart attack.

Gurkipal Singh: These are these documents that I received, also from the United States Congress, and what these documents said was very interesting, was that very early on, now this was in 1996 or so, Merck was already considering that there was a possibility that if you did a clinical trial of Vioxx versus a non-selective NSAID, that one would conceivably find that patients treated with Vioxx would have an increased risk of heart attacks and cardiovascular complications. But we have to remember at that point in time, the scientists were not thinking that this is a positive effect, they just thought that perhaps the other NSAIDs were cardio-protective. But nevertheless, it’s my personal opinion that this was a discussion that then should have taken place in the scientific literature. But this discussion never took place, which I find was quite unfortunate; I think the risk benefit assessment at that point in time should have been done to show what was going on.

Wendy Carlisle: Earlier on, Dr Singh had tried to get more information out of Merck about Vioxx. It was then that the company started writing letters of complaint to his supervisors at Stanford University.

Gurkipal Singh: That is true. “When I was publicly asking questions I was warned that this would not be good for me…” When I was publicly asking questions I was warned that this would not be good for me; what I was doing was wrong. I mean I was being a scientist, I was asking questions. That’s what my job is, that’s what I’m paid to do, that’s what as a researcher you are supposed to do, is to ask questions.

Wendy Carlisle: The specific nature of the threat was that you would ‘flame out’ if you continued your anti-Vioxx lectures, or what they perceived as anti-Vioxx lectures.

Gurkipal Singh: You’re right.

Wendy Carlisle: What does flame-out mean?

Gurkipal Singh: I don’t know what flame-out means.

Wendy Carlisle: The Chairman of the US Congress Economics Committee is Senator Chuck Grassley. He’s a Republican from Iowa. The subject of his Congressional hearing was whether the FDA had done enough to protect the public over Vioxx. In his opening statement, Senator Grassley set the parameters for what he called the biggest drug disaster in US history.

Chuck Grassley: Merck and Company has a reputation for excellence in research and development. Yet today, Merck is faced with one of the worst drug disasters in history. Merck acknowledged that Vioxx carried with it serious cardiovascular risk, when it withdrew the drug from the market. During today’s hearing we will hear about the red flags that were raised about those risks in the years before and the years after Vioxx was approved by the Food & Drug Administration.

The Finance Committee has jurisdiction over …

Wendy Carlisle: One of those people who raised the red flag about Vioxx early on was Dr David Graham, and Associate Director of the Drug Safety Division at the FDA. He had to get whistleblower protection to testify before the US Congress.

David Graham: When I went, I didn’t think of myself as a whistleblower. I’d been requested by Senator Grassley’s office to testify and I thought that was my duty as a civil servant, an employee of the Federal government, to testify about the research I’d done. What I realised after I testified was that I needed whistleblower protection in order to preserve my job. It’s ironic that in the United States, if you work for the government, and you have a truth to reveal that calls into question the policies of your government, that unless you get the protection of somebody in Congress, you’ll be fired.

Wendy Carlisle: Dr Graham says the issue at the heart of his worry about Vioxx was the argument that Naproxen had a protective effect.

David Graham: Well it didn’t convince me, and it shouldn’t have convinced anyone. And the reason why it shouldn’t have convinced anyone is that there was clear data to show that Naproxen was not a better inhibitor of platelets than aspirin. If Naproxen had been protective against heart attacks in the Vigor study, it would have meant that Naproxen was reducing the risk of heart attack by about 85%. So it would be three times more effective than aspirin at protecting the heart against heart attack. And that’s what preposterous, and so for the company to have proposed that, I think wasn’t scientifically rigorous, and for the medical community to have believed it I think, was a sort of willing suspension of disbelief.

Wendy Carlisle: Dr Graham told the Congressional hearing that the Vigor study should have set the alarm bells ringing that high dose Vioxx, 50 milligrams a day, was potentially dangerous.

