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.

FDA Presentation: Vioxx (Rofecoxib)

DR. VILLALBA: Good afternoon. My name is Lourdes Villalba and I am a medical officer in the Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products. I have been the primary reviewer for Vioxx since 1998 when the NDA was originally submitted for approval.

DR. WOOD: You need to move closer to the mike.

DR. VILLALBA: So the important thing, I have been the primary reviewer for this since 1998, since its original submission for approval for the treatment of acute pain, dysmenorrhea and osteoarthritis.

I am going to show you an overview of my presentation. First of all, my goal is to show you that we were not sleeping behind the wheel, that we have been actively engaged in reviewing the enormous amount of data that came to our division throughout the years, and this has been a very challenging application, a very complicated process to review a lot of information that was not always that clear to interpret.

The other issue is that I want to point to some observations that may help you to think about the best study designs. Everybody is talking about future studies to clarify the question but the issue is exactly what kind of studies we need; what should be the comparator; how long, etc.

So, first of all, I am going to show you a brief background with a chronology of events to point out just some specific areas that I want you to remember. Then I am going to give you an overview of the Vioxx data sources we reviewed and that will be presented also in a chronological order. Then I am going to spend a few minutes talking a little bit again about the different classification of cardiovascular events. Then I will go into the different Vioxx databases showing cardiovascular safety in the way we saw it at the time they were presented to us. Then a summary, pointing out again to the challenges in interpreting this data.

This is a busy slide and I apologize for it but I want to point out a few areas here. The NDA was originally submitted in 1994 and it was approved in '99 after the data was presented at an advisory committee meeting. Around the time of approval there were all sorts of submissions of IND investigational new drug applications for other indications. One of them was submitted to the Division of Neuropharm. Products for the evaluation of the role of Vioxx in the prevention and treatment of Alzheimer's disease. Another one was submitted to the Division of Oncologic Drug Products and that was approved, the adenomatous polyps prevention trial that now led to the withdrawal to the product. It was initially submitted to the oncology division and then was switched to GI. That is just a detail. This was back in '99.

Then we had the results of VIGOR in the year 2000. The advisory committee meeting of February, 2001, and after that we reviewed a lot of information and finally got the labeling changes in April, 2002. Later on, in October of that year, there was a submission of another study in the Division of Reproductive Products to evaluation the role of Vioxx in the prevention of prostate cancer. About the same time Merck came to us with a proposal for conducting a pooled analysis of some of these studies, particularly APPROVe, the prostate cancer prevention and another study that was being conducted in Europe.

The Alzheimer's data was very important data that I will go into detail later, but I want to mention that preliminary data from these studies that were placebo-controlled studies were initially submitted in July, 2001. The final data from this database was provided to us in March, 2004. This is an overview of all the databases we reviewed and this does not include APPROVe. As you can see here in the first column, although it says "indication" the indication refers to the line. But here we have the treatments. We have Vioxx at 3 doses, the 2 approved for chronic use and also for acute pain, the 50 mg, as well as some comparators, ibuprofen, diclofenac, nabumetone and placebo. The original NDA did not have naproxen.

Then with have VIGOR which had Vioxx 50 and naproxen. We had other studies. Unfortunately this slide is not the last one. There are missing 2 important marks, the 25 mg dose in study 102, also known as ADVANTAGE study, and that was 25 mg versus naproxen; then the rheumatoid arthritis efficacy database that compared Vioxx 12.5, 25 and 50 to naproxen and placebo. Then we had several studies, safety outcome reports for various indications with different comparators and also with placebo. I want to point out here with placebo that in the NDA database we had up to 18 weeks. Most of the studies were 6-week studies but there were 18-week placebo-controlled studies that were endoscopic studies.

We have placebo here in the rheumatoid arthritis efficacy data base, but the most important data we had was here, in the Alzheimer's studies that were long-term placebo-controlled in an elderly population. We had data for at least 3 years. So, we put a lot of weight on this information. We also had access to the adverse event report system but, unfortunately, it is known that it is not very helpful to look in this way when we are talking about relatively prevalent events such as cardiac events. Then we also have literature, epidemiologic studies, re-analyses and meta-analyses of data that had been published.

