Your Vioxx Lawyer - Vioxx, Celebrex & Bextra FDA Transcript

Your Vioxx lawyer provides you the complete transcript of the February 16^th, 2005 joint meeting of the FDA's Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee. We have formatted the complete transcript of the three day conference for easy of navigation to provide you with the best possible vioxx information. To contact a Vioxx Lawyer, click here for a FREE case evaluation.

Committee Questions to the Speakers

DR. WOOD: Thank you very much. Could you go back three slides, and then I am sure Dr. Fleming will want to ask you a question?

DR. VILLALBA: Which one?

DR. WOOD: The third last slide in the handout. That one.

DR. VILLALBA: This one?

DR. WOOD: Yes. Am I right?

DR. FLEMING: You read my mind. I wanted to follow-up on this because it is also a follow-up to a question I asked this morning. Just to get a sense of what the totality of the data is telling us about whether there is an all-cause mortality risk increase, and the two studies on the left definitely strongly suggest that there is. In the discussion this morning it was pointed out that there are other sources of data that might complicate the interpretation, the ADVANTAGE trial being one of those. But if you look on sponsor slide 54, which we won't go back to now, the other studies are all very small relative to the numbers of events. More than a half of the total deaths in the meta-analysis of all the studies are from the VIGOR study and the Alzheimer's studies and that is where we are seeing the signal. The ADVANTAGE study that we were told about that didn't show significance still had one more death, and you said in your presentation it was 4 versus 0 in the wrong direction. There are 2 in the cardiovascular.

I guess my concern here is that when I look at this it is on-drug, and I think it is getting back to a question Ralph was asking earlier today. All of these analyses, are we correct, are only giving us that deaths that occurred within--what?--30 days of being on drug?

DR. VILLALBA: Two weeks actually.

DR. D'AGOSTINO: Yes, I raised that morning. I mean, why weren't these individuals followed till the end of the study to find out about mortality?

DR. VILLALBA: Well, actually that is a good question to the sponsor because we know that they were followed as much as they could do it, but it was not mandatory. They tried to collect all the data they could but it was actually--I would prefer them to answer.

DR. WOOD: Well, let's not involve motivation right now. Let's just keep going with the facts. So, Tom, keep going.

DR. FLEMING: Well, that is the essence that I wanted to get at. It was just to understand that this is just on-drug and there is nothing else you can provide us in terms of a true ITT? Is that correct?

DR. VILLALBA: There were more deaths also after but there was not a balanced exposure.

DR. WOOD: No, what he is asking is do you have an intention-to-treat analysis?

DR. FLEMING: Correct.

DR. VILLALBA: No, I don't have it with me. That is why I said this is still under review. There is pending information.

DR. WOOD: But before we leave this slide though, it is important to remember why we are here. I mean, this is a drug whose indication is a safety indication, and the reason to give the drug was to reduce an adverse event which is always thrown up as causing this terrible outcome, although the outcome has improved substantially over the last 10, 15 years. It is certainly worrisome when a drug that is supposed to produce a safety benefit, in fact, is producing an increase in mortality, it seems to me, and that is worthy of some discussion. Certainly, an ITT analysis would have been important.

DR. VILLALBA: Again, I completely agree. We are concerned, but we don't know how other NSAIDs would look here.

DR. WOOD: I understand.

DR. VILLALBA: We need to put it into context.

DR. WOOD: That is what my teenaged kids say as well. Curt?

DR. FURBERG: I was wondering whether you, within the agency, considered the risk of heart failure. I mean, when I look at the tables and in your presentation you are using the term heart arrest signal in a narrow sense. There is nothing in your tables on heart failure. It is an issue. As the Chairman found out a little bit earlier, in the APPROVe study, a 4-fold increase in a long-term trial. Do you have information from the Alzheimer trials on heart failure? If you look at the adverse effects of the drug, we shouldn't just narrow it to heart attacks and stroke. Let's broaden it to heart failure and make that part of our evaluation.