David Graham: Now why did FDA not act more decisively, or why didn’t FDA for example ban the use of the high dose of Vioxx in 2000 when they had this evidence. The Centre for Drug Evaluation, they had approved this drug just six or seven months earlier. “They’re incredibly resistant to doing anything that would suggest that their approval had been premature.” When they got the results of the Vigor study, March or April 2000, and they had just approved it six months earlier, so they just had this recent approval; they’re incredibly resistant to doing anything that would suggest that their approval had been premature, because Vioxx had been a fast-track approval.

Wendy Carlisle: Dr Graham believes the FDA should have insisted that Merck conduct proper safety trials into Vioxx after the Vigor study in 200.

David Graham: It’s clear to me that FDS is serving industry, that industry is the primary client that FDA serves. Certainly that’s the client that the Centre for Drug Evaluation serves, and the public, the people who pay the taxes, the people that FDA is supposed to be representing, supposed to be protecting, are placing their interests above all others, that’s not what happens. And I think that that aspect of my testimony was probably what generated the most anger and hostility.

I think the second thing was that the implications of my testimony were that FDA was responsible for the deaths of tens of thousands of Americans, and they are. But what FDA did do was allow Merck to continue to make however many billions of dollars it made on the drugs.

Wendy Carlisle: When Dr Graham heard evidence that the internal Merck emails were discussing the possibility that Vioxx might show an increased risk of heart attack compared to the other arthritis painkillers, he became deeply concerned.

David Graham: Merck scientists were concerned about the theoretical possibility that Vioxx could increase the risk of heart attack, and that when they were designing the Vigor study, that their scientists were actually discussing this in emails, about the exclusions that were being designed into the study, excluding patients at higher risk of heart attack. By doing that, Merck was trying to design a study that would make it less likely to find a heart attack problem, and what was testified about at the hearing, was the emails, these conversations among Merck scientists, so that clearly it seems to me, Merck had some at least theoretical concerns that the drug might increase the risk of heart attack. Now if that’s true, well I think that that’s an important observation for people to be aware of.

Wendy Carlisle: With the US Congress hearing into the FDA and Vioxx big news in America, reports began to filter out that Vioxx patients were mustering class actions against Merck. The US magazine Business Week reported that Merck had set aside $20-billion to deal with them, and the news sent Merck’s share price tumbling by 25%.

Shortly after the Vioxx recall, Merck’s senior executives in the United States took to the internet with their own statement, saying the company had acted ethically and swiftly once definitive evidence on Vioxx had come to light.

Peter Kim: I’m Peter Kim, President of Merck Research Laboratories. I want to spend a few minutes providing you with the facts about Merck’s decision on September 30th to voluntarily withdraw Vioxx from the market. That decision was based entirely on doing what we believed was in the best interests of patients. In the weeks that followed, we have tried to answer straightforwardly and completely, the questions that have been raised. Plus, incomplete and sometimes inaccurate information has been presented by others about Merck’s scientific integrity and our commitment to ensuring patient safety.

I want to review with you how we extensively studied Vioxx before seeking regulatory approval to market it. “Within one week of learning these results, we voluntarily withdrew Vioxx from the market worldwide.” We continued to conduct studies after the FDA approved Vioxx, and we acted promptly when information from one of the trials, the approved trial, showed for the first time, the increased risk of confirmed cardiovascular events beginning after 18 months of treatment in patients taking Vioxx, compared to those taking placebo. Within one week of learning these results, we voluntarily withdrew Vioxx from the market worldwide.

Wendy Carlisle: Background Briefing requested an interview with Merck; the company issued us with a statement which we’ll put on our website. Merck said they would also be vigorously defending their actions.

Arthritis is one of the most common chronic illnesses in Australia.

Wendy Carlisle: I’ve got it, Mum.

In the four years that Vioxx was on the market, nearly 10-million prescriptions were written by Australian doctors. It was so common that even my mother was given it.

Wendy Carlisle: Are you on the phone to your doctor?

She was prescribed Vioxx by her doctor, but was suddenly taken off the drug, back in 2001, when her blood pressure went up.

