Vioxx Side Effects - Your Vioxx Lawyer - Vioxx, Celebrex & Bextra FDA Transcript

Your Vioxx side effects 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.

Sponsor Presentation: Vioxx (Rofecoxib)

DR. KIM: Mr. Chairman, members of the advisory committee and FDA and ladies and gentlemen, my name is Peter Kim and I am President of Merck Research Laboratories. My colleagues and I welcome the opportunity to present information at this advisory committee meeting, and I would like to begin with just a few introductory comments.

As you will hear, to determine both its risks and its benefits, Merck extensively studied Vioxx before seeking regulatory approval to market it, and we continued to conduct clinical trials after the FDA approved Vioxx.

As Merck continued to monitor the cardiovascular safety of Vioxx, we recognized the value and interest in obtaining additional cardiovascular safety data on this medicine. After deliberations with numerous outside advisors, Merck developed and discussed with FDA a plan to prospectively analyze cardiovascular event rates from 3 large placebo-controlled trials.

It was preliminary information from one of these long-term trials, the APPROVe trial, that led to Merck's decision to voluntarily withdraw Vioxx. When Merck made the decision to voluntarily withdraw Vioxx from the market, we stated that we believed that it would have been possible to continue to market Vioxx with labeling that would incorporate the data from the APPROVe trial. We concluded, however, based on the science available at that time, that a voluntary withdrawal of the medicine was the responsible course to take given the availability of alternative therapies and the questions raised by the data. Since that time new cardiovascular safety data for other COX-2 inhibitors have become available and were reported on just this week in the New England Journal of Medicine. We look forward to hearing and seeing presentations of these data and to hearing discussions and interpretation of them during this advisory committee meeting. Thank you, and now I would like to turn the podium over to Dr. Ned Braunstein.

DR. BRAUNSTEIN: Good morning, Dr. Chairman, members of the availability committee, FDA, I am Dr. Ned Braunstein, Senior Director of Merck Research Labs.

Millions of patients suffer with painful arthritis and need effective therapies. The recent data that have come to light on NSAIDs and selective COX-2 inhibitors raise many questions. Patients and physicians need information and guidance on the use of these effective medicines that we know are not without risk. We recognize that the cardiovascular safety of the NSAID and coxib classes is an important public health issue and we welcome the opportunity to present this advisory committee information that we believe will help the FDA and the committee in their work in developing recommendations in the best interest of patients. To assist us today, we have brought along as consultants Dr. Marc Hochberg from the University of Maryland School of Medicine, Dr. Marvin Konstam from Tufts University School of Medicine, and Dr. Loren Laine from the University of Southern California School of Medicine. They are here to help answer your questions and otherwise assist the committee.

Merck's objective today is to provide you with data on rofecoxib and review how those data affected our assessment of risk/benefit over time. The presentation will focus on GI and cardiovascular data or rofecoxib, starting with the data in the original NDA and proceeding through the voluntary withdrawal of Vioxx and the APPROVe data.

In talking about the data, I will try to highlight some of the methodology we used to obtain, adjudicate and analyze cardiovascular data, and I will spend some time discussing the considerations that went into designing a study of cardiovascular outcomes with rofecoxib as the information may be useful in considering similar studies.

The presentation of data will end with a presentation of new exploratory analyses that we have performed and I will follow with a risk/benefit assessment, the review the major outstanding questions of the day, and the next steps we are taking and/or propose.

I will start with an overview of the issues we face today. Starting with the GI tract, as you have already heard, NSAID gastropathy has been the most common cause of drug-related morbidity and mortality in industrialized nations. The development of rofecoxib was based on the desire to limit and reduce this problem.

You have also heard already about the COX-2 hypothesis. I just want to emphasize two points. First, all NSAIDs inhibit COX-2 in a dose-dependent manner and selective COX-2 inhibitors do not inhibit COX-1 at clinical doses.

The rofecoxib develop program confirmed the COX-2 hypothesis and demonstrated a reduction in clinical upper GI events, that is, actual GI outcomes with rofecoxib versus non-selective NSAIDs. This was shown for rofecoxib in the VIGOR study and, based on that, rofecoxib was the only selective COX-2 inhibitor with a modified GI warning. Since that time we have accrued additional information that extend the GI benefit of rofecoxib and have shown that the reduction in clinical upper GI events is consistently seen with rofecoxib versus diclofenac, ibuprofen and naproxen.

Although rofecoxib is associated with a reduced rate of upper GI events compared to these NSAIDs, rofecoxib is not placebo. In addition to the upper GI findings, we have also observed a reduced incidence of lower GI events compared to naproxen in VIGOR, So, although there remain some unanswered questions, for example for aspirin users, the GI benefit for rofecoxib is clear.

As we have also learned, there are important cardiovascular findings with these drugs and perhaps with the larger class of NSAIDs. In 1998 Merck had implemented an adjudication standard operating procedure to methodically study the cardiovascular effects of its COX-2 selective inhibitor drugs in clinical trials. Clinical data on thrombotic cardiovascular events with rofecoxib show an increased risk of events relative to placebo. This was seen in APPROVe with long-standing use.

In contrast to the difference seen from placebo, we have not observed a difference in cardiovascular event rates between rofecoxib and NSAIDs other than naproxen. Long-term data, however, are limited. In contrast to what had been observed versus the placebo, the increased risk compared to naproxen appears after short-term use.

I think it is worth noting that similar observations have now been made with other selective COX-2 inhibitors. We believe that these new data on rofecoxib and COX-2 inhibitors raise several questions about these drugs important to the public health.

First, based on the data available, how do we currently assess the relative risks or benefits of selective COX-2 agents? I cannot speak to the data on all of these drugs but I can talk about rofecoxib. Clearly, there are risks versus placebo, and not just cardiovascular risks. however, placebo is not a choice for patients with chronic arthritis and pain who require chronic NSAID therapy. For these patients the question is the risk and benefit of selective COX-2 agents versus non-selective NSAIDs. I will present data on this question related to the GI and cardiovascular safety of these drugs.

Second, can we identify factors associated with the observed increased risk for thrombotic cardiovascular events with these drugs? Although we do not have definitive answers, I will present the data that we have.

Finally, is the increased thrombotic cardiovascular risk that we have observed with rofecoxib indicative of a larger class effect of COX-2 inhibitor? If so, how big is the class? That is perhaps the central question of this meeting. At present we do not know the long-term cardiovascular effects of traditional NSAIDs. Other than aspirin, these agents have not been studied long term versus placebo. We believe that long-term studies are needed and, in particular, comparator studies between selective COX-2 agents and non-selective agents to better understand the relative risk/benefit profiles.

I will now turn to a presentation of the data, and will do so chronologically as it highlights the magnitude of data that were ultimately needed to dine the long-term cardiovascular risks of selective inhibitors. This information may be useful regarding the development of future COX-2 inhibitors and in informing this committee on its decisions.

I would like to start by reviewing the initial GI and cardiovascular data that were in the new drug application. There were two main clinical components of the GI safety program in the original rofecoxib NDA, the GI endoscopy studies, which are described in your background package, and a pooled analysis of clinical upper GI events, shown here. Investigator reports of suspected upper GI perforations, ulcers or bleeds or PUBs were adjudicated by an external committee of blinded adjudicators, and the confirmed events formed the basis of this prespecified analysis.

The Kaplan-Meier plot of the data is shown on this slide. Throughout my presentation I will be showing several of these so I would like to take some time to walk through this first one. Time is shown on the X axis, and below that the number of patients remaining in the studies at the different time points. Cumulative incidence is shown on the Y axis and also shown are summary statistics, relative risk confidence interval and a p value.

At the time of the original NDA a significant difference was demonstrated between rofecoxib and the combined NSAID comparators, mostly data on ibuprofen and diclofenac. The relative risk of 0.45 corresponded to a 55 percent risk reduction with rofecoxib and, thus, we believe that we had established a GI safety advantage over these older NSAIDs.

These are the cardiovascular safety data from the OA development program. Rates per 100 patient years of investigator reports or cardiac, cerebrovascular and peripheral arterial and venous serious thrombotic events were examined both in aggregate, as shown on this slide, and also in individually, as shown in your background package. As you can see, then rates were similar for rofecoxib compared to the NSAIDs diclofenac, ibuprofen and nabumetone and for rofecoxib compared to placebo.

These cardiovascular and GI data, along with our other data, were submitted to FDA in 1998 as part of the new drug application for rofecoxib. They were discussed at the April, 1999 Arthritis Advisory Committee and the FDA concluded that there was a favorable risk/benefit profile for rofecoxib, and rofecoxib was approved in May of 1999.

Around that time we were completing our Phase III osteoarthritis studies. The results of studies that we were doing in collaboration with Dr. Garret FitzGerald became available, and he has already told you about those and the hypothesis that selective COX-2 inhibitors could be prothrombotic by inhibiting systemic prostacyclin production without inhibiting thromboxane production.

In addition to that hypothesis, there were other hypotheses being discussed in the clinical literature and in the basic science literature at that time, including the possibility that NSAIDs, through their effects on COX-1, might decrease the risk of cardiovascular events. Another was that perhaps by inhibiting COX-2 there may be a beneficial effect by inhibiting the enzyme in atherosclerotic plaques.

