Merck CEO Ray Gilmartin
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SUSAN DENTZER: Let’s go back to 1999 when Merck received approval from the FDA for Vioxx. What did you think you had on your hands at that time as a company in terms of Vioxx as a product?
MR. GILMARTIN: Well, in May of 1999 when Vioxx was approved by the FDA, this was a drug in a new class, a drugs called Cox II inhibitors that had the potential to reduce the side effects associated with typical NSAIDS like Ibuprofen, and because the traditional NSAIDS have a high risk of GI [gastrointestinal] events–perforations, ulcers, and bleeds–something on the order of more than 100,000 people a year go to emergency rooms with these kinds of GI side effects. More than 15,000 dies.
So what we had was a drug that not only relieved pain and inflammation but also a drug that had the promise of reducing these GI events by a significant amount. And we had underway at that point a study to prove exactly that called the VIGOR trial.
The VIGOR trial results came out in March. The preliminary results came out in March of 2000 and did prove, did show that we could reduce those serious events by more than 50 percent, which was a positive.
But the same trial also showed that Vioxx had a higher rate of cardiovascular events compared to our comparative drug Naproxen. Now, as soon as we had that information, we issued those preliminary results; we issued a press release; we notified the FDA of these findings.
Two months later we submitted these findings to The New England Journal of Medicine; it was later published in November. We also two months later presented this data at a medical symposium or forum, because the question was at that point: Was this chance, or did Naproxen cause fewer cardiovascular events or did Vioxx cause more? And the weight of the evidence around Naproxen being known as having an effect similar to aspirin, the weight of the evidence was that Naproxen had fewer events.
But then we submitted this data to the FDA, and through the process this data was incorporated into the label for Vioxx, both the GI safety benefit as well as other data against placebo, which showed no difference, and then also the difference between Naproxen and Vioxx.
SUSAN DENTZER: And the FDA says it was always skeptical of the argument that Naproxen was, in effect, cardio-protective, and in fact it at one point warned Merck through a letter not to have detail people going around saying that.
MR. GILMARTIN: And in the label it says “chance,” or Naproxen could be lower or Vioxx could be higher. But because of these kinds of questions, we had started a trial almost at the same time that the preliminary data from Vigor came out called APPROVe. The VIGOR data, preliminary data, came out in March, and we had started trial in February to see if we could prevent the occurrence of colon polyps as a result of the effect of Vioxx.
We later added to that study two other studies, one using Vioxx basically with people with prostate cancer and others in colorectal cancer, and pre-specified at the outset looking for cardiovascular events. So these were studies that were to be long-term in nature that were designed to not only answer the question about a new indication but also to answer the question about increased risk of cardiovascular events.
Now, it was the APPROVe Study that we had started just the month before the preliminary data from VIGOR came available that resulted in this remarkable outcome, that for the first 18 months there was no difference between placebo and Vioxx. And then after 18 months, the trends started to change toward increase risk for Vioxx. And the point that we heard from our outside investigators, which was on a Thursday evening, September 23rd, at that point we undertook the analysis of the data and with this new information, and within a week, basically, did a voluntary withdrawn of the drug from the marketplace.
SUSAN DENTZER: What does the company believe is the possible mechanism that produced these results that, as you say, showed up on the APPROVe trial?
MR. GILMARTIN: Well, the mechanism at this point is uncertain. I mean first of all to go for 18 months with no difference and then start to see a trend toward increased risk starting at 18 months is really quite an unusual outcome. So that mechanism is uncertain at this point. And we have –we’re working now to put together the experiments, if you will, the trials to try to understand what is going on here.
Now, the results around a molecule such as Vioxx can’t necessarily be generalized to the entire class because each molecule in the class is different, chemically different. So that right now is uncertain as to what’s going on here.
SUSAN DENTZER: The plaintiffs’ attorneys who have brought suits already and are preparing many more, are making a lot of some particular details in this whole story, one of which is that the drug was approved by the FDA on a fast-track basis and, they say, approved at that point with only 90-day studies on safety.
First of all, please feel free to comment on the accuracy of that, of that assertion, but also as they are trying to put together their cases, they’re essentially saying this is a fundamental weakness of the approval process of Vioxx.