Before I show every database I want to spend a few minutes on the cardiovascular endpoints because there are many different ways of looking at cardiovascular endpoints. At the FDA we routinely look at all adverse events reported under that category--cardiovascular deaths, discontinuation due to cardiovascular adverse events, serious cardiovascular adverse events--this is routine and this is what we did in the NDA application. We did the same as well with all the other organ systems. So it is a very in-depth review.

At the time of VIGOR and all studies subsequently, the sponsor used a standard operating procedure that used a subset of cardiovascular serious adverse events, a category of cardiovascular and thrombotic adverse events, and these were referred for adjudication to a blinded adjudication committee. The committee of three cardiologists would determine if the events were confirmed or not confirmed. Another definition that was used was if they were part of the APTC definition or not.

So, these two ways of looking confirmed cardiovascular/thrombotic and APTC are not a subset of one analysis; they are complementary. The APTC endpoint, the composite endpoint that looks at cardiovascular and unknown cause of death is non-fatal myocardial infarction and non-fatal stroke. It includes ischemic and hemorrhagic events, but does not include unstable angina, transient ischemic attack and peripheral events. These kind of events are included in this definition up here. But this does not include hemorrhagic events.

So, we looked at the data in all these different ways. Again, at the NDA stage we looked in this general way and we became more sophisticated and looked in all ways, the original one and the others.

This is very important. Let me show you just an example from VIGOR so you can have a clear idea of what I mean. You have different ways of looking at it. If you look at all investigative cardiovascular and thrombotic events you are going to have more events. If you look at confirmed or adjudicated events you still see the difference but the number of events is small. The same with the APTC. Therefore, this way of looking is more specific because it looks at the hard endpoints. Although it may be less sensitive, the other way of looking--let's say we have here all cardiovascular events submitted under that category, we would have for VIGOR 600 events and 400 events.

So, in my presentation I am going to use the APTC way of looking at it because it also makes very clear if there were cardiovascular deaths or not. This is a different way of presenting the data that was already presented by the sponsor.

Here we have the NDA database. The NDA, submitted in 1998, was very large and involved 5400 patients with substantial exposure in multiple dose trials of 6 weeks, 6 months and up to a year studies. Some of the 6-week studies had extensions to 21 months.

I want to point out that this number is a substantial number for an NDA. This is greater than most NDAs. Although most of the COX-2 selective agents have had this kind of size of NDA, but before that we used to approve products based on much smaller data. These numbers are above minimum requirements by the International Conference on Harmonization Guidances.

In this database, looking the way I told you, looking at all adverse events that were cardiovascular adverse events and were potentially thrombotic, serious and non-serious, this is what we found. This was kind of a definition that I made myself to look at these events. This has not been validated but, in any case, this is what we saw.

In the 6-week studies with Vioxx with all doses we have 0.7-1.1 rate, and these are crude rates here. There was 0.4 with ibuprofen; 0.2 with placebo. Therefore, we said, okay, there may be something here but if you look at the number of patients exposed, they were different. There were more patients exposed to the Vioxx doses. And we didn't really know what to do with these percentages. What dose it mean with an endpoint that is not really well defined?

Then, in the 24-week studies that had placebo, up to 18 weeks, the crude rates on Vioxx at all doses were right between ibuprofen and diclofenac. Ibuprofen was 0.5 percent; diclofenac, 2.0; and placebo was 0.8 which was also in between. So, based on these data, based on the fact that they looked similar to the other NSAIDs and that it was a pretty large database, of course, not designed specifically to address cardiovascular issues, what we said was that there doesn't seem to be a big problem here, however, we cannot rule out that there could be something but this is not the right database to address it. On the other hand, this was 1998. There were theoretical concerns regarding that inhibition of prostacyclin could induce prothrombotic events. But based on these data, there was not much to say about it. Also, Celebrex had recently been approved, in December, '98, and Celebrex had not shown anything either.

So, again, based on adequate evidence of efficacy, safety for the intended uses and the similarity to the comparators, this drug was approved in May, 1999. If you look at the safety profile, it was pretty similar to other NSAIDs. Cardiovascular safety was between ibuprofen and diclofenac. Hypertension, there was a very clear dose response with the 50 mg being greater than the 12.5 and 25. Endoscopic data suggested that Vioxx was better than ibuprofen and the liver suggested that Vioxx was better than diclofenac. So, it was an NSAID.