Merck recognized that it would be important to continue to acquire cardiovascular data with its selective COX-2 inhibitors. To address these hypotheses, in 1998 Merck initiated a vascular event adjudication standard operating procedure to standardize the evaluation of cardiovascular events in all of its COX-2 inhibitor studies. Adjudication of events was based on predefined criteria. Under the standard operating procedure all source documentation on events was collected and the data were then reviewed by blinded, external adjudication committees. With this procedure, over 92 percent of cases had sufficient data for definitive determination and adjudication. Thus, we can be confident in the quality of the data. By eliminating questionable events, we would amplify and improve the clarity of any signal if present. The standard operating procedure called for a pooled analysis of events across all studies to improve the precision of what would be obtained from individual studies.

In order to obtain more data on the effect of rofecoxib on GI outcomes Merck initiated the Vioxx GI Outcomes Research, or VIGOR, study in January, 1999. GI events would be adjudicated using the same approach as had been done for the osteoarthritis studies. The cardiovascular events in VIGOR fell under the new standard operating procedure.

VIGOR was designed to definitely assess the GI components of the COX-2 hypothesis. It was conducted exclusively in rheumatoid arthritis patients because Merck believed that a GI benefit had already been established in osteoarthritis patients. Rofecoxib of 50 mg, 2-4 times the recommended chronic dose, was chosen to provide a rigorous assessment of safety. We chose as a comparator naproxen 500 mg twice a day to extend the GI findings to an additional NSAID and because that was the most commonly prescribed NSAID regimen in rheumatoid arthritis. Patients using aspirin were excluded to avoid COX-1 inhibition as this could confound the ability to rigorously assess the COX-2 hypothesis.

The primary endpoint was reduction confirmed clinical upper GI events. There were 56 events on rofecoxib and 121 on naproxen. The time to event curve separated early and they continued to separate, and the relative risk of 0.46 corresponds to a 54 percent risk reduction with rofecoxib. The p value, as you can see, was highly significant. A similar GI benefit was seen with confirmed complicated events, and in a post hoc analysis for lower GI events.

A second finding in VIGOR was the difference in the rates of thrombotic cardiovascular events between the two treatment groups. There was a relative risk of 2.4 for the confirmed events, as shown here. The p value, again, was highly significant.

Examination of the individual types of events broken down by vascular bed, cardia, cerebrovascular and peripheral shows that the difference between treatment groups was largely driven by the difference in myocardial infarction, 20 on rofecoxib and 4 on naproxen. Of note, there were similar numbers of patients with strokes in the two groups.

Additional exploratory analyses were undertaken to better understand these cardiovascular findings. I will focus on the types of analyses that I will show later for APPROVe. In VIGOR the use of 50 mg, a dose 2-4 times the recommended approved chronic doses, was associated with a higher incidence of hypertension adverse experiences than with naproxen. In analyses described in the background package the relative risk of events was similar in patients with or without increases in blood pressure during the study. The relative risk of events was also similar in patients with or without baseline risk factors for cardiovascular risk.

Finally, multiple analyses were performed to examine the patterns of risk and relative risk over time, both by Merck and the FDA. Merck's interpretation was that there was no significant increase in relative risk over time for rofecoxib versus naproxen. However, the FDA felt that a change in relative risk over time could not be excluded.

Because VIGOR did not have a placebo control, we turned to other data from other studies to better understand these results. Merck had initiated a program to assess the ability of rofecoxib to delay the onset of Alzheimer's disease in patients with minimal cognitive impairment or to slow the progression of Alzheimer's disease. In these studies, rofecoxib 25 mg was compared to placebo in an elderly population.

An initial review of the cardiovascular data, in March, 2000 when the VIGOR results were first learned, did not show an imbalance. In a subsequent review, undertaken in September, 2000, in advance of the VIGOR advisory committee, which I will show you next, at that time there were over 2000 patients enrolled, with a median duration of therapy of approximately one year.

The analyses at that time were based on investigator-reported events since at that time few had been adjudicated. Subsequent analyses that I will show using the adjudicated data were consistent with these initial analyses. Clearly, there was no evidence to suggest an increased risk with rofecoxib based on the aggregate endpoint shown on this slide, or based on the analysis of individual type of events such as myocardial infarction or stroke shown in the background package.

Consistent with the approach envisioned in the adjudication SOP, we also performed a pooled analysis of all the available cardiovascular data to obtain more precise estimates of the relative risk for rofecoxib versus each of the various comparators. The pooled analyses include all randomized, controlled trials from Phase IIb through our Phase V postmarketing trials of 4 weeks or longer duration that had been completed by September, 2000 and also included the Alzheimer's data that I just showed you.

Studies were included if there was a placebo or an NSAID comparator. For the pooled analysis we prespecified to use the anti-platelet trial as collaboration combined endpoint of myocardial infarction, stroke and vascular death. There were several reasons for this choice. First, the rofecoxib pooled analysis included data from studies that antedated the adjudication SOP. Investigator reports of the APTC endpoints had the highest confirmation rates in the studies that were adjudicated so restricting the analyses to these events ensured consistency among the data. Second, the APTC combined endpoint was a standard and would allow comparison to other published reports. The analysis pooled double-blind patient level data stratified by disease. In September, 2000 there were data from over 28,000 patients and over 14,000 patient-years of exposure.

In the analysis for the three data sets, placebo, non-naproxen NSAIDs and naproxen controlled data, a difference was only observed in the naproxen data set. It was, therefore, considered not appropriate to combine the three data sets as this would tend to obscure the difference from naproxen.

In our plots the triangle points to the estimate of relative risk and the size of the triangle is proportionate to the overall exposure. The 95 percent confidence interval is shown as a horizontal line, and the same information is provided numerically along with the numbers of events in each data set.

In the placebo and non-naproxen NSAID data sets the data do not suggest an increased risk standard rofecoxib. The data in the naproxen set were largely driven by the VIGOR data and, consistent with VIGOR, there was an increased risk for rofecoxib compared to naproxen. The 95 percent confidence interval did not cross 1, consistent with the statistically significant difference.

Our conclusions: There was a clear evidence for GI safety benefit of rofecoxib compared to non-selective NSAIDs. Because the data did not suggest increased risk of cardiovascular events with rofecoxib compared to placebo or non-naproxen NSAIDs, we believe that the weight of the evidence was most consistent with naproxen having provided a cardioprotective benefit in VIGOR. Data to support that naproxen 1000 mg can provide sustained anti-platelet effects, as well as animal data with naproxen and clinical data on agents with similar properties are all provided in the background package. Subsequent data with other selective COX-2 inhibitors would also show a cardiovascular difference from naproxen while having similar cardiovascular events with non-naproxen NSAIDs.

The Arthritis Advisory Committee agreed that the VIGOR study had shown a GI safety benefit for rofecoxib compared to naproxen. With regard to the cardiovascular data, they determined that the results were inconclusive. They recommended that both the GI and cardiovascular data be described in the rofecoxib label. Those recommendations were, indeed, reflected in the approved labeling. There is now a modified GI warning acknowledging that the risk of GI toxicity with rofecoxib 50 mg once daily is significantly less than with naproxen 500 mg twice daily.

There was a new cardiovascular precaution which provided the cardiovascular results from VIGOR and from the Alzheimer's disease studies which concluded that the clinical significance of the cardiovascular findings were unknown. The specific precaution stated that caution should be exercised when Vioxx is used in patients with a medical history of ischemic heart disease.

Finally, because there were dose-related trends and NSAID type adverse experiences with rofecoxib 50 mg and no greater efficacy at 50 mg compared to 25 mg, the new label further emphasized that the chronic use of rofecoxib 50 mg was not recommended.

I would like to turn now to the period starting after we learned the results of VIGOR up to the unblinding of APPROVe, and I will focus on the unique information that Merck can provide to this committee, information on our approach to the design of a study of cardiovascular outcomes that we implemented in 2002, and the final data from our programs in arthritis and Alzheimer's disease that were completed in this time frame. I will briefly touch on data that others will be presenting or have presented, such as epidemiology studies and the ongoing preclinical work, and will end this section of the presentation with our assessment of the data available before APPROVe.

In considering outcome study designs, we recognized two different approaches we could take. Each had different merits and would answer different questions. The first would be to perform an NSAID-controlled study. This could involve arthritis patients so we could study the patients in whom the drug was indicated, knowing, however, that a placebo control would not be appropriate in a several-year study of patients who require chronic NSAIDs, and the use of chronic NSAIDs over several years was not appropriate in patients who did not have that need.

The alternative was to do a study versus placebo. Obviously, this would preclude the ability to study patients with chronic arthritis. So, the applicability of the finding to arthritis patients would need to be inferred. Despite this potential limitation, we decided for rofecoxib to answer the question for difference from placebo.

I think it would be useful to discuss with this committee how bit these studies need to be. As we all know, it is easier to prove a difference than to prove similarity. In order to exclude even a 30 percent increased risk with 95 percent confidence and with 90 percent power, you need data on over 600 confirmed events. Based on anticipated event rates and typical dropout rates on our studies, this would require enrolling approximately 25,000 patients for a study design to run over about 3 years. To exclude a 20 percent increased risk you would need approximately 1300 events and over 60,000 patients. To exclude a 10 percent risk you would need approximately 4800 events and over 200,000 patients in the studies.