Wendy’s Mum: I went on it on 23rd May and by 6th June my blood pressure, which had been normal all my life, went up to 170 over 90 and he took me off it immediately.

Wendy Carlisle: Mum, this was the Vioxx, was it?

Wendy’s Mum: Yes.

Wendy Carlisle: So why did you go on it?

Wendy’s Mum: I was originally on Voltarin, and Dr Harvey really was against Voltarin. So he put me on Celebrex. I didn’t like that Celebrex. I said, ‘I don’t like this nonsense’, so that’s when he put me on the Vioxx, and I was on it for barely – 23rd May to 6th June, and he took me off it. And ever since then of course, I’ve been on blood pressure tablets.

Wendy Carlisle: Ever since the Vioxx episode?

Wendy’s Mum: Yes.

Wendy Carlisle: So it didn’t go away?

Wendy’s Mum: I’ve been on these tablets since then, and as it’s keeping my blood pressure at bay, I should not give it away.

Wendy Carlisle: And what did you go on to?

Wendy’s Mum: Back on the Voltarin.

Wendy Carlisle: Did he tell you why he put you on Vioxx in the first place?

Wendy’s Mum: Because he’d seen so many people with haemorrhage of the stomach.

Wendy Carlisle: So he thought it would be safer for you?

Wendy’s Mum: Yes. And I met a woman the other day and she went through the same experience and was taken off it. It was very fashionable.

Wendy Carlisle: Why was it fashionable?

Wendy’s Mum: It was a new drug. Would you like a drink?

Wendy Carlisle: Yes, let’s have one.

Wendy’s Mum: Well I opened a bottle of Peter’s rotten red wine to put in the chicken.

Wendy Carlisle: Well we won’t have the rotten red wine.

Wendy’s Mum: Well, it might be all right.

Wendy Carlisle: One of Australia’s leading pharmacologists and rheumatologists is Professor Richard Day. He was also one of the co-authors of the Merck-funded Vigor study. Professor Day’s been a great advocate of these drugs, and when Vioxx was pulled from the market last year he was unprepared for the news.

Richard Day: I was surprised when it was pulled.

Wendy Carlisle: Were you? Surprised?

Richard Day: Yes, I was. I was actually very much involved in the study that really identified the –

Wendy Carlisle: The Vigor study?

Richard Day: Yes, I was an author of the Vigor study, and heavily involved in it and the writing of the paper, and analysis of the results and what-have-you. and although there was the theoretical basis that this might lead to an increased risk of myocardial infarctions and other cardiovascular problems, when that result came out, that was a surprise to us, a great surprise; this the authors of the article.

Wendy Carlisle: Professor Day says those working on the Vigor study firmly believed it wasn’t Vioxx that was causing the heart attacks.

Richard Day: So that was a sort of a time for a couple of years where there was great debate and uncertainty, and people, myself included, were trying to say to prescribers, ‘Look, we don’t really know what’s going on in the cardiovascular area precisely, but you ought to be very careful about how you manage people with these conditions, and if you do decide to use a Cox-2 inhibitor, then you need to take these type of things into consideration’.

“We don’t really know what’s going on in the cardiovascular area precisely, but you ought to be very careful about how you manage people with these conditions.” I guess what’s emerged is that there is a cardiovascular risk which is now definite. I don’t think there’s great debate about when people it was definite, but I think the control trials, everyone agrees there’s a definite risk now, but it relates to the dose of the drug given and the types of patient you give the drug to.

Wendy Carlisle: Professor Day does agree that scientists were aware of the theoretical risk that Vioxx could increase the risk of heart attack, but he stands by the Vigor trial that was designed to show the drug was safer on the stomach.

Richard Day: We were particularly looking at the GI safety and the study was set up to really see that, and it really wasn’t in our mind that we should set it up to sort out whether or not there was heart attack risk with Vioxx.

Wendy Carlisle: Did you know that Merck scientists were concerned back in 1997 and this is based again on the emails that were read into evidence in the US Senate investigation, that the scientists back then were concerned that Vioxx could actually cause heart attack?