DR. VILLALBA: Yes, I don't have slides with me regarding congestive heart failure but, again, we don't have the data for other NSAIDs. That is the only thing that I can keep saying. But there was more heart failure, for example, in VIGOR clearly as compared to naproxen.

DR. WOOD: I sense that there is a response coming from the sponsor. Do you want a couple of minutes to think about that before you get up? You can take a couple of minutes and we will take another question, if you want. Take your time; we won't forget you. Dr. Bathon?

DR. BATHON: I am a little confused about the aspirin issue. On your slide 35 you showed a decreased hazard ratio or relative risk for the aspirin users compared to non-aspirin users. But in Dr. Braunstein's presentation it was the opposite. I realize that the outcomes were measured a little bit differently.

DR. VILLALBA: That is a very good point. These are APTC endpoints and the way that Dr. Braunstein showed it was all cardiovascular/thrombotic events that included also peripheral events, unstable angina and TIA. So, the point of this slide is precisely that when we design a study that is going to address these issues in the best possible way we need to choose the right endpoint. And I don't know what that endpoint is because if you look at all cardiovascular events you may see more than if you look only at APTC.

DR. WOOD: Dr. Shafer?

DR. SHAFER: I know it is always easier in retrospect to try to make sense of things than prospectively when you are looking at many possible adverse outcomes and trying to figure out where to focus one's attention. But if you could go back to slide 23, what we see here, in slide 23, is a lot of suggestions of danger signals. Dr. Braunstein made an interesting point earlier when he said that it would take about 30,000 patients to demonstrate an increased risk, and yet we see danger signals in very small studies of short duration. So, that has obviously to be a cause for concern.

Then along comes the VIGOR trial. As I understand, basically VIGOR had a 2-5X increase in serious adverse cardiovascular events depending on the endpoint you chose to look at. Now, there are two possible interpretations of that. One interpretation was that rofecoxib increased risk. At the time you had this background worrisome signal rate which was consistent with the mechanisms that Dr. FitzGerald spoke about, and if that were the true state of things, then potentially millions of patients were being placed at risk.

The converse choice is that Naprosyn decreased risk. There were very weak data to support that. As we heard from Dr. Nissen, the effect was too large to be really explained by any known effect of aspirin. And, the safety data that were used to support the safety of rofecoxib was far less than the 30,000 patients that would be required to significantly show the difference. By Dr. Braunstein's own statements, you know, it would take far more patients to really statistically significantly show that up.

What I first thought was the company and the FDA chose to give pretty good credence to the naproxen hypothesis. It sounds from the comments today that that is still the position of Merck. What would it have taken, what kind of data would it have taken, given the results of the VIGOR trial and the two alternative hypotheses, for the FDA at that point in time to either put a black box warning or perhaps even remove Vioxx from the market? What kind of data would you have had to have in addition to what you have?

DR. VILLALBA: I cannot answer that question. What I can tell you is that this was as compared to naproxen. We never bought the naproxen theory, but we also did not have evidence that Vioxx was worse than placebo or other NSAIDs.

DR. SHAFER: You have great evidence in VIGOR though.

DR. VILLALBA: I completely agree but it was naproxen, and I think the presentation tomorrow with the epidemiologic data on naproxen will be very informative about how confused we are until today.

Regarding the signals, yes, those were observed but that was after VIGOR, not before. Again, we have that long-term, placebo-controlled data in Alzheimer's patient elderly population that had shown no difference in myocardial infarctions or strokes. There was that signal of cardiovascular death that, by the way, was put in the label. But there were 8 versus 3 events and we didn't know what to make of that.

DR. KONSTAM: Hi, there. I am Marv Konstam. I am from Tufts University and I am here with Merck as a consultant. In 2001 I was first author on the overall pooled analysis for the entire rofecoxib database so I just think I want to speak to it, and the interpretation of VIGOR and where the company I think was, and the world was, at that point.