The sponsor wanted to pursue the claim that this was a COX-2 selective agent; this needs to be different. We really don't want to see the GI warning template in our label. And, that was even before the NDA was submitted. It was discussed a long time before. If you really want to have a substantial change in the GI label, then you have to do large outcome studies or at least one large outcome study. That is why we had VIGOR. VIGOR was not a requirement. It was something that the sponsor decided to do because they wanted to distinguish themselves from the other NSAIDs.

We know the result of VIGOR. I am showing here the APTC results. From now on I will use the same format for all my slides. So, please bear with me for this first slide. We have the APTC total events in the first row; then cardiovascular deaths; non-fatal myocardial infarction; non-fatal stroke; and non-fatal hemorrhagic stroke. We have the comparators here. N is the number of patients randomized. Here, in the footnote, I have the number of patients in patient-years of exposure. N gives you the number of events. Rate is the rate based on 100 patient-years of exposure, and the relative rate is the overall rate for Vioxx as compared to the comparator.

I think I don't need to spend too much time describing VIGOR. It was a large study, 400 patients per arm; patients with rheumatoid arthritis, 60 percent using corticosteroids, 40 percent using methotrexate and most were women, and patients on low dose aspirin were not included in this study.

This is what we found. There was a difference in rate of cardiovascular/thrombotic events or APTC events, and the different risk was driven by the non-fatal myocardial infarction. This number was statistically significant.

But if you look at cardiovascular deaths there was no difference. Non-ischemic stroke, there were no differences. So, this was the first time when we saw the signal of Vioxx being different from naproxen. This is the time to vent plot that shows the cumulative incidence of events over time. This is for the cardiovascular/thrombotic events but it looks very similar for the APTC events.

I did show this slide back in 2001 at the advisory committee meeting that we had to discuss VIGOR. You see that the curves start to separate here, at 6 weeks, but this separation is more marked after 8 months. So, if you look at the overall hazard ratio it is 2.4, but after 8 months that hazard ratio increases and is 4.0. There was a lot of discussion with the sponsor about the interpretation of this part of the curve and our position was that there was increased risk after 8 months. Finally we got that into the 2002 label in the form of a table that shows an analysis of cumulative rate of events over time that shows that the hazard ratio increases after 8 months.

In any case, that difference between naproxen and Vioxx was driven by the non-fatal myocardial infarctions. There wee 9 myocardial infarctions during the last 3 or 4 months of the study on Vioxx and there were none on naproxen. The position of Merck was that this was the cardioprotective effect of naproxen. However, we did state clearly at the advisory committee back in 2001 that we were very skeptical about that interpretation and that actually there was biological plausibility for a prothrombotic effect of Vioxx as well.

This is another study that was submitted to us in June, 2000 along with VIGOR. That was also presented to the advisory committee meeting in 2001, showing study 090 and 085. These were two identically designed studies, placebo-controlled, 6 weeks in duration comparing 12.5 mg of Vioxx with nabumetone and placebo. Of note, they have a 2:1 randomization. That means that the number of patients in the active treatment groups was twice the number of patients on placebo.

In this study, study 090, showed 3 non-fatal myocardial infarctions and 1 non-fatal stroke on Vioxx, 1 on nabumetone and none on placebo, and no cardiovascular deaths. Study 085 showed only 1 non-fatal myocardial infarction in the Vioxx 12.5 mg and nothing else in any of the other arms. Therefore, with this information, the small number of events, the fact that study 085 did not reproduce the findings in 090 which, to start with, were very mild, we didn't know what to do with this. This was discussed at the advisory committee and there were not any meaningful conclusions from these studies. Again, I want to mention that there were twice the number of patients in the Vioxx group as compared to placebo.

The conclusions of the advisory committee were that Vioxx showed a superior GI safety profile as compared to naproxen; that the cardiovascular signal was of concern, however, given the study design it was unclear how it would apply to other populations, other doses, NSAIDs other than naproxen in populations that were at high cardiovascular risk because this trial had excluded patients using low dose aspirin. And, that labeling changes should reflect both benefits and potential harms and that additional data were needed to clarify these issues. There was no recommendation for a specific trial to be conducted, or specific design. That is why I think it is important that today you actually give some kind of firm recommendations and give us direction as to which kind of studies you want to see.