Richard Day: Well I think that we as a sort of an academic and industry grouping, everyone I think was concerned about whether or not there was a risk of heart attacks, and the question was whether there really was or there wasn’t, and if there was, what might be the size of it. So I think really right from certainly the Vigor results, there was constant discussion and there was even before that, the sort of theoretical basis for this possibly emerging.

Wendy Carlisle: Was the Vigor study actually designed to show a minimal risk of heart attack?

Richard Day: No, it was designed to show in the most rigorous way to date, that there truly was a benefit in terms of the risk for gastro-intestinal bleeding, and that was the big question, the huge question, and still is actually.

Wendy Carlisle: But there was no effort to design Vigor so that maximum effort was put in to trying to downplay any risk of heart attack?

Richard Day: No, absolutely not. And in fact myocardial infarction concerns weren’t on the radar. They obviously came on the radar with the results.

Wendy Carlisle: But when the Vigor study showed that Vioxx could increase the risk of heart attack, Professor Day thought it wasn’t because of Vioxx, but because the other drug in the study, Naproxen, actually prevented them.

Richard Day: Naproxen acts very much like aspirin. It inhibits platelets, it’s an aspirin-like drug, but not as effective.

Wendy Carlisle: There are many people who are not convinced by that argument.

Richard Day: Well there are many people who are convinced by it. This is science. So it wasn’t unreasonable to say ‘Look, there was a difference’ which was significant and worrying, and there was a bit of a rationale for this.

Wendy Carlisle: But a lot of people felt that the result of higher cardiovascular serious adverse events from taking Vioxx in that Vigor study, was not unexpected when you looked at the science of it.

Richard Day: Well at the time, the science was very much emerging. We knew about the lack of effect on platelets, that was understood. So therefore the rationale, if you like, was undeveloped at the time.

Wendy Carlisle: It’s almost possible to be blinded by the science for the Background Briefing listener when they listen to you. But when I go back to this FDA study that was based on looking at the Vigor study, it found that the risk of having a serious adverse event from taking Vioxx was much higher from taking Vioxx than it was taking the old-style drugs. So I suppose as a patient, I think that’s important to know that.

Richard Day: Now the serious adverse events, you’ve got to know what we’re talking about there. What that is, is death, hospitalisation, now it could be anything, it may or may not be related to the drug. Now in the Vigor study that everyone’s worried about, there was no difference in death rate. If you were hit by a bus in a clinical trial, that’s a serious adverse event and is reported as such.

Wendy Carlisle: But that’s not a fair comparison then is it?

Richard Day: Not in this particular case, but you’ve got to understand what a serious adverse event is.

Wendy Carlisle: As Professor Day is on the Australian Advisory Committee to Merck, Background Briefing asked him if he was aware of Dr Gurkipal Singh’s concerns about Vioxx.

Richard Day: Well I’ve certainly known him very well, and along with lots of other people there were lots of concerns expressed about the whole class, as they should have been. So there was certainly all sorts of opinions expressed quite openly and freely and available to affect people’s opinions, and what should be done and what shouldn’t be done. So I think that was very healthy, as it should have been.

Wendy Carlisle: But did you have conversations with Dr Singh about his misgivings about Vioxx?

Richard Day: Well I had lots of conversations with him about his views about all the Cox-ibs, and good views, and entirely reasonable views.

Wendy Carlisle: Did they include the risks of the heart attack, the concerns he had there?

Richard Day: Well I think most of my discussions with him were about Celecoxib, the alternative drug which he was very much involved with and the risks associated with that.

Wendy Carlisle: Were you aware that when he started to express his concerns about Vioxx publicly in lectures and so on, about the risk of heart attack and his concerns about the drug, that he gave evidence to the US Senate that he was threatened by Merck because he was expressing those views.

Richard Day: No, I wasn’t aware of that.

Wendy Carlisle: He didn’t tell you that?

Richard Day: No, I mean I speak to him as a scientist-to-scientist from time to time; it’s not as if we’re talking on the phone twice a week about these matters.