I think it is really difficult to look at individual studies with very, very small numbers and find signals, and one can draw all kinds of conclusions from them; and there may be signals in the other direction in some of the other small studies.

So, what was done at that time was, you know, there was a signal from the VIGOR study. This finding was unexpected. It showed an adverse effect on cardiovascular endpoints. Now, one thing I want to stress about that is that of all of the information that could be brought to bear, I think the point estimate for the hazard ratio from that is probably the least important to me. You know, you are looking at very small numbers of events, unexpected finding, wide confidence intervals. So, I just want to point that out. What was done at that point was that the entire rofecoxib database to that point was reviewed in a systematic way, and all of the data were pooled. They were divided, as you heard, between Naprosyn comparator, other NSAID comparator but, most importantly, the placebo comparator. Because VIGOR was an active controlled study and none of us to this day know exactly to what extent the result was contributed to by an adverse effect of rofecoxib, a favorable effect of Naprosyn or a combination. So, the most valuable data are the placebo-controlled data. And, reviewing all of the placebo-controlled data to that point, pooling all of those data, there was 3000 patient-years of follow-up, there was not a hint of an adverse signal--not a hint of an adverse signal.

Now, granted, there were confidence intervals around that signal so that is real. We still didn't know, and I think we know a lot more today thanks to the APPROVe study, but at that point in time if you look at all of the placebo-controlled data that existed there was not a hint of a problem, which I think led me at that time and I think led others at that time to say this may be contributed to by a significant beneficial effect of Naprosyn.

DR. WOOD: Just let me make sure I understand. Are you saying that that is still your position?

DR. KONSTAM: No, no. That was the position at that time. One might then ask, okay, what is different between the APPROVe data, and I might say that I was on the data safety monitoring board for APPROVe, and why is APPROVe different than the pooled placebo-controlled at that time? I think that is a really cogent question to ask and I have asked myself that question.

I believe the difference now, in retrospect, is exposure time. From APPROVe we see no evidence of a hazard in the thrombotic events through 18 months and then there is a separation. The median follow-up in that pooled analysis that I just referred to is relatively short. I don't know what it was exactly but it was months. It certainly wasn't the 9 months that was there in the VIGOR study or the 2.4 years in the APPROVe study. So, that is a substantial difference. There are other differences, but to me that may be the explanation for why the pooled analysis, back in 2001 and as it went forward, showed no problem but APPROVe then came and did show a problem. I think it probably was the exposure time.

DR. WOOD: But just to be absolutely clear, you are not saying that you still believe the VIGOR study was due to a totally protective effect of naproxen, are you?

DR. KONSTAM: No, no, I am not.

DR. WOOD: Good. I just wanted to be clear on that.

DR. SHAFER: While you are there, Dr. Konstam, in terms of the relative risks of the two possible choices--either rofecoxib increases risk or Naprosyn decreases risk--was that part of your thinking as well? What are the possible outcomes of the two competing hypotheses? The truth is probably somewhere in between.

DR. KONSTAM: Well, first of all, let me just add one other point that I should have mentioned. The other point about the VIGOR study was the dose. So, there was a very high dose used in VIGOR and there were lower doses in the pooled analysis. APPROVe was 25 mg; an intermediate dose.

What was your question again? I am sorry.

DR. SHAFER: There are somewhat different potential concerns with the conclusion that rofecoxib increases risk as opposed to the conclusion that Naprosyn decreases risk. Was that part of your decision analysis at the time?

DR. KONSTAM: Yes, thinking back at that time, there was no adverse signal from the placebo-controlled data. I don't think, you know, most people were completely satisfied with that. If you look back at what the company did at that point, first of all, there was a warning put on the label and we can argue whether that was good enough or not. But then we embarked on a large placebo-controlled program with a prespecified adjudication process for cardiovascular events, and that is the process that led to the definitive finding of APPROVe, even with a much smaller N than they were planning to do so they had a much larger program planned and we decided to stop APPROVe because we saw it in APPROVe.