We considered several placebo-controlled designs. One study in acute coronary syndrome was rejected for a variety of reasons after extensive discussions with our consultants. First, these unstable patients are at particular risk for bad outcomes associated with GI or renovascular effects known to be present with rofecoxib, and considering the unknown benefit this raised concerns.

Second, these patients would all need to be taking aspirin and, as you recall, one of the hypotheses at the time, and it still continues to be a hypothesis, was that aspirin would abrogate any increased cardiovascular risk of selective COX-2 inhibition and, thus, a negative finding would not have answered the question raised by VIGOR.

However, the emerging data on possible chemopreventative benefits of COX-2 inhibitors and the extending database that we had of chemoprevention studies with rofecoxib versus placebo provided an alternative means to address this question. In addition, these patients present a broad spectrum of cardiovascular risk similar to the arthritis patients in whom rofecoxib was being used. Thus, it was decided to develop a study of cardiovascular outcomes for rofecoxib based on a combined analysis of placebo-controlled chemoprevention studies.

The APPROVe study comparing rofecoxib 25 mg to placebo had already been initiated during 2000 and a second study, also comparing rofecoxib to placebo, was initiated in 2002, VICTOR, a study to assess reduction in colon cancer mortality. A third study examining the ability of rofecoxib to prevent prostate cancer in men at risk, the ViP study, was initiated in 2003. Together, these three studies would provide information on thrombotic cardiovascular events in over 25,000 patients and targeted to enroll 20-30 percent of patients on aspirin. The combined analysis had its own protocol analysis plan and an external safety monitoring board to monitor the cardiovascular safety in the three combined studies.

The protocol for the combined outcome study was finalized in October of 2002 and was submitted to and discussed with the FDA and with the regulatory agency in the United Kingdom.

Also during the 2000-2004 time frame final data became available from our programs in arthritis and Alzheimer's disease. As the data became available, we performed updates to our cardiovascular pooled analysis and, in 2003, performed a final cardiovascular update. Also, in 2003 we updated our pooled analysis of upper GI clinical events so I will show you now the final GI and cardiovascular data from these programs.

Final GI data from the osteoarthritis and rheumatoid arthritis programs were analyzed in pooled analysis of clinical upper GI events using the same approach to the data as in the initial analysis I showed before, except now we had data that extend up to 30 months of treatment. The pooled analysis included all Phase IIb through Phase V randomized clinical trials 4 weeks or longer and excluded VIGOR as those data would otherwise overwhelm the data in the pooled analysis, and that is shown separately on this slide.

As you can see, even excluding VIGOR, the relative risk of a confirmed clinical upper GI event for rofecoxib compared to the combined NSAIDs was 0.36, a 64 percent reduction, and a similar benefit could also be demonstrated for confirmed complicated events.

In this final pooled analysis there was sufficient data to assess whether the findings for the combined NSAID groups were consistently observed for each of the comparator NSAIDs, diclofenac, ibuprofen and naproxen and, as you can see, this was clearly the case.

I will turn now to the cardiovascular data. This is the Kaplan-Meier plot of the final data for the osteoarthritis Phase IIb/Phase III studies for rofecoxib compared to the non-naproxen NSAIDs. Over 30 months the curves are indistinguishable from each other, although starting around 18 months, as you can see, the numbers of patients begin to drop off and the 95 percent confidence intervals begin to widen consistent with the data becoming sparse.

This is the time to event plot for the final cardiovascular data. For the Alzheimer's disease studies, these are the confirmed events from these studies. The average relative risk across the Alzheimer's program was very close to 1. However, in this data set there was a statistically significant non-constant relative risk, with an apparent decreased incidence for rofecoxib compared to placebo for the first approximately 24 months of the study and an apparent increased risk for rofecoxib thereafter. however, as the overall relative risk approximated 1 and as data in our pooled analysis did not suggest this pattern of changing relative risk in any of the data sets, the data from Alzheimer's were interpreted to represent variation about a mean and no difference between the treatment groups.

I want to point out that there were 90 patients with confirmed cardiovascular thrombotic events in the Alzheimer's disease data and there have been over 70 in the osteoarthritis data set. Thus, each of these data sets was large enough to exclude the 2-fold increased cardiovascular risk with rofecoxib that we had seen in VIGOR.

This is the final update to the pooled analysis. The pooled analysis included data now from 28 studies in over 32,000 patients and over 19,000 patient-years of exposure. Again, relative risk for rofecoxib compared to placebo and rofecoxib compared to non-naproxen NSAIDs approximated 1. However, the relative risk compared to naproxen continued to show a difference with a 95 percent confidence interval excluding 1 and, thus, indicating statistical significance.

So, what was our assessment of the data in 2004 before we learned the results of APPROVe? The data available in 2004 came from three sources, observational epidemiology studies, preclinical studies and randomized controlled trials. There were 10 observational epidemiology studies, either published or publicly presented, on the cardiovascular risk with these drugs and an increasing literature on preclinical models. These are described in detail in the background package and I will not go into these data as others will be speaking to them.

With regard to these other studies, I will just observe that the results were mixed and they did not provide clarity on the cardiovascular risk with rofecoxib or selective COX-2 inhibition. We believe that clarity would best come from the outcome study that we had initiated.

Also in this same time frame the TARGET study results with lumiracoxib were published. These were consistent with the pattern of overall cardiovascular findings that with had observed with rofecoxib, with cardiovascular event rates similar to a non-naproxen NSAID, in that case ibuprofen, but a cardiovascular event rate higher with lumiracoxib than with naproxen. With rofecoxib we had also observed similarity to placebo in the Alzheimer studies. Thus, in assessing these different data we place the greatest emphasis on data from randomized clinical studies and, based on these, the assessment was that the risk/benefit profile remained favorable for rofecoxib. With regard to any remaining questions our ongoing study of cardiovascular outcomes would provide the answers.

APPROVe was the first component of the study on cardiovascular outcomes. It was anticipated to complete in November of 2004. However, on September 23 we received a call from the administrative committee that they had accepted a recommendation from the external safety monitoring board to terminate treatment in the study.

APPROVe studied rofecoxib 25 mg versus placebo in approximately 2600 patients. Stratification was by baseline aspirin use because aspirin had been shown in previous studies to reduce the incidence of colon polyps. There was a 3-year on drug treatment period and 1-year off-drug period. Colonoscopies were performed at screening, year 1, year 3 and there was a year 4 follow-up after withdrawal of therapy to assess the possibility of rebound. The primary endpoint was the cumulative incidence of patients with adenomatous polyps at year 3. The first patient was screened in December of '99 and the first patient was randomized in February, 2000.

Patients had to be 40 years or older and have a histologically confirmed large bowel adenoma at screening. Patients with a prior history of thrombotic cardiac events could be enrolled if they were more than a year post event; 2 years for a cerebrovascular event. Patients were excluded if they were medically unstable, for example, if they had uncontrolled hypertension or angina or CHF at rest.

The data that led the ESMB to terminate the study early are the data on this slide. These are the preliminary data from the ESMB September meeting. In the final data, which are now published on-line, there were two additional events, one myocardial infarction in each treatment group so the current curves look very similar. Overall, there was an approximately two-fold increase in risk with rofecoxib compared to placebo. However, there was a statistically significant change in relative risk over time. Event rates were similar to placebo over the first approximately 18 months, consistent with our previous data. Starting after 18 months of treatment the curves began to separate with the difference becoming significant.

Looking at the types of events, you can see that there were imbalances in myocardial infarction, 20 versus 8 here or, in the final numbers 21 versus 9, and imbalances in stroke, 11 versus 6. In addition to these findings, we also observed differences from placebo in NSAID-like renovascular effects, for example, edema, congestive heart failure and hypertension.

After APPROVe our assessment of the risk of cardiovascular thrombotic events with rofecoxib had changed. APPROVe was the first study to show a statistically significant increased risk of cardiovascular thrombotic events with rofecoxib 25 mg versus placebo. Although the risk had been similar to placebo for the first approximately 18 months, the risk in APPROVe began to diverge from placebo starting after approximately 18 months.

The mechanism for this finding at that time was uncertain. At the time, available clinical data on other agents did not support a class effect so we were left with a potentially molecule-specific effect. As I previously indicated, the administrative committee indicted its recommendation to terminate study treatment to us on September 23 and, on the basis of the data Merck voluntarily withdrew Vioxx from the market on September 30th.

APPROVe was the first clinical trial with rofecoxib that showed an increased cardiovascular risk versus placebo. At the time alternative therapies were available without evidence of a similar cardiovascular risk and, thus, Merck believed that voluntary withdrawal best served the interests of patients.

Since withdrawal of Vioxx we assiduously worked to obtain the final data from APPROVe and preliminary data from the other placebo-controlled chemoprevention studies, VICTOR, the colon cancer study, and ViP, the prostate cancer study. I will start with the final analyses of the APPROVe data and additional exploratory analyses that we performed to identify possible relationships between various risk factors with increased relative risk.