MR. GILMARTIN: Oh, not at all. I mean the thing is, is that this drug was approved on a sort of the normal approach which is large numbers of patients in trials looking for efficacy as well as safety. And in continuing the trials we had data on 28,000 patients in varying health status against Vioxx against placebo and against NSAIDS such as Ibuprofen in which we saw no difference in cardiovascular risk.
So it’s important to continue to recognize that there was no difference even for 18 months. Had we stopped this trial at 18 months, we would not have seen a difference. Fortunately, the trial continued beyond that, and then at that point it was possible to pick up that there was an increased risk of cardiovascular events, and based on that new data we moved quickly to take the drug off the market, voluntarily.
SUSAN DENTZER: The attorneys are, and other critics are suggesting that this drug never should have been brought on the market in the first place. What’s your response?
MR. GILMARTIN: Well, first of all, the reason this whole class was developed, and the reason this drug was developed was to reduce the risk of perforations, ulcers, and bleeds, which is a serious side effect of NSAIDS. And we proved it with this drug, that we could reduce that and those events by over 50 percent. So, therefore, the risk of ending up in the emergency room with a bleed, or the risk of dying as a result of that were, you know, basically a significant reduction in risk. So there was real benefit from this drug. And even today in terms of the pain aspects of it, you know, we receive letters from people who said this was the only drug “that really gave me relief.”
But the reason the drug was developed in the first place was to reduce these GI events, which we demonstrated.
SUSAN DENTZER: And this was the only one of the Cox II’s that was able to demonstrate that.
MR. GILMARTIN: This was the only one of the Cox II’s that demonstrated that benefit. In fact the other Cox II on the market at that time failed to demonstrate that benefit.
SUSAN DENTZER: I want to come back to this assertion about the 90-days of safety [data]. As I say, the argument that’s being made is that that was too short a period of time for–of the safety aspects of the drug to [be studied to] win approval. MR. GILMARTIN: We’ll have to give you more of the detail about this, because it’s much more data than that, but–
SUSAN DENTZER: That was inherent in a new drug application.
MR. GILMARTIN: In the approval.
SUSAN DENTZER: The other assertion that is made by many of the critics is that this was a drug that was–not withstanding the benefits that was able to be demonstrated–that it wasn’t just marketed on that basis; that it was in fact marketed much more broadly as a pain reliever, even though it did lose a head-to-head trial on the pain relief aspects with other more conventional NSAIDS; and that the company over-marketed this drug to the general population.
MR. GILMARTIN: Vioxx, basically, had indication for acute pain, so it was indicated that in its label and as well as for osteoarthritis and rheumatoid arthritis. So the drug had been studied in pain and in acute pain and having approval for that.
SUSAN DENTZER: Yes, I understand that. The additional argument, though, that is made is that it was marketed as if it was–it was over-marketed to a population that was suffering pain, but not necessarily at risk of GI adverse events, which was essentially its key advantage over the other NSAIDS.
MR. GILMARTIN: The key advantage that Vioxx had over other NSAIDS was the fact that it could reduce GI events. But it was indicated for us broadly in people with rheumatoid arthritis, osteoarthritis, as well as acute pain.
SUSAN DENTZER: And to the charge that it was over-marketed, oversold, which is the gist of the argument.
MR. GILMARTIN: This drug was sold completely within the label and the indications and the approvals that we had with the FDA, and was very effective in meeting those indications.
SUSAN DENTZER: Another piece of the argument that the plaintiffs’ attorneys in particular point to is that in an earlier edition of the Merck Manual there was specific discussion of the fact that this–that the drug, that the molecule had a role in the clotting process. And the plaintiffs’ attorney are pointing this out and also saying that this was removed from a subsequent edition of the Merck Manual, suggesting that this was a sign that Merck knew very early on that there was some difficulty that was possibly going to crop up as a cardiovascular risk.
