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

Your Bextra side effects lawyer provides you the complete transcript of the February 17^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 bextra information. To contact a Bextra Lawyer, click here for a FREE case evaluation.

Committee Discussion (continued)

DR. D'AGOSTINO: I want you to recall that the Framingham studies said just the opposite, it was the observational study that didn't agree.

DR. NISSEN: Thank you, Ralph, you are usually right.

DR. WOOD: You were down next to speak, Ralph, is that your question?

DR. D'AGOSTINO: Oh, is it my turn for my question?

DR. WOOD: Yes.

DR. D'AGOSTINO: When we have placebo-controlled trials, randomized controlled trials, I mean in some sense it is I think the gold standard, and when you have positive comparators, randomized controlled, it's the next level, I think that we have a lot of data that is well developed in terms of the studies.

We have questions about the dropout, and so forth, and I raised them also, but I think the randomized controlled trials have put us in the situation where we can minimized in some sense the observational studies.

Yesterday, I made my comment about torturing the data. We can torture the observational studies forever and ever, but I think our weight should shift on the placebo-controlled

So, a step up is the large-linked databases or the active surveillance systems, and I think this is what a lot of what we have been talking about with these observational studies. They give us numerators and denominators, they give us more complete ascertainment, but they still have unavailability often of confounder information on

aspirin use, smoking, outcome specificity and sensitivities are less reliable.

We have talked earlier today about how it is extremely difficult in that context to do a valid ITT type analysis and have a time zero cohort and minimize lost to follow-up, and ultimately, you are not randomizing, and randomizing doesn't solve all problems, but it does, in essence, eliminate the systematic occurrence of imbalance.

It doesn't eliminate randomly occurring imbalances until you have large numbers, but you cannot, with covariates, go back and adjust for what is different in an observational study, because I always say the known and recorded covariates are just the tip of the iceberg, so you are left with a great deal of uncertainty about bias.

Where they are very effective is understanding natural history, understanding event rates, understanding covariates, understanding how people are treated, but we really want to use them to understand causality, does intervention have an effect.

Essentially, if it is a very large effect, you can get some reasonable senses, but in most cases, I think they serve a very useful purpose, but it's hypothesis generation, it's development of clues.

So, if we look at the overview that David Graham gave, my sense is he was able to give us insights about a wide array of issues that we have not yet got adequate randomized trials, so specifically, the nonspecific NSAs, what does it look like there, and issues about dose, but I would call those hypothesis generation or clues.

I would be very reluctant for the majority of what we saw from those analyses to take those results as established. It rather gives us a guide because we can't do randomized trials in every setting. It gives us a guide for how to design those trials and where the most pressing questions are.

So, the observational studies go hand in hand, but the ultimate answers in most cases really come from the randomized trials.

DR. WOOD: Right, and the estrogen studies shouldn't be forgotten, right? Dr. Morris.

DR. MORRIS: I think Tom said a lot of what I wanted to say, but a lot better. In terms of causality assessment, living through what the Agency of Healthcare Policy and Research went through for outcomes, I think the conclusion is unless you randomize, you are never really sure.

In terms of observational studies, I think it is interesting that like event rates or something like that, where we think it is so much better, yet, I was struck in the discussion today of some of these drugs is how much the event rates varied by center or study or country. What isn't done in observational studies, what could be done, is more of a population-based sampling, so we have a better understanding of how much or how well that particular database is representative of the broader population of the U.S., so we can do some kind of sampling or extrapolation and get much better event rates, where I think observational studies can really do a much better job than clinical trials because they can measure naturally occurring events much better.

DR. WOOD: Dr. Domanski.

DR. DOMANSKI: You know, one always hates to admit ignorance, but I want to pursue this business of a wild arm. I mean I have seen some pretty wild arms in clinical trials, but never as a third one.

I don't understand where that is, I have not heard of that one, and I would like to learn more about it. Can you explain that?

DR. PAGANINI: I will give you an example of an NIH-VA study that is now ongoing looking at dose of dialysis delivered in which there is a high dose delivered and then there is a low dose delivered. Then, there is the thought process of putting a third arm on there is what is everybody delivering anyway, so it is whatever the wild type is, to see if, in fact, people are artificially placed into one dose versus a second dose, and that, in and of itself, is an artificial placement of patients as opposed to what people usually do.