We asked for more data and we got more data. That came continuously right after the advisory committee and at the end of February we had the application for the rheumatoid arthritis efficacy indication. It was relatively large. There were 1500 patients on Vioxx and the active comparator was naproxen. There were not other comparators. There was also placebo here.

There were 5 studies. The endoscopic studies were 12-week studies but the other studies had a 12-week base study with re-randomization of patients who were on the lower doses of Vioxx to Vioxx 25 and 50. And placebo here, to 25, 50 or naproxen. So, it was a pretty complex NDA to review.

In any case, here we have the summary. This follows a different format but this is the summary of the results. In the first column you have the treatment and the number of APTC events; patient years at risk; and risk per 100 patient-years. As you can see here, it is clear that Vioxx 25, 50 and 12.5 showed a greater risk than naproxen and than placebo. However, if you look at the number of patient-years at risk you really cannot reach the conclusion that there is a clear signal against placebo. What is clear is that there is a signal against naproxen because exposures to naproxen and Vioxx were closer. I think that the risk with the 12.5 dose is 6.9 as compared to 0.3. So, there is something wrong; you have too small numbers to compare. If you were to believe this, I mean, here naproxen had half the risk of placebo.

So, the conclusion was that Vioxx 25 and , both doses, in a rheumatoid arthritis population had a higher risk of cardiovascular/thrombotic events as compared to naproxen.

Then we had the ADVANTAGE study. I am presenting you this data on one slide but this took months to review, and we were not looking only at cardiovascular safety; we also looked at GI, renal, liver, everything, fractures, so anything that was of a theoretical concern we were looking at. So, this took months. Also, when you get the information you get questions, get the responses within one or two months so it is a long process for each one of these studies.

That was for the RA. This was ADVANTAGE. ADVANTAGE, or study 102, was submitted in March and another piece in April, 2001. This was a 3-month study in patients with osteoarthritis comparing Vioxx 25 mg with naproxen. Approximately 2700 patients were randomized to each arm. Here you have the patient-years of exposure, although I don't like to use this number because this is a 3-month trial but, still, you have it there in case you are interested. But if you look at the numbers, the number of APTC events was about the same. There was a signal for cardiovascular death and non-fatal MIs. There were 9 events here and 1 here. However, there were 6 non-ischemic strokes on naproxen and 1 on Vioxx.

So, again, the conclusion here is that there is a signal. There is a signal for Vioxx as compared to naproxen but we still didn't know what the role of naproxen was here because it may have some role but it wasn't clear what the extent of that was. Based on epidemiologic data, the data were conflicting. I think I would like to know if someone knows exactly what is the role of naproxen from all these findings.

Then we had several safety update reports that came in July, 2001 that included studies in the original NDA and that were follow-up from patients who had been included in the original NDA. There were also new studies, short-term studies and long-term studies. The most important was the study 083, the bone density study with Vioxx 25 versus ibuprofen. The most relevant data for us was the Alzheimer's data that compared Vioxx 25 with placebo. That included 3 long-term studies.

There was also an updated meta-analysis of cardiovascular events. The sponsor had presented a meta-analysis in February, 2001 at the time of the advisory committee initially and here there was an update. Basically there was no difference in confirmed or thrombotic APTC events. Actually, I am talking about these other studies because the meta-analysis was done with APTC events only.

Here is a description of the Alzheimer's studies. There were 3 studies, 2 of them on established Alzheimer's disease that had identical design, 15 months in duration, placebo-controlled, 350 patients per arm, with age of at least 65 years or older.

One of these studies has been completed and showed no efficacy, and the median exposure in this trial was 13 months. The second one being conducted was stopped because the first one had not shown efficacy. The median exposure was 6 months. Then there was another study that was ongoing at the time of the safety update. That was study 078 that was designed as a 2-year study and was eventually extended to a 4-year study and had 730 patients per treatment arm. At the time of the safety update report that we received in July, 2001 the exposure in this study was 18 months. Regarding the population here, 60 percent of them were male with a mean age of 75 years, and aspirin was not allowed in this study initially but it was then amended to allow low dose aspirin for those patients who needed it. Approximately 7 percent of patients were on low dose aspirin.