Wendy Carlisle: Does it surprise you?

Richard Day: Well it does surprise me. I think anyone who’s pressured not to talk about the data and to discuss it in appropriate forums, that’s inappropriate.

Wendy Carlisle: How would you describe Dr Singh as an expert on Cox-2s, is he a world leader, or what is he?

Richard Day: Well he’s certainly one of the leading rheumatologist epidemiologists, he’s been involved with a very important program which is collecting data on patients from all sorts of centres across America.

Wendy Carlisle: Professor Day believes that with the wisdom of hindsight, much more should have been done much earlier, to test the safety of the Cox-2 drugs, including Vioxx.

Richard Day: And the FDA, what it’s been doing, it’s been criticised that it didn’t move fast enough, and I could agree with that, but I think we could all agree with that, that what we’ve learnt is that what should have happened quicker was a control trial to test the cardiovascular safety of these drugs; I absolutely agree with that. But in terms of where it was obvious and people were dragging the chain, I think that’s a very debatable point.

Wendy Carlisle: The Vigor study, and its then-contested finding that Vioxx increased the risk of heart attack, triggered an intense debate in the Australian medical fraternity. At the Royal Adelaide Hospital is Professor Leslie Cleland, another leading rheumatologist. He’s been studying the safety profiles of the arthritis painkillers for years. In 2001 he was so concerned about Vioxx that he wrote an article in The Medical Journal of Australia.

As Director of the hospital’s rheumatology unit, he doesn’t use these drugs in practice, but when patients come to his unit, they often arrive with packets of Vioxx. Professor Cleland then pulls out a special graph that he’s made up, showing the risks and benefits of the drug, and he lets the patient make the call.

Leslie Cleland: The thing about weighing risks in fact, it gets to this business of informing people of what the risks are, and what their choices are. And if you look at the Vigor study, there was a trade-off between there were fewer serious upper GI events, which generally means bleeding. “The risk for death from a heart attack is far greater … given that you have one or other event you’re more likely to die from a heart attack than from having an upper GI bleed.” Most people will recover from an upper GI bleed without any long-term consequences. That’s not to say it can’t be fatal and there is a fatality rate associated with it. But the risk for death from a heart attack is far greater than the risk from – I mean given that you have one or other event, you’re more likely to die from a heart attack than from having an upper GI bleed.

Wendy Carlisle: Which begs the question, why take the drug?

Leslie Cleland: Well exactly, and in fact I know from my own experience through explaining to people that their was this increased cardiovascular risk, that most people would stop it. In fact I mean I think there were many patients to whom I gave the advice, and I think there was only one who ignored it.

Wendy Carlisle: In the years immediately after the Vigor study, a lively discussion was occurring in the major medical journals around the world, debating the safety of Vioxx and the other Cox-w drugs, including Celebrex. Concerned about how all this might affect Australian doctors’ attitudes towards using them, in the summer of 2002, Pfizer, the maker of Celebrex, and Merck, the maker of Vioxx, assembled a working group of 23 people to come up with some guidelines for doctors on how best to use the drugs.

The group they put together was mainly comprised of medical specialists with financial connections to the drug companies, either through research grants or paid advice, but eight of the working group had no financial connections.

Finding agreement in this group was easier said than done. There were meetings and hundreds of emails flew back and forth, arguing the toss on the scientific evidence. Were the drugs safer? No agreement. Were these drugs more effective? Again, no agreement.

And in the end, they agreed to disagree.

Six of the group refused to sign off on the final document. Some of the drug company scientists felt it was too tough on their drugs, and some of the rheumatologists thought the benefits were overstated.

The final statement, published in The Medical Journal of Australia, in 2002, made the following observation.

Whether these drugs pose a risk to cardiovascular safety remains subject to debate.

Wendy Carlisle: Professor Leslie Cleland was on that working group, and it seemed curious that he agreed to a statement about heart attack risk that seemed weaker than what he really thought.

Leslie Cleland: It wasn’t that I thought that the statement was adequate I suppose, but one needs to remember I was virtually a lone voice in stating the case, and I had a concern actually that if I dropped out that nothing would be said at all.