I want to start by pointing out, however, that we performed numerous post hot exploratory analyses of the data to identify factors that might predict patients with increased relative risk. We looked at well over 10 different baseline risk factors. We looked in multiple different analyses and we also examined patients who were not taking aspirin. We also examined over 40 analyses of blood pressure. We analyzed these by one subgroup factor at a time with tests for treatment-by-subgroup interaction.

Given the large number of subgroups tested and the post hoc nature, the data that I am about to show you need to be regarded as hypothesis generating and not definitive. So, let me start with the analyses of risk factors other than blood pressure.

This slide shows the relative risk for rofecoxib versus placebo for different cardiovascular risk factors. To conserve time, I am only showing the few in which possible trends were seen. Patients with what we called increased risk are patients with two or more baseline cardiovascular risk factors, or a history of symptomatic atherosclerotic cardiovascular disease; aspirin users in the study which we defined as patients who used aspirin at least 50 percent of the time on study and before an event; patients with diabetes; and patients with a history of atherosclerotic cardiovascular disease. However, these four subgroups were not independent. The events in the patients with a history of atherosclerotic cardiovascular disease were also included in the aspirin user and in the increased risk subgroups and, in fact, were driving the differences in these subgroups. So, what we have are potentially two independent risk factors, patients with a history of atherosclerotic cardiovascular disease and patients with a history of diabetes. For these two subgroups, the test for treatment-by-subgroup interaction was borderline, with a p value between 0.05 and 0.1. At this time these observations can only be regarded, as I said, as hypothesis generating.

We also looked at blood pressure in APPROVe. Blood pressure was measured in this study once per visit which occurred at 4-month intervals. The blood pressure measurements, however, were not standardized across sites for example with respect to time of day or measurement technique. And, blood pressure changes in APPROVe were typical of what had been published for NSAIDs, between group differences and the change from baseline and systolic blood pressure of about 4 mm Hg systolic and for diastolic about mm Hg. Baseline mean systolic and diastolic blood pressure data from population studies or from studies on the cardiovascular effects of lowering blood pressure, the change in mean systolic and diastolic blood pressure we observed in APPROVe would not appear to account for the magnitude of the cardiovascular findings that we have observed. Nonetheless, we performed numerous analyses to assess whether associations could be identified between the blood pressure and cardiovascular data.

Multiple blood pressure analyses are described in your background package. Neither the preliminary nor the final analyses identified consistent patterns or consistent patient subgroups or covariates associated with increased relative risk. Variables assessed included baseline blood pressure, change from blood pressure, on treatment blood pressure and hypertension reported as an adverse experience. The one subgroup of the many we tested in which a trend was identified was in patients with systolic blood pressure greater than or equal to 160. However, other data sets, in particular VIGOR and our placebo-controlled data from the pooled analysis, did not show a similar trend when assessed in this manner.

With the final data we also learned the results of the efficacy endpoint. The primary efficacy endpoint was the cumulative incidence of patients with recurrent colon polyps over the 3-year treatment period. The primary approach to the data was intention-to-treat, and the primary population was patients at increased risk for colorectal cancer based on baseline risk factors such as histology and number of polyps. Rofecoxib use was associated with a 24 percent reduction in the risk of colon polyp recurrence, and the p value was highly significant.

As I indicated earlier, the study of cardiovascular outcomes was the pooled data from APPROVe, ViP and Victor. We have preliminary data from ViP and VICTOR and wanted to share those preliminary data with you as well.

This slide shows a pooled analysis for the primary endpoint that we had prespecified for the cardiovascular outcome study confirmed thrombotic cardiovascular events. Again, I want to emphasize that VICTOR and ViP data are still preliminary. There are still five cases that are pending adjudication to which we remain blinded. For VICTOR we have very limited information on overall exposure and on patient demographics.

The study was conducted by Oxford and they are working hard at getting the information to us. Given the preliminary nature of the ViP and VICTOR data, we are unable to draw at this time definitive conclusions from these data.

Also with the data available, we can provide a comprehensive perspective on mortality in the rofecoxib clinical program. Shown is all-cause mortality. This is a bit busy so let me orient you. Rofecoxib is shown in yellow; NSAID comparators are shown in blue; and placebo is shown in white. The figure provides mortality rates per 100 patient-years and 95 percent confidence intervals.

Compared to the NSAIDs, overall mortality rates were similar for rofecoxib. In one instance, the osteoarthritis Phase IIb/III studies, there were significantly fewer deaths on rofecoxib than the comparator but this was not reproduced in other data sets. With respect to placebo, mortality rates were similar between rofecoxib and placebo in all the data sets except the Alzheimer's disease where there was a significantly higher rate on rofecoxib and the difference was statistically significant. We looked at this carefully. Although some of the imbalance was due to a difference in mortality due to thrombotic cardiovascular events, the larger part of the difference was due to trauma, poisoning and infections, causes that one would not expect to be associated with an NSAID type drug effect. So, we don't have an explanation for this observation in the Alzheimer studies.

What do we believe the implications of these data to be? As I alluded to earlier, we believe that there are several public health questions raised by the new data. The first is the risk/benefit for selective COX-2 inhibitors relative to standard of care in their established indications. Rofecoxib has a GI safety profile superior to ibuprofen, diclofenac and naproxen.

The cardiovascular profile is more complex. Although there have been no differences observed between rofecoxib, ibuprofen or diclofenac, based on what we learned from APPROVe, the type of long-term data needed to establish similarity to these agents does not exist and at the time we withdrew data for a class effect of COX-2 inhibition was limited.

Amongst the non-selective agents, naproxen 100 mg appears to have the lowest risk of thrombotic cardiovascular events, but also the highest risk of upper GI clinical events. Can we identify risk factors associated with increased risk for thrombotic cardiovascular events with these drugs? I have shown you our data to support the effect of duration in our exploratory analyses on patient demographics. More work needs to be done to investigate the hypotheses raised by our data. With regard to dose, our data cannot definitively address this.

Finally, is the increased cardiovascular risk that we observed with rofecoxib a class effect of COX-2 inhibition? We believe that the data that have been reported on celecoxib from the APTC study and on valdecoxib and from the CABG study, together with the APPROVe findings, strongly suggest an effect of COX-2 inhibition on increasing cardiovascular risk.

If the committee agrees that this is a class effect, the next critical question will be determining the size of the class. Traditional NSAIDs such as ibuprofen and diclofenac have not shown a different cardiovascular risk profile from the selective COX-2 agents. However, those data are limited beyond one year. We would argue that long-term comparative studies of these agents are needed to better assess the relative cardiovascular risk.

Well, what do we think are next steps? At Merck, we are continuing to analyze our clinical data and we will be analyzing, for example, frozen samples from patients to try to identify markers that correlate with an increased relative risk of cardiovascular events with COX-2 inhibition. In addition, patients in APPROVe are being followed off-drug as had been prespecified in the protocol, and we are in the process of meeting with consultants to further explore scientific hypotheses for the findings.

We are also aware of efforts that are under way to analyze data across the different drugs, and we support those efforts. Finally, comparative outcome studies, we believe, are needed to determine the relative risk amongst these agents in relevant populations. Dr. Curtis will talk to you tomorrow about one such study that we are conducting at Merck, the MEDAL study. This is the largest study in arthritis patients ever conducted and compares the long-term safety of etoricoxib with that of diclofenac, the most widely used traditional NSAID worldwide. We believe MEDAL will provide the kind of information needed to weigh the risk/benefits of these drugs and improve the ability of physicians to make recommendations for arthritis pain and treatment that is in the best interest of their patients. Thank you, Dr. Chairman, members of the committee, FDA. I am available for your and the committee's questions.

DR. WOOD: Great! Thanks very much. As I am sure you would agree, the primary job of this committee is to assess all the risks and benefits that these drugs can produce, and we have certainly been encouraged to do that by everybody who has spoken so far.

That being the case, I was very surprised not to see the Kaplan-Meier curve for pulmonary edema. can you show us that from the APPROVe study?

DR. BRAUNSTEIN: Certainly. That would be slide 213.

DR. NISSEN: Yes, heart failure and pulmonary edema would be helpful.

DR. BRAUNSTEIN: We certainly examined that. You know, the question that has been on the table--we believe the hypothesis we were exploring was the incidence of thrombotic cardiovascular events. Pulmonary edema is a mechanism-based effect of selective COX-2 inhibition that has been well appreciated and, in fact, is already described in product labeling.

So, we did see an effect. This is in our publication. As shown here, we saw an effect. This is a combined endpoint of congestive heart failure, pulmonary edema of cardia failure, so all congestive heart failure type of events that we observed in the study.

DR. WOOD: And this had a hazard ratio of 4.6 and a p value of less than 0.004. Right?

DR. BRAUNSTEIN: Yes.

DR. WOOD: So, I mean, it is important for the committee--and this goes to all the speakers I think, that if there are other hazards with a hazard ratio of 4.6, that we see these as they are presented so that we can make some cumulative estimates of what the hazards are for these drugs. Just because they are in the label does not mean we shouldn't hear about them here, it seems to me.