MR. GILMARTIN: That’s not the case at all. The Merck Manual is independent of what we do as a company. It’s run as an independent operation, and there’s no influence on the Merck Manual because of this hypothesis that was out there about the potential for clotting. But there was also one about the potential for [Naproxen being] cardio-protective was one of the important reasons that–why we undertook, particularly after getting the VIGOR data that showed a lower rate of cardiovascular events from Naproxen–why we started a trial, a long-term trial, to also be pre-specified for cardiovascular events. We studied this drug on a timely basis, and as soon as we had the new data –which as I said was remarkable in the fact that there was no difference against placebo for 18 months–as soon as we have the new data we moved quickly within a week to voluntarily withdraw that product.
SUSAN DENTZER: Dr. [Eric Topol of the Cleveland Clinic] is one of those who has estimated that as many as 30,000 to 100,000 excess heart attacks and strokes took place in the population taking Vioxx. And, obviously, the inference from there is that a number of those people also died. What does Merck think is the case now with respect to the number of adverse incidents that were suffered and the number of deaths?
MR. GILMARTIN: Well, I would just note that–a couple of things. One is that the FDA, in their press release upon and commenting on our voluntary withdrawal of the drug in which they said we did the right thing, also noted that the risk for any individual patient for a stroke or a heart attack was very small.
Secondly, in the trial which extended for close to three years, the difference in deaths between placebo or sugar pills and there was no difference between that and Vioxx. There were five on sugar pill and five on Vioxx. And then beyond that, you know, just one cannot generalize through populations at large because of so many differences in health status.
SUSAN DENTZER: But the argument that is made again by those who looked at the data is with 20 million patients on this drug, if indeed the APPROVe data is correct and there were twice as many incidents, that would suggest that at least a thousand or so as a minimum additionally deaths took place as a consequence of this.
MR. GILMARTIN: Well, there were 2 million people that were taking the–you know, actively taking the drug based on our best estimates at the time that we withdrew it. And as I say again, as the FDA commented in their press release, the chance of a cardiovascular event, a heart attack or a stroke for any individual was very small.
SUSAN DENTZER: Okay. The other point that is made by the critics, Dr. Topol and others, is that in addition to the studies that you had ongoing, there were other studies coming out over this period that also suggested the higher cardiovascular risk, the 2002 study of the Tennessee Medicaid population being one of those; and that the evidence was beginning to accumulate very strongly outside just the trials that Merck was involved with that this was a drug that had some significant difficulties with respect to cardiovascular risks.
How much did you take that additional data into account as Merck was contemplating what to do over this period?
MR. GILMARTIN: There were a number of what are called epidemiological or observational studies that were conducted that started to be published in 2000 and beyond. And they had conflicting outcomes. Some studies showed that there was a higher rate of cardiovascular events for Vioxx against placebo. Other studies showed that there was no difference. So the only– these kinds of studies are used to generate hypotheses to suggest other studies that should be done to test what’s, you know, definitely what’s happening.
The study that we had underway, the APPROVe trial, which was a randomized control, a clinical trial with pre-specified for cardiovascular events as well as for the indication we’re looking for, was the way to settle the question about whether or not there was an increased risk of cardiovascular events. But these observational studies, or epidemiological studies which are not controlled, which can only be–have limitations, had different outcomes. And I think a classic example of some of the limitations that these studies is the observational study around hormone replacement therapy, because the believe was, based on those studies, that HRT would be cardio-protective.
When the control trial was done, the randomized control clinical trial was done, the answer came out exactly the opposite. So that’s a clear example of limitations of looking at these studies.
So we were aware of them. We saw the conflicting outcomes, but we were doing the definitive study to answer the question from a scientific standpoint.
SUSAN DENTZER: Dr. Topol’s editorial in The New England Journal, as you know, was called “Failing the Public Health,” and he accused Merck of having failed the public health and the FDA of having failed the public health. Let’s leave the FDA out of this for the moment, but did Merck fail the public health?
MR. GILMARTIN: Merck, at every step of the way in terms of its conduct with Vioxx, basically reflected our values that we put patient safety first. So we studied the drug in great detail with lots of clinical trials; we disclosed the results of those trials and the preliminary results of the Vigor Trial for example, which raised the question about whether or not Naproxen lower the rate of heart attacks or cardiovascular events, or whether Vioxx increased them. We put that into the public domain right away.