Wendy Carlisle: So you stayed in that group to just basically have that very –

Leslie Cleland: I thought it was a statement that needed to be made.

Wendy Carlisle: Because others quit the group, didn’t they?

Leslie Cleland: I guess actually it was quite interesting because I found myself putting arguments about the cardiovascular risks principally because no-one else was giving that much emphasis, and it was something that I had a special interest in.

Wendy Carlisle: What was it that made Professor Cleland concerned that Vioxx and Celebrex might increase the risk of heart attack back in 2002?

Leslie Cleland: Well firstly, we had the evidence from the Vigor study that there was an increased risk of serious thrombotic cardiovascular events.

Wendy Carlisle: But you weren’t convinced by the views put by the drug companies and in fact some of the opinion leaders that the Vigor study couldn’t really say that?

Leslie Cleland: No, I wasn’t, for several reasons actually. I thought that that was an unbalanced argument. When you look at the outcome of a study, you need to look at it in several ways. Firstly there was an argument that this increased risk was unexpected. Well in fact, it may not have been expected, because obviously expectation is conditioned by thinking about whether something’s going to happen or not. Certainly when it did happen, while it may arguably have been unexpected, it was certainly not inexplicable.

Wendy Carlisle: Professor Cleland believes that this concerns about Vioxx and Celebrex went unheeded simply because there was so much positive attention on the drug.

Leslie Cleland: Well on the one hand you’ve got the company saying ‘Well everything’s all right’. You’ve got the vast majority of the profession that might make a claim to knowing something about it, either saying it’s all right, or thinking it’s all right. And you have a few people, for example, in the Cox-2 story, worldwide, there were about half a dozen small research groups expressing concerns around the world. I mean in terms of signal and noise, most of the signal was that it sounds as though this is all right.

Wendy Carlisle: And most of that signal was coming from drug companies?

Leslie Cleland: Well not necessarily coming from drug companies, but conditioned I guess, by messages from drug companies.

Wendy Carlisle: What’s that code for? What do you mean ‘conditioned’? Through opinion leaders, opinion-makers, people like that?

Leslie Cleland: That sort of thing, and through company detailers.

Wendy Carlisle: Company promotions to doctors?

Leslie Cleland: Exactly. Meetings about the products. And this is the standard way in which any new product is promoted. Obviously we regard ourselves as practising what we call evidence-based medicine, so that we make decisions based on what the randomised control trials show. The reality is that we’re able to be expert in a narrow area, and frankly, one of the things that concerns me most is that I’ve had this experience in an area that we know quite a lot about. The concern one has is, what other stories does one have insufficient insight into in other areas, where one just has to follow the standard advice.

Wendy Carlisle: Back in August 2000, former Health Minister, Dr Michael Wooldridge, approved this new class of arthritis painkillers, the Cox-2s, Celebrex and Vioxx for listing on the PBS.

It was a controversial story at the time. ‘Four Corners’ did a program revealing that key members of the Pharmaceutical Benefits Advisory Group were opposed to listing the new drugs, believing them no safer than the much cheaper drugs already on the PBS. The Pharmaceutical Benefits Advisory Committee had recommended tight price controls on the drugs, but the Minister over-ruled them.

‘Four Corners’ also revealed how a lobby group of drug companies, known as the Benelong Group, so-named because many are headquartered in the Prime Minister’s electorate, had met with Mr Howard at Kirribilli House to discuss the government’s policy on new drugs.

But it was the claim that these new Cox-2 drugs, Vioxx and Celebrex, were much safer, that inspired Dr Wooldridge when he was doorstopped by journalists shortly after the announcement.