The second question I have, which has always worried me, is when you go back to the original label change that you made, you know, when you changed the label to say caution should be exercised when Vioxx is used in patients with a medical history of ischemic heart disease, as a physician what am I supposed to do with that? Am I supposed to say to patients take the drug slowly, or swallow it with milk, or only take it with the lights on? Tell me what I am supposed to do with that information. I am not being facetious here because as we go through this process we are going to have to decide how we make whatever labeling changes we make, if that is the decision we make, and that doesn't seem to me to have been helpful. But maybe you knew something that I didn't. So, what did you intend me to do with that information? DR. BRAUNSTEIN: At the time when we conducted negotiations with discussions with FDA on that labeling, there were no specific data that showed a statistically significant increased risk in one patient group or another. However, given the uncertainty in the data, it was felt to be prudent to recommend that caution be exercised in that patient group if you are considering using the drug.

What we meant by that was that you need to carefully weigh the risks and benefits of the different treatment options. We think that when evaluating the options on patients it needs to be done on an individual patient case-by-case basis. Patients differ with respect to their cardiovascular risks, with respect to their GI risks, with respect to their history of allergies and with respect to how they responded to these different medications in the past, and all of that information needs to be taken into consideration when assessing and determining what type of therapy should be used versus another. And, we felt that one of the things that should be considered was cardiovascular history, and that is what we meant by that.

DR. WOOD: Okay. Other questions? Stephanie?

DR. CRAWFORD: Thank you. I appreciate the presentation. I heard both the speakers say that the sponsor, Merck in this case, made the decision to voluntarily withdraw rofecoxib in the interest of public health although the drug could have been continued on the market. When we look at adverse events we desire to predict uncontrollable events and control controllable events. The bottom line question which is really important to me as we consider these issues when we look in this case at the issue of hazard of cardiovascular events is how much is too much? In other words, how did the sponsor come to the conclusion that the evidence was so compelling as to take the step of voluntarily removing the drug product from the market?

DR. BRAUNSTEIN: Well, at the time when we saw the increased risk compared to placebo there were not data to allow us to conclude that this could be a class effect, and we felt that there were other options available to patients, including therapies that adverse event not known to have this increased cardiovascular risk. So, given those options and alternatives, we felt that the responsible action at the time was to withdraw Vioxx.

DR. CRAWFORD: Excuse me, but I am asking specifically what was that signal that was at the level where, in the interest of caution or whatever the mechanism was, you said this level is unacceptable at this time based on the given evidence?

DR. BRAUNSTEIN: Well, we saw overall a two-fold increased risk and that was seen versus placebo so it was something that we knew was statistically significant. The magnitude of the risk was on the order I think of one or two percentage points, but still at the time the other agents--it was a determination that amongst the choices that patients had available to them there were other agents that were not known to have this risk and, given the ability for patients to have alternatives that they could discuss with their physicians, we felt that we should withdraw Vioxx at that time.

DR. WOOD: Dr. Shafer?

DR. SHAFER: Two questions. I will make them fast. Do any studies show improved analgesia on Vioxx?

DR. BRAUNSTEIN: No. I mean, all of our efficacy studies show very similar results at comparable doses to NSAIDs.

DR. SHAFER: Okay. The other thing is can you go to slide number 36?

DR. BRAUNSTEIN: Yes?

DR. SHAFER: I just can't help but notice, but the upper bounds of the confidence intervals for the first two groups encompass the mean of the naproxen comparison. Does that give you pause in justifying excluding naproxen as a separate comparison group? If you take a look at the upper bounds, they include the mean of naproxen which might suggest that statistically those groups really shouldn't be segregated as you have done.

DR. BRAUNSTEIN: Well, when you look at this, if you were to combine all the data one would not see a statistically significant difference. It would tend to obscure the naproxen finding, and we felt, given what we observed in VIGOR and what we had observed all along the program, that that wasn't the right way to go, especially given the difference pharmacologically. I mean, in terms of looking at the data we also were taking into context what we understood about the pharmacology of these agents and the ability for naproxen to provide that kind of inhibition of COX-1 that Dr. FitzGerald talked about. So, we thought that not only were there differences in the clinical data but there were differences in the pharmacology data that supported keeping naproxen separate.

DR. WOOD: Dr. Gibofsky?

DR. GIBOFSKY: One of the stratifications we are asked to do during the next three days is, of course, the risk/benefit relationship. I am wondering if you have calculated the risk/benefit of cardiovascular thrombosis outcome versus the benefit of cancer prevention in the population. I can understand where the relative risk of 1.92 is. I understand what it means when the relative risk goes up above a certain number above 1.0 but, you know, you can't go much below 1.0. So, have you calculated to what extent your risk of cardiovascular events is related to your protection against cancer?

DR. BRAUNSTEIN: Well, we didn't actually study cancer as an outcome. We were looking at polyps which are precancerous lesions.

DR. GIBOFSKY: The same question basically.

DR. BRAUNSTEIN: Well, even there, you know, polyps are easily--there is a different mechanism. There is an alternative therapy available for the treatment of polyps. So, in order to evaluate risks and benefits one has to compare the risks and benefits of one treatment option versus the risks and benefits of another treatment option. In doing so, I think that this wouldn't-- DR. GIBOFSKY: Well, let me ask it another way then, if you did not see a cardiovascular signal in APPROVe would you have concluded that the reduction in risk in polyp formation was efficacious?

DR. BRAUNSTEIN: We concluded that the reduction in risk in polyp formation was efficacious regardless of the cardiovascular finding. Are you asking whether the overall risk/benefit would have been favorable???

DR. GIBOFSKY: Yes.

DR. BRAUNSTEIN: That would be speculative for me. We haven't looked at the data with that specific question in mind. I think we would need to take a look at all the patients that we looked at in all the different subgroups to see if that remained the case. You know, you saw some congestive heart failure. We say NSAID type typical effects that one would see in one of these studies, not just cardiovascular risk but there was a small increase in ulcers, not as much as one would anticipate to see with a non-selective NSAID but still present. There was a small increase in other NSAID type effects like edema and hypersensitivity. So, we haven't made a formal risk/benefit assessment.

DR. GIBOFSKY: Just one last point, you stressed the concept of their being other modes of therapy available and so that factored into your decision to take this agent off the market. But there are other ways of treating polyps as well, which leads me to question in that context the rationale for the APPROVe study.

DR. BRAUNSTEIN: We thought this was an interesting and important scientific question that had been raised in the literature.

DR. WOOD: That sounds like a retrospective question so I will let you off the hook. Let's move on. Ralph?

DR. D'AGOSTINO: Two quick questions. In slide 48 you, I think quite sensibly and again post hoc, split out the cardiovascular risk and redid the analysis. Now, if this were preplanned and I got a result like that I would say that this is great; this shows me that placebo is better no matter what I do. I mean, the cardiovascular does increase a bit but the placebo is still maintaining itself even in individuals without cardiovascular risk.

DR. BRAUNSTEIN: This slide shows the relative risks in each of these groups. It is not placebo and then rofecoxib.

DR. D'AGOSTINO: Well, it is all against placebo.

DR. BRAUNSTEIN: It is all compared to placebo, yes.

DR. D'AGOSTINO: Right, and placebo wins everywhere. So, no matter if you have cardiovascular risks or not, still placebo was better. Am I misinterpreting this?

DR. BRAUNSTEIN: You know, in this we only see trends for some subgroups and in others we don't identify particular subgroup factors where there is an important difference.

DR. D'AGOSTINO: Well, that is a subgroup and it sort of indicates consistency to me. In slide 42 there was consistency regardless of CV risk. In slide 42, if I look at those numbers on the bottom, I presume those are individuals available. You are dropping about 100 individuals after 12 months or so. Do we know anything about the loss to follow-up on these individuals?

DR. BRAUNSTEIN: We did not see differences, for example, in changes in cardiovascular risk associated with patients who discontinued--

DR. WOOD: Wait a minute, these are not all patients who dropped out, are they?

DR. BRAUNSTEIN: These are all the patients who remained in the study. DR. WOOD: So, some of these patients may not have advanced to the end of the study.

DR. D'AGOSTINO: Well, if you start at the beginning--that is my question, I mean it is randomized, right? So, there must have been about a 50-50 break so you would think at each point you would have approximately the same numbers in the two groups.

DR. BRAUNSTEIN: Well, there is a differential dropout due to adverse experiences for example that one would normally see in an NSAID trial against placebo.

DR. D'AGOSTINO: Well, why couldn't they be followed for CV events? Why wasn't it like an intent-to-treat analysis or something?

DR. BRAUNSTEIN: Yes, the way we had prespecified the analysis was that all events were determined up to 14 days after discontinuing therapy. The only intention-to-treat analysis was one done for mortality overall.

DR. WOOD: Dr. Nissen?

DR. NISSEN: Yes, I think Ralph's point is very, very important. We need to see an intent-to-treat analysis. You are telling me that 14 days after they dropped out of the study these folks were not followed beyond that?

DR. BRAUNSTEIN: We are following patients who are off-drug, who terminated treatment in the study, and we don't have data yet on that.

DR. NISSEN: Because there are a lot more people dropping out of the rofecoxib arm and the question is why are they dropping out and what happened to them. The signal here could be a lot stronger than we see using this somewhat selective analysis. I am used to an intent-to-treat analysis, Ralph, for a trial like this and I am confused as to why it was done in this way. You know, a cardiovascular hazard, if this is a pro-atherogenic therapy, is going to persist quite a while after you stop the drug. So, I think we really do need to see--I mean, to clear the air here we have to see that intent-to-treat analysis. I would track those people down and find out what happened to them.