DR. WOOD: Let's go on. Dr. Nissen?

DR. DOMANSKI: We have heard a lot of discussion about who know what, when, and we have seen a tremendous amount of data presented, and in the end this committee is going to have to make some recommendation about what to do going forward. I am very interested, if we could, in hearing from each of the pharmaceutical manufacturers, as well as everybody else of course, before they sort of go away into the distance. I am very interested, given the totality of data that are currently available--not what you knew when or who should have known what, how or when or who should have done something else--I am very interested in what you think ought to be done now going forward, knowing what we know. What recommendation would you make? What would you like to see come out of this? Or, maybe what do you think we should see come out of this?

DR. WOOD: Dr. Nissen?

DR. NISSEN: Yes, a quick comment and a question. The comment is--and I think for people in the audience who may not fully understand why we are drilling down on this intent-to-treat aspect of the analysis--that it may be that the individuals who are dropping out of these trials because of adverse events, that received the COX-2 inhibitor, they may be pharmacogenomically more susceptible to the adverse effects of COX-2 inhibitors. So, you are taking out of the trial the people that are at greatest risk. If you don't follow those people you may not find that out. This idea of censoring events after two weeks--you know, I think we have to all learn something from what happened here, and this is the first time I really realized that that was the way these studies were conducted. That was a mistake. Once a patient is exposed to drug you ought to follow him as long as you can because there may be a persistence of risk and we learn something from that. So, a lesson is learned. I think it is a useful lesson to learn.

I guess the second question--and, you know, you may or may not want to answer this but if you had to do it all over again would you do it differently?

DR. WOOD: Let's keep the tense in the future tense. Let's not keep regurgitating that. Bob, do you want to say something in the future tense?

DR. TEMPLE: Yes. I just want to remind people that intent-to-treat analyses are generally loved by people because they are conservative analyses. They ten to make effects go away. That is why we like them. If you are worried about informative censoring and other stuff like that--

DR. WOOD: But it tends to make efficacy effects go away.

DR. TEMPLE: That is correct. They also make time effects go away.

DR. WOOD: Not if you are dead. (Laughter)

DR. TEMPLE: No, no, you have to count the deaths. It is not that you shouldn't follow people up but the analysis that includes all people long after they are off the drug has a very high likelihood, I believe, or not showing the effect of the drug. You have to remember it is a conservative analysis for looking for effects. Before we get too enthusiastic about it, if I make the effect look less when it really doesn't deserve to look less--

DR. FLEMING: Could I just quickly add to that? Historically we look at safety and often we do truncate follow-up after two weeks or a month. That is based on the premise that safety risks are acute. If they are, in fact, acute, then you are going to get a clear sense of what is going on with the type of approach you are talking about. Mortality effects, I would think, are much more difficult to justify as being purely acute. There is a basis to what you are saying. If you follow everybody for a long time after they are off therapy there could be some diluting. Nevertheless, if you want an unbiased assessment of the truth you need to do what Steve is talking about, an ITT analysis, and then make your judgment as you look at the hazard ratio over time.

DR. D'AGOSTINO: We are sitting here and we don't know the answer. It may have washed it away and it may not have.

DR. TEMPLE: I am not saying don't get the analysis but, for example, our ordinary position in an outcome study is that we want to see the intent-to-treat analysis.

DR. WOOD: Let's hold this for the discussion. Let's just keep focused on the questions right now. Any further questions for the speaker? I am not forgetting about you. Hang on just a moment. Dr. Holmboe?

DR. HOLMBOE: I just had a question to the speaker. Again, we are trying to give you some advice and some guidance as to this. Given, as Alastair said earlier, that this drug was really evolved for a safety indication, therefore, being compared to another class of drugs, in retrospect learning that those comparisons were based on drugs approved prior to new knowledge that has been accumulated, such as presented by Dr. FitzGerald, it would be helpful for me to hear what has the FDA learned about the process or form? What can you tell us that might help in the future when you are faced with these sorts of things? For example, the diclofenac is a perfect example, well, it turns out that maybe it is not, you know, your run-of-the-mill NSAID. A lot of what you presented in the original data was, like, well, it was between ibuprofen and diclofenac, therefore, we determined it was probably okay. So, I would be anxious to hear what you have learned since you have been with this project now for seven years.