Michael Wooldridge: I’ve got some good news. Cabinet has decided to fund a new category of drugs under the Pharmaceutical Benefits System. This is the biggest single decision that’s been taken in the 52 year history of the Pharmaceutical Benefits System. We’re going to fund the drug category called Cox-2 inhibitors. The fact that we do take some old drugs off the PBS, like nasal sprays, enables me to put these new modern drugs on the PBS that are actually life-saving. So it is a big change and it going to be an additional cost to the budget, but it’s a very good cost to the budget. It will save a lot of illness; it will save a lot of people ending up in hospital with bleeds, because of the non-steroidal anti-inflammatory drugs they use now, and it will prevent a lot of side effects that older people currently get from their arthritis medication.

Reporter: Does it essentially give pain relief Doctor?

Michael Wooldridge: Yes, it does give pain relief. It works in a similar way to the non-steroidal anti-inflammatory drugs, but it doesn’t have the side effects, and that is the great breakthrough. In the Cox-2, is short for Co-oxygenator-2, there’s two of these enzymes in the stomach; the current drugs inhibit both of them, and when you inhibit both of them you get bleeding in the stomach. This drug is much more specific in its action and it doesn’t have the bleeding side effects. So it’s not more effective, it just has dramatically fewer side effects and that is the great advance. Thank you.

Wendy Carlisle: We now know that one of the Cox-2 drugs, Celebrex, is no safer on the stomach than the other non-steroidal anti-inflammatories. And that the other Cox-2 drug, Vioxx, has been pulled off the market because of fears it could increase the risk of heart attack. Between them, these two blockbusters have cost the taxpayer over $800-million.

Now, in addition to Vioxx being pulled, there are safety questions hanging over all the other Cox-2 drugs, including Celebrex and the other one called Mobic.

When Vioxx was banned by the Australian drug regulator, the Therapeutic Goods Administration, last year, it ordered a review into all the Cox-w drugs. And while it waits for the results of those to come through, it’s ordered that a black box safety notice be put on all the Cox-2 drugs, Celebrex and Mobic, telling patients there could be cardiovascular risks with these drugs, too.

But just last week, the manufacturer of Mobic, Boehringer, was granted an injunction in the Federal Court stopping the TGA from putting a black box warning on Mobic, arguing it would have a severe financial impact on the company and the science did not support the TGA’s concerns.

Pfizer, the maker of Celebrex, has also appealed the TGA’s black box warning for the same reasons. But they’ve taken their complaint directly to the Health Minister, Tony Abbott.

One group of people who’ve questioned the safety of these drugs for the last four years is an outfit called ‘Healthy Sceptics’ which is based in Adelaide. Dr Peter Mansfield is a local GP in Willunga, just out of Adelaide, and when Background Briefing paid him a visit, he was reviewing how the popular doctors’ press had been covering the story.

Peter Mansfield: Australian Doctor Weekly is the publication that’s most read by doctors, and that’s because they tend to make issues easy to understand. Here’s their report on 18th February: the headline is ‘Black Box warning for Cox-2. Australia spearheads tough stance on drug class’.

Wendy Carlisle: Well that sounds good, Australia is leading the way.

Peter Mansfield: Yes, but in fact I think it’s inaccurate. I don’t believe that their stance was nearly tough enough. I think a much more accurate headline would have been ‘Australia does too little, too late’. And certainly the weakness of our response can be seen by comparing us to New Zealand. In New Zealand they have made a very clear statement that the benefits of these drugs don’t justify the risks, so that it’s not appropriate to use them.

Wendy Carlisle: One of Dr Mansfield’s concerns is that we may never know the true extent of how many people may have been harmed by Vioxx and Celebrex because the system of reporting patients’ adverse reactions to drugs if flawed.

Peter Mansfield: It’s only about 1% of adverse reactions where a doctor actually takes the time to fill in a report.

Wendy Carlisle: So you’re saying that 99% of adverse reactions from drugs are not reported?

Peter Mansfield: Oh, no it’s much higher than that. It’s about 1% of the serious reactions get reported. When it’s a minor reaction, something that’s already known, it would be very rare for a doctor to report that.

Wendy Carlisle: So it’s not a mandatory system?