As a cardiologist, I obviously use a lot of low dose aspirin so I am very familiar with the low dose aspirin literature, and we see in low dose aspirin perhaps up to a 20 percent reduction in cardiovascular risk in individuals who are at risk. So, what I am really confused about is that you attributed what you found in VIGOR to the beneficial effects of naproxen, but you are talking about a 4- or 5-fold difference in myocardial infarction rates and I just want to know how you came to the conclusion that that amount of difference could be explained by naproxen. Naproxen would have to be a lot more effective than aspirin. We know aspirin inhibits platelets as well as anything else out there. So, how did you guys arrive at that conclusion that it was naproxen related?

DR. BRAUNSTEIN: Well, other than in addition to the data that support that naproxen can have this effect, and specifically with regard to the magnitude that you are pointing out in myocardial infarction, there were only 24 events in VIGOR. The cardiovascular outcome studies that you are referring to oftentimes have hundreds, if not thousands, of events that they are assessing and that allows one to very carefully and with precision identify what the relative risk reduction is. In VIGOR we had fairly wide confidence intervals and, in addition, VIGOR studied exclusively patients with rheumatoid arthritis. These are patients with chronic inflammatory disease, elevated C-reactive protein and in those patients we know that the effect of aspirin is also magnified. So, given those factors, we felt that it was certainly compatible with an aspirin-like effect.

DR. NISSEN: Again, I am not sure I buy that. You know, post-MI patients have a very elevated risk and the most we ever expect from aspirin is perhaps a 20 percent reduction in recurrent events. Even with dual platelet antagonism with aspirin and clopidagrel we don't get a whole lot more than that. So, this story about naproxen, as I think Garret FitzGerald apply discussed--it doesn't stand the test of any kind of scientific rigor.

I guess the other question I wanted to challenge you on is this comment that you made that the blood pressure effects in APPROVe were consistent with what is seen in other NSAIDs. I hope many of you have had a chance to look at the Archives manuscript that compares a meta-analysis of blood pressure effects. It sure looks like rofecoxib is an outlier here, showing a weighted mean difference of about 5.5 mm Hg or almost 6 mm Hg compared to NSAIDs which are substantially smaller. Is it your position that rofecoxib does not produce greater degrees of hypertension than comparable NSAIDs?

DR. BRAUNSTEIN: Most of the studies that are referenced in that analysis, unfortunately, are confounded by dose. We think it is very important when one looks at a pharmacologically mediated effect, especially one that is known to have a dose-dependent association, that the drugs be assayed at doses that provide pharmacologically equivalent degrees of inhibition of COX-2. For example, for rofecoxib and celecoxib that would be 25 mg of rofecoxib and 200 mg twice a day of celecoxib.

DR. NISSEN: Okay. I want to clear the air on one more thing and, obviously, this drug has been the subject of a great deal of public attention and I think it would be a great opportunity for you to explain, from your perspective, why did it take 14 months, from February of 2001 to April of 2002, for the label to change? Were you fighting the FDA? Was there a big battle over what the wording ought to be of the label? I mean, it seems like 14 months is an awfully long time after an advisory committee meeting that recommended a warning to take for agreement to be reached about what that warning ought to say.

DR. BRAUNSTEIN: The advisory committee--

DR. WOOD: I think that is something probably we should let him pass on--unless you want to; go ahead.

DR. BRAUNSTEIN: No, no, no.

DR. WOOD: Go ahead.

DR. BRAUNSTEIN: After the advisory committee there were a lot of discussions with FDA. There were data requests from them which we provided to them. We submitted at that same time the NDA supplement for rheumatoid arthritis because we felt it was important. As you know, VIGOR had been conducted in rheumatoid arthritis patients at 50 mg and it was important to communicate to physicians that the appropriate dose in those patients was 25 mg. So, there was a lot of information for the FDA to review. They also asked for updated analyses of all our safety data. So, they had a lot of work cut out ahead of them, and we worked diligently with them to provide the information, conduct the analyses that they requested, and collaborated in that way to make sure they had that information, and then we worked assiduously to conclude a label. So, I don't think, considering the wealth of information, that the time frame is unusual.

DR. WOOD: And after 14 months, it was "take the tablets slowly."

DR. BRAUNSTEIN: Well, after 14 months the advice was that cardiovascular risk factors, cardiovascular history should be taken into account--

DR. WOOD: Well, that is not what it said. It is most important to remember it didn't say you shouldn't give it to people with cardiovascular risk factors. It didn't say it shouldn't be given to people who had had an MI or any other expletive statement like that. It said caution should be exercised in patients with history of heart disease. That is quite different.

DR. BRAUNSTEIN: What I tried to say or at least what I was trying to communicate was that the risk/benefit assessment we felt needs to be done on a patient by patient basis and, in addition to taking GI risk into account, one should also take cardiovascular risk into account given the uncertainty of the data that was available at that time and, as the label said, the clinical significance of these cardiovascular findings were unknown and that, therefore, the cardiovascular information should be taken into account when considering the use of rofecoxib.

DR. WOOD: Dr. Hennekens?

DR. HENNEKENS: I would be interested in knowing the total number of deaths in the randomized trials of rofecoxib against all other comparators and then against placebo, non-naproxen NSAIDs and naproxen.

DR. BRAUNSTEIN: You have that on your slide. The numbers of deaths are underneath the rows. I don't have the numbers at the top of my head. We would have to do a quick tally. Also, the only problem with looking at the numbers is that the numbers themselves don't take into account imbalances in exposure, which is why we showed them as rates per 100 patient-years because it certainly takes into account the differences in exposures. Compared to the NSAIDs we did not see differences in the rates, and compared to placebo we did not see differences except, as I pointed out, in the Alzheimer's disease study where there was a statistically significant higher rate with rofecoxib.

DR. WOOD: Dr. Cannon?

DR. CANNON: You mentioned in the VIGOR and APPROVe clinical trials that the major driver for the increased cardiovascular events on rofecoxib was acute myocardial infarction. My question is were these myocardial infarctions apparently random events or was there any setting in which they seemed to occur more frequently? For example, in relationship to a procedure, including a coronary interventional procedure, or surgery, or were the myocardial infarctions random events? I am thinking in terms of Dr. FitzGerald's presentation and the recent valdecoxib experience with bypass surgery.

DR. BRAUNSTEIN: We haven't identified any kind of associations such as you are asking. But I am not sure that we have specifically looked at the question the way you are asking. So, I am not 100 percent sure.

DR. WOOD: Dr. Abramson?

DR. ABRAMSON: Yes, I guess one of the surprises or unexpected findings in APPROVe was that it took 18 months for these curves to separate with rofecoxib. I was unaware of the heart failure and pulmonary edema data until this morning. Often fluid retention occurs early in the course of putting people on NSAIDs. So, I am wondering could you tell us more about when those heart failures occurred over the course of time. Were they early events, or was this also something that took some time to appear in the population?

DR. BRAUNSTEIN: As one would expect from an NSAID, fluid retention, heart failure were early events. If you look at discontinuations for example due to edema-related adverse experiences, including heart failure, patients tended to discontinue--if they were going to discontinue, they discontinued early and then the two groups continued in parallel. But, yes, it was an early finding as you would expect.

DR. WOOD: Tom?

DR. FLEMING: Could you show us the curves back from the VIGOR trial that looks at complicated confirmed upper GI?

DR. BRAUNSTEIN: Complicated confirmed upper GI?

DR. FLEMING: Correct.

DR. BRAUNSTEIN: We don't have those.

DR. FLEMING: You just quickly referred in your presentation to the results being positive.

DR. BRAUNSTEIN: The results were that the two curves showed the same V-like difference and they continued to separate over time. I am just looking here and apparently we don't have that slide.

DR. FLEMING: You showed us the confirmed upper GI and those cumulated to rates of 4.5 against 2.1. The data we have been provided separately for the complicated confirmed upper GI are 1.4 against 0.6. So, it is the same relative risk but a much less frequent event.

DR. BRAUNSTEIN: Sure, yes, and those were mostly GI bleeds.

DR. FLEMING: I was just curious to see a pattern as to whether that is, in fact, cumulatively increasing or more apparent early in time.

Let me go on to the next point. That reflects approximately numerically almost exactly the same number of prevented cases of complicated confirmed upper GI as there were excess numbers of thrombotic cardiovascular SAEs. In essence, what you have said is that the analgesia was comparable. So, essentially what we are really looking at is relative safety profiles and the goal here is to reduce the upper GI. And, we are essentially preventing an equal number of upper GI complicated events for equivalent numbers of excess events in the thrombolytic cardiovascular arena. Yet, essentially I think you were saying the latter didn't seem as established yet numerically it was the same.

There were also in the trial excess numbers of deaths of 22/15 and when you presented the Alzheimer's data you gave us I think slide 35 that indicated that when you looked at the Kaplan-Meier curves for confirmed thrombolytic cardiovascular events that didn't seem to reinforce the excess rates that you were seeing with VIGOR and, yet, it did reinforce the excess mortality as you have now circled back and reported at the end. In 2003 the excess mortality is quite significant but it was also significant in 2001. The latter date is in Tab G, page 2 but the former data is in Tab F, page 39 where excess mortality was significant at 33/20 and the cardiovascular were 8 to 4. So, you were seeing from these two sources excess mortality and you were seeing excess numbers of thrombolytic events that were equivalent in number to the number of prevented complicated confirmed upper GI events. Am I correct on this summary?