Here we have the results of that study. Again, here you have the APTC events. I am sorry, this is wrong. This should be 0.73 but still it is below 1.0. If you look at total events you have 17 and 27. This doesn't look bad for Vioxx. If you look at cardiovascular deaths, yes, there were 8 and 5, of which 3 were thrombotic and 1 was hemorrhagic and the other was a ruptured aortic aneurysm. There was twice the number of non-fatal myocardial infarctions and 12 non-fatal ischemic strokes.

So, based on these data, it was puzzling that cardiovascular deaths tended to be against Vioxx but, still, the number is relatively small. You have 8 versus 5. Looking at the myocardial infarction and stroke, there were more events on placebo than on Vioxx. So, that is why I am saying the interpretation of this data was very challenging. How do we put together this information for 14 months, because there was a median of 14 months. Putting the 2 large studies together, 091 and 078, had a median duration of 14 months and here we do not see the signal that we saw with VIGOR.

Here is the table with the summary of the meta-analysis that was conducted by the sponsor, the updated meta-analysis comparing Vioxx all doses with placebo events. I think this is the most valuable part of this slide because the other one is comparing non-naproxen NSAIDs and I would agree that not all non-naproxen NSAIDs are the same. But the total number, in any case, doesn't look bad for Vioxx. The relative risks are below 1.0.

Here is what we had so far. In the NDA database in '98 where we didn't look specifically at APTC but, let me tell you because I forgot to mention it before, there were 3 cardiovascular deaths with the 12.5 mg dose of Vioxx. There were no cardiovascular deaths with the 25 and 50 mg doses, and there were 3 cardiovascular deaths with diclofenac, and diclofenac had much lower exposure, number of patients and time of exposure, as compared to Vioxx. So, there were not signals in the original NDA.

Then we had VIGOR that showed a signal in APTC and non-fatal MIs. Then we had the rheumatoid arthritis ADVANTAGE study that, as compared to naproxen, showed trends. Again, this should be all yellow and this, here, should be "no" because there were no cardiovascular deaths in the rheumatoid arthritis database.

Then we have the safety update reports with the Alzheimer's studies that had 14-month, placebo-controlled studies without difference in MIs and strokes, but with that cardiovascular trend.

After 2001, after the presentation at the advisory committee meeting of 2001, there were several epidemiologic studies and re-analysis of the data that had been presented or published, and meta-analysis but they showed conflicting results. Basically we had to do our labeling changes. By this time we were around October, November probably of 2001. After negotiations with the sponsor, we ended up in April of 2002 including a label that for many of you may be very confusing or not helpful, but that was the situation in which we were at that time. We had conflicting data. So, what we did, we put the result of VIGOR there. We included two tables showing the cardiovascular events over time, the list of cardiovascular events by category. There was also some language in the precautions section and the indications because the rheumatoid arthritis indication was approved now, after we reviewed all the data, not 6 months before when we should have approved--not 6 months, we have a 10-month clock to review efficacy supplements.

Anyway, they were not approved until we had reviewed a substantial amount of data. There was something also in the adverse reaction section that pointed out to the risk of hypertension in patients with rheumatoid arthritis with the lower dose. Before we had something that referred to the 50 mg dose being worse than the 25 and 12.5 but in rheumatoid arthritis patients the 25 mg dose also showed to be worse than naproxen. There was also some language in the dose and administration.

I am not going to go through all this, don't worry, but I just want to point out that we put a lot of information there and we said that we didn't know how to interpret this data; that prospectively designed studies have not been conducted.

Following these label changes--again, I am not going to insist on this but we also had language regarding the 50 mg dose not being recommended for chronic use.

In October, 2002 we had the proposal by the sponsor to conduct a prospective analysis of cardiovascular thrombotic events that I mentioned earlier in the 3 long-term placebo-controlled studies. One of them was ongoing already since early 2000. Another one was being conducted or was going to start soon in Oxford. They submitted the prostate cancer prevention study at that time so it had not even started. But all the 3 studies together were going to provide approximately a 25,000 patient database that was placebo controlled. the prostate cancer prevention studies were planned to be up to 6 years in duration. So, we had potentially a lot of information there.