We had a trial underway to answer the question definitely, and so we acted completely responsibly and completely with our values. And we had new data about the drug, the surprising new data that after 18 months that we saw a difference, within a week we voluntarily withdrew the drug from the market.
SUSAN DENTZER: The question arises, what is this a case study in? And we put that question to everyone we’ve interviewed, including the FDA, and will put it to everybody. Stepping back from this story, what is this story all about from your standpoint?
MR. GILMARTIN: Well, I think that the important lessons from this are the fact that a company such as ours continues to study these drugs; that as we come up with new findings and a surprising finding in this case about safety, how important it is to disclose that immediately to put that information into the public domain in the variety of ways, as we did with Vigor initially, and as we did with the results of Approve in which, therefore, for the first time we had new data that showed that Vioxx did cause a higher rate of cardiovascular risk as compared to placebo.
So it’s important to disclose the results of clinical trials, get them to regulators right away, and continue to study the drug to answer, definitively, any of the uncertainties or questions that are raised about it based on other less controlled trials.
SUSAN DENTZER: In the broadest sense, the argument is made that this suggests that we have, not just with respect to Vioxx but with other drugs, an issue here which is that, increasingly, we have drugs coming out that are aimed at a chronic disease population. They’re intended to be taken over a long period of time, and that risks could crop up as large numbers of people take these drugs.
How, in your view, do we incorporate that awareness into what we do going forward? What is this company going to do differently going forward, having learned the lessons it learned from the Vioxx?
MR. GILMARTIN: Well, Merck, as a result of the Vioxx experience, you know, awoke and reinforces the approach that we follow, which is to continue to study our drugs with long-term data and to disclose those findings on a prompt basis, both to the general public through the media as well as to regulators, and also through the peer review journals and at medical meetings. So it’s very much of our policy, and so we’ve published results of studies whether they are favorable or unfavorable.
This experience with Vioxx shows that that policy that we followed is particularly important now that more and more drugs are being developed for long-term use, and, for example, with Fosamax, or a drug against osteoporosis, we’ve just published safety data for 10 years, which shows that the drug is well-tolerated. And so therefore our behavior and how we conduct ourselves has been very much reinforced by this experience.
SUSAN DENTZER: What about the question of how soon, though, drugs should be approved now? If it’s understood that they’re going to be used for long periods of time, should they be approved on the basis of a very short-term safety studies on which they are now approved?
MR. GILMARTIN: Well, I think that in each situation that the kind of data that is required for approval varies according to benefit the drug data brings and what is known about the class of drug. And I think what’s important to keep in mind at all times here that these drugs bring real benefit, and so, therefore, delaying them to market to do studies that at the end of the day may have not be relevant at all, I think would not be good policy.
I think it’s important, though, that once a drug is approved that to continue, as we have, to continue to study that drug and continue to look not only for new indications for the drug but at the same time, as we do, to gather–to continue to gather additional safety data.
SUSAN DENTZER: Let’s talk, just briefly, about the financial repercussions of the company is undergoing with respect to having pulled Vioxx off the market. And you’ve said publicly what this portends for earnings for the fourth quarter, for example, et cetera. Just in the broadest possible sense, what’s the financial impact on this company of withdrawing Vioxx?
MR. GILMARTIN: Well, we withdrew Vioxx solely, and made the decision solely on the basis of what’s in the best interest of patient safety.
When Peter Kim, head of research, called me the morning after receiving the notification from our outside investigators that they recommended stopping the trial that we had underway, and he’d reviewed the data on that Friday morning, the first thing I said to Peter Kim was, “Don’t think about anything else, Peter, except what’s in the best interests of patient safety,” which he’s said on several occasions since that time was important clear direction that we set.
But that was totally consistent with what Merck is all about. Now, because of the kind of business that we’re in and the kind of risks that drug–losing a drug or having a drug fail in clinical trials represents–we have always managed the company in a very conservative way as far as its financial health is concerned. And so therefore, we have a very strong balance sheet. We were financially strong before the withdrawal of Vioxx, we’re financially strong after the withdrawal of Vioxx; and we’ve got very strong cash flow, so therefore we could say with certainty this does not affect our dividend at all.
The task ahead of us from this point on is to resume the growth of the company, and we have the opportunity to do that.