DR. VILLALBA: Well, actually we wanted to have the recommendation from you to know how to proceed now because we have close to 20 approved NSAIDs so what do we do with them?

DR. WOOD: Ever the optimist, right! Dr. Domanski?

DR. DOMANSKI: I guess before Merck gets away I would still like to hear their view of where we should go from here. I am really quite curious about that. I understand about intention-to-treat. We do clinical trials. But I would just like to hear what their thoughts are.

DR. WOOD: Their thoughts on what? DR. DOMANSKI: What their thoughts are on where we should go from here.

DR. WOOD: I thought we were talking about where we have been. I am happy to hear them on where they should go. Do you have thoughts on that, Bob?

DR. DOMANSKI: No, I am asking that of Merck.

DR. WOOD: Oh, I am sorry.

DR. BRAUNSTEIN: I think we showed that on our last slide. Can I see our last slide, 57? I mean, for the short term what we are trying to do is trying to better understand our data; trying to better understand which patients were at increased risk for the events that we observed in APPROVe based on both the clinical data and also the specimens that we have from these patients. We also are working with various people to try and explore different hypotheses for the data, and we are collaborating with others who are looking at the data across all the drugs in order to get a better feel to see if we can understand when we pool all the data because I don't think any one data set that we have is powerful enough to address these questions. So, hopefully, by pooling the data we will be able to get a better feel for this. The last is that we think we need to do comparative outcome studies to better understand the relative risks of the selective COX-2 agents with the traditional NSAIDs. There are not long-term data on the traditional NSAIDs to really establish what their cardiovascular risk profile is, and we think that the study that we are doing, for example the MEDAL study is one such study in the right direction.

DR. WOOD: Merck wanted to present some other data. Right? DR. REICIN: I think there was a question about congestive heart failure in the Alzheimer studies.

DR. WOOD: Right.

DR. REICIN: So, just put up slide for us 12-22 and then we will go to 12-28. I showed you this slide just at the beginning and you noted that in our 6-month population--so this is a shorter population than either APPROVe or what I am going to show you in Alzheimer's--the rates were quite low and they were similar to the NSAIDs.

If you go now to 12-28, in the Alzheimer's studies, in protocol 078 which was a 4-year study, interestingly, the rate of congestive heart failure was similar between the two groups, 2.2 percent on rofecoxib 25 mg, 2.6 percent on placebo. In 091, however, which was a one-year study the rate was a little bit higher on rofecoxib, 3.2 percent versus 1.4 percent. I think these rates are more what you would expect in an elderly population. The mean age of this patient population was 75 years old.

DR. WOOD: Thanks.

DR. REICIN: One other thing, there was a question about ITT mortality. In APPROVe we are following patients in an ITT way for mortality. That is still ongoing. To date, there were 3 thrombotic events in each treatment group following that 14-day period.

DR. WOOD: Dr. Paganini?

DR. PAGANINI: I have a question on the comparative data with other NSAIDs. Is there not a post-approval period of time for drug review, and from that post-approval Phase IV type studies can you not draw anything from that to compare to?

DR. VILLALBA: Phase IV commitments are made at the time of approval. If there were not specific agreements between the FDA and the company to conduct those studies we have no legal power to mandate any kind of studies. So, some studies are done basically pursuing different--I mean with promotional, advertisement or whatever there are many studies. But those are really not usually large outcome studies. They are short studies with small numbers of patients. I don't know if I answered your question.