We agreed with the concept of pooling these studies and we specifically said it is possible that these studies may address the question we have, however, we cannot assure you that if you don't show anything in this study you are out of the woods So, that was a review issue. Also, there were a lot of discussions regarding the data analysis plan for these pooled analyses.

Here we have the result of the updated data from the Alzheimer's studies. This was submitted to us in March, '04. As you can see here, the rate of APTC events still is not worse than placebo. It is about the same. There are more events on placebo but there was also longer exposure if you look at patient-years of exposure. There was no difference in cardiovascular deaths as adjudicated by the committee. There were 14 and 14 non-fatal myocardial infarctions; 17 and 6 non-fatal strokes. The strokes were all in the placebo group--sorry, not all. The point is that here we don't see a signal on stroke; we don't see a signal on MI. Death kind of is there, maybe or maybe not, because if you look at the subset of cause of death then you may argue that, okay, there were more sudden deaths in Vioxx as compared to placebo maybe but all together they looked about the same.

So, this is what we had up till March. Actually, when the APPROVe study was presented to us this application was still under review. It is still under review because we had requested additional information so it takes time until it comes to us and we can review that data again. So, there are still many questions we have regarding this database.

Let me show you the Kaplan-Meier curve first. This is again the percent of patients with events versus time. As you can see here, placebo was about here up to almost 24 months and then they completely overlap. But the confidence intervals all along were very wide.

If you look at this table that I took from the sponsor looking at relative risk over time, again you see that after 18 months the risk was higher on placebo as compared to Vioxx and after 18 months the risk switches and is higher on Vioxx compared to placebo. Again, if you look at adverse events with an overall risk you have a number, but it is very important to look at risk over time because down here, after 36 months, it seems that Vioxx is picking up. But, still, I mean the confidence intervals are so wide we can't make any conclusion out of this.

This is the total-cause mortality in the Alzheimer's studies. As I think has been pointed out before, there was a difference in total-cause mortality in Vioxx versus placebo, but if you look at the cause of death they were kind of not clustered under one specific organ system. They were all over. Also, this is the first time that we had a placebo-controlled database of 3 years of an NSAID or a COX-2 selective NSAID. So, it is very hard to make any conclusion based on a comparison of Vioxx with placebo when we do not have any information on diclofenac or ibuprofen, the same kind of data up to 3 years. Still, it is of concern because, as I said, we are still reviewing this application.

Then I want to mention the epidemiologic studies because there were many epidemiologic studies and re-analyses and meta-analyses. Although I will mention that those meta-analyses did not include substantial information that we had access to. Unfortunately, we could not share that with the world if they were not published in the literature. But epidemiologic studies in general, the ones looking at Vioxx and the ones looking at naproxen--some of them were conflicting. What was consistent was that there was increased cardiovascular/thrombotic risk for Vioxx 50 and that was in the label already. Actually, we have said that for everyone with ischemic disease people should be cautious. There was no clear evidence with the 12.5 and 25 mg dose. Again, we had seen the signal but as compared to naproxen, not to placebo. And, there was conflicting evidence regarding the cardioprotective effect of naproxen. Out of 9 studies, 5 would say it is cardioprotective and another 5 would say it is not, or 4 would say it is not and 1 would say it actually causes myocardial infarction.

So, I think that up to today I am not clear as to what is the role of naproxen. I think that it is possible, it is plausible that there is a prothrombotic effect of Vioxx but that big effect that we saw in VIGOR and in the other databases as compared to naproxen--I think that naproxen does have a role there too but that does not explain everything, for sure.

In the meantime, during this time we were awaiting the results of the long-term placebo-controlled studies and then we had APPROVe. This is data submitted to us in January, 2005. So, I am not sure if they are exactly the same numbers that the sponsor has shown because there was another submission from October that is slightly different. Anyway, the point is that here it is very clear if you look at APTC events--for fatal MI there was only 1. So, if you look at non-fatal MI, there were 10 and 8. For ischemic stroke there is also a signal, but not for hemorrhagic stroke. But looking at cardiovascular deaths, there were 6 and 5.