SUSAN DENTZER: And would you put down on the record what you said earlier, which is that in the fourth quarter, for example, Merck expects now to forego about $700-to-$750 million in revenues from the loss sales of Vioxx?
MR. GILMARTIN: Well, in the fourth quarter that we, you know, we will experience something like on the order of $700-to-$750 million in lost revenue from Vioxx, but that is a short-term, impact on our company. And because we are very strong, financially, from a balance sheet standpoint and a cash flow standpoint, we have the resources and the capability to not only protect our dividend but to continue to invest in research and to rebuild the growth of this company.
SUSAN DENTZER: Let’s talk briefly about Arcoxia, which is the next drug in this class that you’ve just now received an approval letter from the FDA. The FDA has asked for additional information now with respect to the cardiovascular risks in particular. What is this company going to do now as it continues to seek approval for Arcoxia in the U.S.?
MR. GILMARTIN: Well, we already have underway a long-term trial called MEDAL which was designed specifically to look at cardiovascular events around Arcoxia. And so that trial will continue.
We also have another trial called “EDGE 2,” which has data for rheumatoid arthritis which will continue, and we’ll continue to collect long-term data on Arcoxia beyond that looking at the safety profile, particularly the cardiovascular events. So we’ve had this underway.
SUSAN DENTZER: Do you think Arcoxia will eventually receive approval in the U.S.?
MR. GILMARTIN: I think that Arcoxia brings some real benefits, and I think, based on the data that we have so far which shows no difference against other NSAIDS, you know, I–and that we would expect a long-term trial data could be positive. But, as we learned with Vioxx, it’s until you have the data that–until you have the data you don’t have the answer.
But it’s, at this point, it’s premature, and it’s not necessarily appropriate to generalize the data from Vioxx to other molecules in the class. Arcoxia has a different chemical structure altogether.
SUSAN DENTZER: Merck already faced before the withdrawal of Vioxx a number of lawsuits over safety issues involving Vioxx and now faces many, many more. How do you expect all of those lawsuits eventually to be resolved? Will Merck, in effect, make a large settlement over the drug?
MR. GILMARTIN: Well, it’s, you know, I can’t speculate over just about lawsuits and just what effect they would have. I would point out that the–this effect of any difference between Vioxx and placebo and cardiovascular events only occurred after 18 months and that, as the FDA pointed out in their press release, that the chance of an individual having a stroke or heart attack due to Vioxx was very small.
SUSAN DENTZER: So in terms of whether these cases are all put together in multidistrict legislation–or multidistrict litigation, excuse me–and eventually class action lawsuits and you’re not willing to speculate at this point whether there would just be a large settlement to get the–
MR. GILMARTIN: I can’t speculate about just what–what the outcome of all this could be. We believe strongly we have meritorious defenses, and we’re going to defend ourselves vigorously.
SUSAN DENTZER: Okay, great. I think we’ve pretty much covered it. Let me just–oh, I do want to go back. This company has had a longstanding motto of “Do the right thing and the profits will follow,” in effect. And I assume what you were alluding to earlier that that was a guiding principle as to how you worked your way through this whole issue about whether to approve–or withdraw Vioxx or not.
What, personally, did you think about over that whole period as you were mulling over the issues of withdrawing the drug and what the impact, the long-term impact would be on the company?
MR. GILMARTIN: Well, the primary value of this company is the patient comes first. And that was best expressed by the modern day founder, George W. Merck in his–in a speech to–to a medical school in 1950 in which he said that medicines are for the people, not for profits. If we remember that, the profits will follow.
When Peter Kim told me that we had a problem with Vioxx and that he was going to go over the data over the next couple of days to see what should be done, just without even thinking I said to him, “Peter, the only way we’re going to make this decision is in the interest of patient safety. Don’t worry about anything else.” And what was interesting to me is that as we gathered more information and we went into the decision-making process, there was no debate; that once we saw the data it was agreed broadly, not only between me and Peter, but also members of the–the other members of the management team as well as our board of directors that the responsible course of action was to voluntarily withdraw Vioxx from the market, and we did that within a week.