Peter Mansfield: Not at all. And it takes time; we’re time-starved. The biggest complaint about general practice is people have to wait in the waiting room too long. So if we’re spending the five, ten minutes it takes to fill in that form, and we’re all running half an hour late, people are going to be understandably angry with us.

Wendy Carlisle: In April of 2002, the FDA instructed Merck to include some important new information to American patients. In the leaflet included in each box of Vioxx, under the heading ‘possible side effects’, was the following statement.

Heart attacks and similar serious events have been reported in patients taking Vioxx.

Wendy Carlisle: In the same year, the Australian doctors’ medical manual, the MIMS, ambiguously reported that patients taking Naproxen in the Vigor trial had a significantly lower incidence of heart attack than those taking Vioxx.

But it took another 18 months after the FDA notice for the Australian drug regulator, the TGA, to tell Australian doctors about possible cardiovascular risks of the Cox-2s.

The Principal Medical Officer at the Therapeutic Goods Administration, Dr John McEwan, says the Australian drug regulator acted on Vioxx with the best knowledge possible.

John McEwan: I think that one needs to have an understanding of the complexities of the issues that arose. I think people have probably spoken to you about the Vigor study, which was a study which was published in November of 2000, and which showed a difference between Vioxx, Refecoxib 50 milligram a day, and Naproxen, with which it was compared, and the published paper and much of the comment that was put forward at that time, was that this may well be a protective effect on the heart of Naproxen, and not an unwanted effect of Refecoxib at that time.

Wendy Carlisle: All right, but in relation to the Vigor study, there was a considerable debate in medical journals in Australia, in the United States, in Britain, about people’s concerns, scientists’ concerns about the safety of Vioxx. Did that not make the drug regulator in Australia think twice about the safety of this drug?

John McEwan: Can I say first of all I think you’re actually overstating the extent of the debate at that time. It’s important to focus on that time. There was some debate, but if you followed through the literature over the next two or three years, what you will find is that everyone, and I was at conferences and heard this reporting, everyone was ploughing through databases, medical record databases in North America and the like, and in the UK, trying to sort out whether indeed Naproxen did have a protective effect. So I think not just us as a regulator, but I think that much of the world of expertise in this area thought that that was a possible plausible explanation, and they tried to sort it out.

Wendy Carlisle: In the United States this has been called the worst drug disaster in history, in US history; would you put a similar description on the Vioxx story in Australia?

John McEwan: No, I wouldn’t. For a start I think there’s a lot of rhetoric in the US at the moment, and we need to work through that. One of the important things I think in Australia was the dosage. Much of the initial problem and certainly where the risks are clearly increased with Vioxx, is it’s 50 milligrams a day, and that, both because of the way in which it was approved in Australia, by the fact that that dose limitation was put in, but also one might say perhaps fortuitously, but also the subsidisation in Australia on the Pharmaceutical Benefits Scheme, tended to be at a maximum of 25 milligrams a day. And there data which suggest that very, very few Australians actually were taking the higher dose.

Wendy Carlisle: But there is an editorial in the Medical Journal of Australia which suggests that Vioxx might have caused a couple of thousand extra heart attacks in Australia. Will we ever really know the true extent of the injury and perhaps the death that Vioxx has caused in Australia?

John McEwan: Well we may not know the number. My belief is that that number is an excessive number, but we get into rather theoretical calculations, that I think are not terribly rewarding.

Wendy Carlisle: Background Briefing’s Co-ordinating Producer is Linda McGinnis. Technical operator, Angus Kingston. Research and Webmaster, Paul Bolger. You should also watch Four Corners tomorrow night on Vioxx.

Executive Producer is Kirsten Garrett. I’m Wendy Carlisle, and you’re with ABC Radio National.

Further information

Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors – Abstract
Journal of the American Medical Association

Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis – abstract.
The New England Journal of Medicine

Applying a research ethics committee approach to a medical practice controversy: the case of the selective COX-2 inhibitor rofecoxib.
Journal of Medical Ethics

Lessons from the withdrawal of rofecoxib
The British Medical Journal – Editorial

The letter from Merck Sharp & Dohme to Background Briefing