DR. PAGANINI: You did in a way. One of the issues that I think we are going to have to face is how do you compare these things, both things that have already been approved and new, to the same standards when they were approved back then to current standards? Perhaps one of the ways around that might be an approval comparison with longer Phase IV commitments by companies to follow-up on what is happening to that drug over time. That way, you would have the ability to compare a new to a similar in a similar population of patients.

DR. VILLALBA: Absolutely. That is something that we learned, yes.

DR. WOOD: Ralph?

DR. D'AGOSTINO: I am all for torturing data and during Lent I always read Dante's "Inferno."

(Laughter)

But shouldn't we be impressed with the APPROVe study? You leave us with a table that compares a lot of studies and you throw out some obviously important questions, but shouldn't we sort of look very seriously at the APPROVe study? It was well designed--

DR. VILLALBA: Of course.

DR. D'AGOSTINO: --and shouldn't we sort of diminish in our view some of the previous studies?

DR. VILLALBA: The Alzheimer's studies, do you mean? Now, yes. What I was saying is that these are different populations and I do not have a good explanation for why we didn't see the same in an elderly population.

DR. D'AGOSTINO: Well, could it be that the APPROVe study was going after a particular set of outcomes and the others weren't, and it was more retrospective?

DR. VILLALBA: No, because in the Alzheimer's studies they also used the same standard operating procedures to adjudicate the event.

DR. D'AGOSTINO: But do they have the same ascertainment? You know, in designing a placebo-controlled study where you go after something retrospectively, looking at that and trying to say the ascertainment might have been the same.

DR. VILLALBA: You are completely right. That is possible but that is a question to the sponsor, if the ascertainment could have been different in the Alzheimer's studies.

DR. WOOD: Dr. Hennekens? Actually, I would like to ask Marvin a question. Marvin, the APPROVe study was scheduled to terminate at about 6 weeks after the early termination on the basis of the board's recommendation that you were on. As I recall, the numbers of events were 45 and 25 at that time. So, was the board unanimous in its decision to terminate, and was the basis clearly related to that particular endpoint?

DR. KONSTAM: Yes. Yes, that is exactly right. I would say that the reason, if I might say why we recommended termination--the reason we recommended termination is that we felt at that point in time that we had a definitive piece of information that wasn't going to change. The reason we recommended termination was that we felt the patients in the APPROVe study were not aware of this and had not been consented to this adverse effect. So, in our judgment, you know, from an ethical viewpoint if you were going to continue you would have to go back and re-consent them and that certainly wasn't practical at that point in time. So, that is the specific reason we recommended termination.

DR. WOOD: But you told them that caution should be exercised in patients with heart failure. Right?

DR. VILLALBA: May I say something?

DR. WOOD: Sure.

DR. VILLALBA: I don't want to leave you with the impression that we think or I think that APPROVe is not important. I just want to show you how puzzled we were with all the data. So, until APPROVe we didn't have a firm reason to really take a regulatory action that was different from what we had done up to that time.

DR. WOOD: Ralph again?

DR. D'AGOSTINO: In terms of the Alzheimer's study, do you have information on the all-cause mortality? I forget what you said. Do you have anything about CVD, cardiovascular mortality when off drugs?

DR. WOOD: Let's take that under advisement unless you have it right there. Do you? No? All right, we will get back to that. Any other questions? Yes?

DR. TEMPLE: Actually, I wanted to respond to Ralph. The thing about APPROVe is that it was longer than the rest of the studies and most of the effects were seen sort of late. So, it provided the kind of information that really didn't exist before.

DR. D'AGOSTINO: When we come to the discussion of designing the trial, there is so much emphasis on how many events we should have and I am always bothered by that because I would like to make sure people have taken the drug for a long enough time. I think this is a case where you are seeing where length is where something is happening.

DR. WOOD: Unless there are any other questions, let's stop our discussion of Vioxx at this point, rofecoxib, and take a ten-minute break. We will reconvene and start on celecoxib when we get back.

(Brief recess)

DR. WOOD: If you will get to your seats we can get started, otherwise we will be here half the night. Just go ahead.

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