This is the time to event plot that you already saw several times. I want to show you this later. What I want to show you now is that up to here what we had was a signal for Vioxx as compared to naproxen. That is clear. But compared to placebo, in the Alzheimer's data the only thing is there was a trend for cardiovascular death. In APPROVe it is completely opposite. You have a negative effect on cardiovascular/thrombotic events, non-fatal MIs, stroke, but not in cardiovascular death. If you look throughout, this is the first time where stroke appears as being a problem with Vioxx.

This refers more to the second goal that I had. Well, first of all, it was to show you that you need to look at risk over time. The other issue is what is the role of aspirin in these studies in how it may affect different endpoints. This is how it affects APTC endpoints. Don't even look to the left side. There are too many numbers here. The point is that the difference in cardiovascular and thrombotic events or in APTC events is driven by the non-aspirin users. In the aspirin users the relative risk decreases, particularly because there is an increase in the patients in the comparator. I think that this has to do with the kind of population that you want to see in the studies. You would want to see patients at high risk but not all patients at high risk because I think that use of aspirin may make it actually difficult to find a difference between treatments. Anyway, we should have both high risk an not high risk. These were not very high risk; they were just patients that needed aspirin.

I am going to show you this slide just quickly. I know that Dr. Temple is going to spend more time talking about blood pressure. The sponsor conducted several analyses of blood pressure and I chose this one, which is a very simplistic one but, still, I think it makes the point that when you look at on-treatment hypertension those who develop no hypertension still had increased risk for Vioxx 25 compared to placebo. The risk is very obvious here, that it increases in patients with hypertension. This is using the definition of patients who develop a diastolic blood pressure of 100 or systolic blood pressure of 160.

The point of this slide is that if we are going to look at those patients with very high blood pressure we are missing the boat here because we need to look at those patients who have not as bad hypertension. We need to look at those patients who are within the range of 140/90 or maybe even high normal blood pressure.

This is again a busy slide and I am not going to walk through it, but just to make the point that if you go through different databases you have different numbers, all over, and the rate of events in the Alzheimer's studies was higher, particularly in placebo. Here in the Alzheimer's study it was 2.07--I am sorry, I am going too fast. Let me start again. You have VIGOR, Alzheimer's database and APPROVe with Vioxx/naproxen; Vioxx/placebo; Vioxx/placebo. Here with have APTC events, myocardial infarction and total-cause mortality. N is the number of events and this is the patient-year rate in 100 patient-years of exposure.

The point was that placebo here--the patient-year rate is 2.07 while here it is 0.54 in the APPROVe study. Naproxen here is in between in the VIGOR study. The point is different populations, different background rates in the active treatment and also in the comparator treatments. So, again, we need to define what kind of population we want to have in these studies.

The other point is that if you look at total-cause mortality, the one that looked bad was Alzheimer's. There was no difference in total-cause mortality in APPROVe. There was a mild imbalance here in VIGOR and in the other databases there was no difference in total-cause mortality.

So, I hope you understand how challenging it was for us as we were reviewing this data. There was a clear signal compared to naproxen that was not consistent when compared to placebo. And, we have no comparative data, particularly cardiovascular safety data, for Vioxx and non-naproxen NSAIDs or not a lot of data on long-term placebo controlled with traditional NSAIDs.

We still need to clarify the role of blood pressure and what is the role of aspirin in protecting for cardiovascular events. I think that is it. I kind of said this while I was talking. So, this is the end of my presentation.

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see also:

Cardio Events & COX-2 Your Vioxx Lawyer - Vioxx, Celebrex & Bextra FDA Transcript - Cardiovascular Events, COX-2
Your Vioxx lawyer provides the complete transcript of the FDA meeting.

FDA: Vioxx Your Vioxx Lawyer - Vioxx, Celebrex & Bextra FDA Transcript - FDA: Vioxx (Rofecoxib)
Your Vioxx lawyer provides the complete transcript of the FDA meeting.

FDA Transcript - Day 1 Conference for Safety - Vioxx, Celebrex & Bextra FDA Transcript
Read here for the complete transcript of the FDA meeting for Vioxx