SUSAN DENTZER: And do you think, now going forward, is the bar going to be higher for Merck to bring a product on the market, initially? And I mean the internal bar?
MR. GILMARTIN: Merck’s internal bar for patient safety has always been quite high and will continue to be so. And it’s rare, although it does happen and it happened to us last year, that we lose drugs in Phase III. And because we have a very high bar as to before we actually develop the drug in great depth, that we’re assured of its safety. And that practice will continue.
SUSAN DENTZER: So this will not add any additional precautions to the processes that the company has internally already.
MR. GILMARTIN: Merck has always had a high bar in terms of patient safety. This experience with Vioxx just reinforces the correctness of that, having that high bar. It also reinforces the approach that we’ve always taken to all our drugs, just continue to study them, to continue to take, to collect safety information, and once having information, either good or bad about the drug, is to disclose that fully to the public and to the medical community and regulators.
SUSAN DENTZER: I want to ask you a final question about the costs of mounting these large clinical trials and, for example, the Nettle trial that you now have underway with, roughly, 23,000 patients, an international trial. What does mounting a trial of that dimension cost a company like Merck?
MR. GILMARTIN: I can’t give you a number off the top of my head, but that certainly is a significant expenditure. But that is typical of the size of trials and the kinds of trials that one would continue to run in support of the medicine that you’re trying to bring to market or that you have no the market.
SUSAN DENTZER: And what I’m getting at here is to help the public understand what it cost to study these drugs for safety, because, of course, this is part of the issue. How long do you study these drugs, how much do you expend on studying those drugs to ascertain safety versus the trade-off of getting a drug to market sooner.
MR. GILMARTIN: It, typically, to bring a drug to market, to get it approved by the FDA takes anywhere from 10 to 15 years of studying the drug. And it involves, finally, very large clinical trials of large numbers of patients, say 20,000 or more patients looking for both efficacy, but also, importantly, safety. And it’s estimated by a professor at Tufts, DeMasi, that to successfully develop a drug costs on the order of $850 million. And that includes the failures along the way of other compounds in that class that were unsuccessful.
So the amount of resources expended and the amount of time and the size of these studies are considerable, all designed, as I said, not just looking at efficacy but importantly looking for safety. And then follow-up studies after that, even after the drug is on the market, to continue to look for not only new indications but to continue to confirm the safety of the medicine.
SUSAN DENTZER: You’ve repeatedly said, that Merck’s internal bar is very high on safety and that this reinforces the need to have a very high internal bar.
From the broadest perspective of the industry, though, the industry now is going to be looked at probably even more critically than it’s already being looked at, and the questions being asked very pointedly: Do we know enough about the safety of these drugs intended for long-term use? How do you think the industry as a whole is going to respond this, or should respond to this?
MR. GILMARTIN: I can really speak for Merck and which is that we have a very high bar for safety. That’s why we continue to study our medicines even after they’re on the market. I think it’s important to emphasize as well, you know, given the bar that we have for safety, that there was a case to be made for keeping Vioxx on the market and going to the FDA with this additional safety information looking for changing in the prescribing information, but the argument would have been not to take the choice away from physicians. We took the responsibility ourselves rather than transferring it to the FDA of saying that in terms of our approach here that since there are alternative therapies on the market and there was a known safety risk, that the responsible course was to withdraw this drug from the market, voluntarily. This is consistent with our values and consistent with our commitments to patient safety and consistent with the statement that medicines are for the people, not for the profits.
SUSAN DENTZER: One additional point that is made by the critics in this case is that a much larger safety trial should have been done even sooner, with a specific set of cardiovascular risk end points, than even was done – that a large, randomized, placebo-controlled trial looking specifically at safety should have happened even sooner than it did.
MR. GILMARTIN: Vioxx was approved in May of 1999. In February of 2000 we started a large controlled, randomized study to not only look for a new indication for Vioxx but also to study cardiovascular risk against placebo. In addition to that with all the trials that we’re doing, we had accumulated about 28,000 patients of various health stat–in varying health status in which we saw no difference between placebo and Vioxx and no difference between Vioxx and other commonly-used NSAIDS like Ibuprofen. And, but we started within months of the approval of the drug a large multiyear, long-term study to look at cardiovascular risk.