DR. BRAUNSTEIN: Well, no. There are a couple of points I would disagree with. First, in VIGOR the difference in mortality was not statistically significant and also in terms of looking at the causes of death, cardiovascular mortality which is the difference we would see was not different between the two groups. There were 7 on rofecoxib and 6 versus naproxen. So, I am not sure--

DR. FLEMING: Well, I don't think we disagreed. I am not talking about statistical significance here. I am talking about what the data are actually suggesting in what is available--

DR. BRAUNSTEIN: Well, I must say there is a lot of data that you pointed out to me and--

DR. FLEMING: Well, just to summarize the
201 essence, while you have emphasized appropriately the upper GI events being decreased, when you look at the actual number prevented in complicated confirmed upper GI it is numerically almost identical to the number of excess thrombolytic cardiovascular SAEs that were seen in VIGOR. You also saw a numerical increase of a relative risk of 1.5 on mortality, which was also seen in the Alzheimer's study which you were saying at the time was contradicting the sense of concern related to the overall thrombolytic excesses. And, what you were seeing at the time, even back in 2001, was a statistically significant excess in death rates with a doubling in cardiovascular-related deaths.

DR. BRAUNSTEIN: Let me ask Dr. Reicin because she perhaps has a better handle on it and I am sort of getting lost in the mass of data that is coming up.

DR. REICIN: I think there are two issues that I think you brought up.

DR. WOOD: Sorry, just for the record, can you identify yourself?

DR. REICIN: I am Dr. Alise Reicin, Vice President of Merck Research Labs. In terms of looking at VIGOR, I think you are correct. There was excess in cardiovascular events on Vioxx and there was a decrease in the complicated GI events on naproxen.

DR. FLEMING: Which numerically were almost identical.

DR. REICIN: And I think that that is also fair to say. If you compare our data versus diclofenac and ibuprofen at the time, there was no difference in cardiovascular events. In fact, numerically it was in favor of Vioxx and, yet, there was a significant reduction in GI events. So, that takes care of that. So, versus naproxen, I think you are right, there was excess in CV, lower in GI versus ibuprofen and diclofenac, however, no evidence of an increase in CV and a reduction in GI.

In terms of the mortality data that we had at the time, we had a significant reduction in mortality on Vioxx versus non-naproxen and the NSAIDs that we had in our Phase III OA studies, and at the time we actually did not make a lot of those. We thought it was potentially by chance. That was actually driven by CV mortality in the non-naproxen group.

In VIGOR there was a numeric imbalance, 22 to 15 in deaths, but cardiovascular mortality was similar. In terms of Alzheimer's I don't think there was statistical significance back at the time of VIGOR. There was a numeric imbalance. In terms of cardiovascular I think the numbers were 8 versus 4. They were put in the label. So, pretty small numbers. The rest of the difference that we saw was due to things like poisoning, electrocution and other things that we thought were no drug related. DR. FLEMING: You are correct, it was 8 versus 4 in cardiovascular related deaths, but it was statistically significant in total mortality at that time as well. It was 33 against 20, with p values reported, depending on the method, of 0.007 to 0.26.

Now, the final data are significant but even the early data were significant and reflected the level of excess mortality that VIGOR was establishing but not in a significant fashion.

DR. REICIN: Again, we didn't see it though in any of our other data sets. In fact, in the early data sets statistically it went the other way, non-naproxens had higher one. I think you can see that in RA also there was no evidence of an excess. In ADVANTAGE there was no evidence of an excess. You see now in ViP and--

DR. FLEMING: But there was in ADVANTAGE. There was an excess.

DR. REICIN: Not in overall mortality.

DR. FLEMING: Yes, in overall mortality--oh, I am sorry, in Alzheimer's.

DR. WOOD: Tom, have you finished?

DR. FLEMING: Yes.

DR. WOOD: Dr. Shapiro?

DR. SHAPIRO: I guess I want to follow up on a comment that you, Dr. Chair, made. I am still concerned about the label change and how helpful or not helpful it was, not only because it may not have been as helpful as it might have been to clinicians but also to patients in the informed consent conversation. What else was made available or should have been made available or could have been made available to clinicians to make some sense out of this, caution should be exercised when Vioxx is used in patients with a medical history of ischemic heart disease?

DR. BRAUNSTEIN: Were you addressing me or the Chairman? Me? What we made available were the data. I mean, I think that is the answer to the question in terms of the labeling and in terms of what we had published.

DR. SHAFER: So, the VIGOR and Alzheimer's results were made available. You just weren't going to analyze them to make any more definitive statements at that time about what clinicians should take away?

DR. BRAUNSTEIN: Well, by 2002 we were also starting to implement our outcome study. We thought the important message to clinicians was that there is a GI benefit and there is also a cardiovascular finding that we don't understand given the differences between the two data sets. It says the clinical significance was unknown and that this information needs to be taken into consideration when assessing the risks and benefits of these drugs in individual patients. Individual patients differ in terms of their risk profiles and that decision on which drug to be used is best made on a patient by patient basis.

DR. WOOD: Dr. Ilowite?

DR. ILOWITE: Rofecoxib was pulled from the market approximately three weeks after its approval in children with juvenile rheumatoid arthritis. I have two quick questions. Were there any cardiovascular events in any of the trials in children?

DR. BRAUNSTEIN: No.

DR. ILOWITE: Second, did you give any consideration to the fact that there were no other COX-2 inhibitors, other than one NSAID that was available as a liquid, before you made the decision to pull it from the market?

DR. BRAUNSTEIN: The focus I think was on the list we had seen versus placebo in the adult patients. This kind of disease, cardiovascular disease, is not very common in children and we hadn't seen anything like that in our population. DR. WOOD: Dr. Boulware?

DR. BOULWARE: I want to go back to the previous question. What I heard was a discussion about an offset between complicated GI events and it sounds like non-fatal MIs. If I understood the discussion back and forth here, they are roughly comparable. Now, in patients requiring an NSAID, and I am not talking about the APPROVe data here but in patients requiring NSAID treatment if there is roughly comparability of complicated gastrointestinal events with non-fatal MIs, it sounds like Merck's thinking was that the risk of a non-fatal MI far outweighs, in a patient requiring NSAID treatment, the risk of complicated GI events and that that was what drove the decision.

The reason I am interested in this is that obviously this meeting is entirely about how you make a risk/benefit calculation. So, your thoughts in September about this issue are I think helpful to us in thinking about these risk/benefit issues.

DR. BRAUNSTEIN: I wouldn't put it exactly the way you stated it, and that is because the individual patients at risk for these problems differ and there were alternative approaches for patients with GI risk that were available at the time. Now, we recognize that rofecoxib had met the highest standard. Well, yes, it had met the highest standard but there were alternatives available and we did not have data on what one could do for more studies. The data was unclear as to the mechanism so we felt that given those options, the withdrawal made the most sense.

DR. BOULWARE: Can I just make a little follow-up comment? It sounds like you are trying to have your cake and eat it too. On the one hand, you would have liked to have said pre-September that rofecoxib was the only COX-2 selective drug that had demonstrated effect in reducing GI toxicity. Now you are saying, after you pulled it from the market, there are lots of other alternatives that are almost just as good. I don't really understand.

DR. BRAUNSTEIN: I couldn't say "almost just." There haven't been head-to-head studies to answer that latter part of your question. There were alternatives. We did not know that there is a class effect for cardiovascular.

DR. WOOD: Dr. Manzi?

DR. MANZI: This question actually may better be answered by Dr. FitzGerald, I am not sure--is he here?

DR. WOOD: Here he comes, just in time.

DR. MANZI: He eloquently pointed out that there is clearly variability in individual dose response with regard to COX-2 inhibition. Since we are grappling with this issue of class effect versus a specific drug effect, is it feasible or helpful to look at the degree of COX-2 inhibition in association with these events?

DR. WOOD: You are up, Garret. Just take that microphone.

DR. FITZGERALD: I would say yes amongst all those things.

DR. WOOD: Amongst all those things? I don't understand.

DR. FITZGERALD: I mean one of the issues that you would hypothesize is relevant to outcome is the degree of selectivity attained in an individual.

DR. WOOD: You mean amongst other things related to the drug?

DR. FITZGERALD: Amongst other things related to the drug and underlying--

DR. WOOD: Sure. Dr. Platt?

DR. PLATT: Compared to other NSAIDs, do I understand properly that 98 out of 100 patients who take the drug would have about the same outcome? That is, the significant difference between the regimens is approximately--2-fold means about a 2 percent absolute difference.

DR. BRAUNSTEIN: Which outcome are you referring to?

DR. PLATT: To the GI outcomes.

DR. BRAUNSTEIN: There is a range. There is a small range because it does seem that we have a larger difference--you know, if you line them up it is a little larger with naproxen and a little smaller with diclofenac but I would say on average it is about two-fold.

DR. PLATT: Right, but that 2-fold translates into about two patients out of 100 having a different outcome than they would have if they had taken the comparator. I am trying to get at the question of whether we can identify those two patients with greater certainty than just treating everyone. And, I would ask the same question about the cardiovascular complications. That is, in this complicated business of risks and benefits, can we do better than we have at guiding both clinicians and their patients in having at least semi-quantitative estimates of what the risks will be and what the benefits will be so they can make an informed judgment?

DR. BRAUNSTEIN: We know that from the VIGOR results because we looked at patients with different baseline risk for GI disease, and this is something that is well understood, what the different risk factors are for GI disease, including things like prior history of a GI event, and we saw the same 50 percent reduction across all the different risk factors. In terms of cardiovascular, we are still introduction he process of trying to see if we can identify particular risk factors that would correlate. So, that is still an open question based on our data.

DR. PLATT: But saying 50 percent really obscures the fact. Some people may have a baseline risk of a serious GI event of 20 percent or 30 percent, in which case 2-fold is a very big improvement for them--

DR. BRAUNSTEIN: Yes, of course.

DR. PLATT: If we knew enough we would know that most people have effectively a zero risk. So, there is very little benefit for them. Have you put the data together in a way that helps us identify the people who stand most to benefit and the people who stand most at risk, and is it possible that those are different groups?

DR. BRAUNSTEIN: Dr. Reicin can I think provide more information on the VIGOR results because she was involved extensively in the VIGOR study.

DR. REICIN: Dr. Laine may come up to help me if I don't remember something. We actually published a paper on looking at specific subgroups in the VIGOR study. What we found is very similar to what Byron talked about during his discussion. Patients with typical risk factors, age more than 65--do you want to add something?

DR. LAINE: I agree absolutely. The reason I actually took these data and published this paper with the VIGOR results is that I have had the same idea. Relative risk isn't important in practice; it is the absolute change, the number needed to treat. So, we looked at that with absolute incidence of number needed to treat and for clinical events, for instance, if you had a prior event you only have to treat ten people for one additional event. But if you don't have a prior event you have to treat, let's say, 60 or 70. The same with age, if you are over 75 you only need to treat ten people for one additional event. But if you are under 65 you need to treat 50 or 60. So, I agree absolutely that at least with the VIGOR data, we stratified by these different clinical risk factors that Byron showed earlier. DR. WOOD: We have three more questions, Dr. Shafer, Dr. Cush and then Dr. Temple.

DR. SHAFER: Two questions. Can you go to slide 48?

DR. BRAUNSTEIN: That is the subgroups, yes? DR. SHAFER: Yes, is the one on various subgroup analyses. Can we show the slides? Just to highlight what the question is, in slide 48, this is following on the comment by Dr. Nissen regarding the aspirin use, what you show in the APPROVe trial is that the risk factor for those with aspirin on board, in fact, is 3.25 with a confidence interval which is wide, as Dr. FitzGerald has suggested it might be because of small numbers, but it goes from 0.98 to 13.81.

Now, the hypothesis behind VIGOR and interpreting VIGOR as an aspirin-like effect, was that aspirin was going to confer safety. Doesn't the data on slide 48 essentially disprove the naproxen hypothesis in VIGOR?

DR. BRAUNSTEIN: No, there is no naproxen in the study--

DR. SHAFER: Right, but the hypothesis was that naproxen was acting like aspirin.

DR. BRAUNSTEIN: Yes.

DR. SHAFER: Yet, here in the presence of aspirin to provide the safety, you are not seeing benefit.

DR. BRAUNSTEIN: I would argue that the mechanism for what we saw in VIGOR, which was a very early difference between the two treatment groups, is qualitatively very different than what we see in APPROVe. So the mechanism for the cardiovascular difference in the two studies is not necessarily the same and, therefore, whatever difference we are seeing here or not seeing with aspirin doesn't really relate to what we saw in VIGOR. I would also point out, as you have already pointed out, there are wide subgroups. I think Dr. Villalba has pointed out that when we looked at the APTC endpoint, which was just myocardial infarction, stroke and vascular death, the difference actually seems to go away but, again, there are very small numbers and we don't want to over-interpret at this point what the data say.

DR. WOOD: But the major point here, just to help you here, is that these people were not randomized to aspirin. So, people who were on aspirin were a different subset than the people who were not on aspirin in terms of cardiovascular risk and so on. So, it is not like naproxen.

DR. BRAUNSTEIN: Yes. Yes, of course. Sure.

DR. WOOD: The one thing I would say while you have that slide on there is that I think is going to be important for us is that our job is not to identify groups that are at particular risk, Richard. Our job I think is to see if we can identify patients who are at low risk--

DR. PLATT: Yes. DR. WOOD: I am not arguing with you. I am just making a generic point and it is not clear to me that there is such a group identified there.

DR. PLATT: Well, it seems to me that there will always be risk--

DR. WOOD: Right.

DR. PLATT: --the question is can we help inform decisions that patients have to make?

DR. WOOD: Dr. Cush?

DR. CUSH: Dr. Braunstein, a few times you mentioned that you made this decision based on the signal that you found in the alternatives existing, and not knowing if it is a class effect. If you knew that this was a class effect would you have made the same decision? And, knowing what your COX-2 potency is, does that factor into that?

DR. BRAUNSTEIN: I couldn't go back and speculate what decision we would have made based on a different set of data.

DR. WOOD: I think that is a fair answer. Let's move on to Dr. Cryer.

DR. CRYER: I would like to come back to a consideration of the potential gastrointestinal benefits of COX inhibitors and specifically Vioxx, and I am going to use your slide 33 to help me with my questions and comments.

You repeatedly made the point that Vioxx, rofecoxib, was unique in its labeling with respect to its gastrointestinal benefit and that was a label revision that was largely derived from a discussion of the data in the VIGOR trial in which naproxen was the comparator.

I want to underscore that the conclusions reached may be as much of a reflection of the comparator as they could be a reflection of properties intrinsic to the COX-2 specific inhibitor. As I look at the pooled analyses from the rofecoxib experience and specifically look at diclofenac, it does not appear that the difference in reduction compared to diclofenac is statistically significantly different.

So, the question that I have for you is do you think that the revisions in the label would have been the same with respect to the GI observations in VIGOR had diclofenac been the comparator rather than naproxen?

DR. BRAUNSTEIN: In an adequately powered study. I think the failure here in these confirmed events, in order to have the confidence interval narrow enough we would need enough power to do that. In fact, when we looked at investigator reports of these events, in all, including the unconfirmed, we did have statistical significance. So, I think that, yes, in an adequately powered study we would show a difference from diclofenac.

DR. WOOD: Bob?

DR. TEMPLE: Actually, I wanted to pursue something Dr. Shafer raised. The aspirin subgroup is a baseline subset. People are probably reasonably well randomized to whether they get--

DR. WOOD: They didn't get aspirin.

DR. TEMPLE: No, I know. They were different populations from people who were on aspirin but they are randomized to the two treatments, and there is about a thousand of them. From everything that I would have understood from Dr. FitzGerald's talk, when you are on both aspirin and rofecoxib you are not on a selective drug anymore, or probably not because you have plenty of COX-1 inhibition. But the hazard ratio there is higher than the other people. I wonder whether that is easily explained, or it could be explained by blood pressure effects which, of course, aspirin will not reverse. Because I think it needs some kind of explanation.

DR. WOOD: So, is that addressed to Garret?

DR. TEMPLE: Either.

DR. BRAUNSTEIN: With regard to aspirin data, they are not robust enough. We are talking about a total of 11 events, as I recall, in that analysis for the APTC. There are not a lot of events in that analysis.

DR. TEMPLE: There were 16.

DR. BRAUNSTEIN: Right, 16 events. There are very wide confidence intervals, as you know. So, I think it is difficult to draw specific conclusions about aspirin. With regard to blood pressure, as I indicated, when we looked at that the blood pressure changes that we observed would not appear to explain the magnitude of the cardiovascular findings that we observed in APPROVe. DR. TEMPLE: One of the reasons to worry is that people with underlying heart disease or diabetes are probably more sensitive to blood pressure effects. There is some evidence of that. Anyway, just a thought. DR. WOOD: Garret?

DR. FITZGERALD: I would just say one can over-parse extraordinarily small amounts of data in retrospect, and that there is enough flexibility in what one would expect to see to account for that. For example, we don't actually know if inhibition of COX-1 has no impact on the blood pressure response to a COX-2 inhibitor. In fact, from what I showed you in mice, one would anticipate if one actually designed a study to address that question that the answer would be yes. So, I think that, coupled with the fact that aspirin, even if one had loads of data, would be expected to modulate rather than abolish the hazard through this mechanism really means that it is not an answered question rather than an answered one.

DR. WOOD: Great! Well, let's stop at this point and break for lunch. We will restart at exactly one o'clock.

(Lunch recess.)

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see also:

Afternoon Proceedings Your Vioxx Lawyer - Vioxx, Celebrex & Bextra FDA Transcript - AFTERNOON PROCEEDINGS
Your Vioxx lawyer provides the complete transcript of the FDA meeting.

Valdecoxib and Naproxen The threat behind Valdecoxib and Naproxen - What Vioxx committee says
Valdecoxib and Naproxen can be potentially harmful in Vioxx - Read why

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