So, therefore, what is the comparison between one dose versus a second dose versus what is usually and customarily done.

DR. DOMANSKI: But don't you usually use a registry for that kind of question, that is, how well does it represent practice I guess?

DR. PAGANINI: It could be retrospective, but in effect now what they are doing is a prospective collection of data of what is normally done in that particular institution when people are off study.

DR. DOMANSKI: Again, registries can be prospective, of course. I am having trouble seeing the difference. I mean are those people randomized, as well?

DR. PAGANINI: No.

DR. DOMANSKI: Okay, so it's a registry.

DR. PAGANINI: It's just a registry.

DR. WOOD: Dr. Hennekens.

DR. HENNEKENS: I would view the strengths and limitations of observational studies to be a function of the effect size. For the moderate to large effects, we can make safe clinical and policy decisions based on consistency of the data from the observational studies.

As the effect sizes get smaller, however, it's a two-fold problem because now the effect sizes we are seeking are as big as the amount of uncontrolled and uncontrollable confounding that is inherent in the designs.

There is a certain seduction from these large-scale databases because you have a large number of data you control confounding on, you could get very robust p values, so you begin to believe that you have really discovered something, but I agree strongly with Tom that for small to moderate effects, they are useful to formulate, not test, hypotheses, so what Dr. Graham told us this morning are useful to formulate hypotheses.

If people took them as serious evidence that this indicated harm, he might be right, but it would have nothing to do with the data that we have seen. I conclude with the statement, I have the privilege to know Sir Austin Bradford Hill who, on this question, and I think Rich would agree with this, he said, "Don't let the glitter of the tea table detract from the quality of the fare."

DR. WOOD: Dr. Elashoff. DR. ELASHOFF: Two comments. One, in this situation, especially when there is very specific evidence that the relative risk may vary over time, looking at the standard way that observational studies lump it all into patient years is bound to be misleading.

A second point has to do with the fact that in a randomized trial, when you are comparing events, the analysis per se tends to be pretty transparent, but in an observational study, in order to understand it in detail, there are many covariates, pretty fancy footwork in the statistical realm, and it may not be very easy to tell exactly what was done or to think of reproducing it.

So, the observational study tends to be a lot less transparent in terms of the way it has been analyzed.

DR. WOOD: Dr. Friedman.

DR. FRIEDMAN: Two points. One, if I can follow up a little bit on this wild arm, if you will. As Dr. Wood knows well, this whole issue came up, to my dismay, if you will, about a year ago when we were dealing with the ARDSNet issue, and I think the general conclusion there was that it, in general, is not a very good way of answering a specific question. It might contribute in some fashion, but in general, it is not all that helpful. Second, I am looking at the specific question here, and it says discuss the role of observational studies in informing regulatory decisions about postmarketing safety. It seems to me that one of the things we might do is suggest ways that the FDA can improve some of the postmarketing surveillance issues.

For example, we have talked about all of the difficulties in using observational studies, and I don't disagree at all with any of them, but if some of them are planned ahead of time, with good ways of collecting data in consistent ways, we won't completely eliminate all of the problems, but we can reduce them, and I think we ought to at least consider that approach.

DR. WOOD: Dr. Platt, last comment on this.

DR. PLATT: To emphasize that point, taking everyone's thoughtful comments into account, it seems to me we have to be careful not to let the best be the enemy of the very good. I think that Tom Fleming's reference to the CDC's large databank for vaccines is quite on point. It seems to me that there is every reason for FDA to require, as part of the approval process, that there be a substantial and organized observational set of studies that give at least a sense that generates hypotheses that would allow us to recognize the possibility that there is a signal of events that never be seen in clinical trials, events on the order of 1 or 2 or 3 per 1,000.

It is possible to do that with what in the scheme of these discussions we are having would be a relative small investment, and we wouldn't have to rely on the occasional observational trial or the clinical trial that shows up to start a discussion like this.

It seems to me that that is a very easy, relatively small step for CDC to take, to have every manufacturer of a new drug commit to doing a reasonable observational study.

DR. WOOD: But, Richard, isn't that the problem that Tom highlighted ages ago, that that sort of registry approach will pick up events that are relatively rare in the background, like devastating encephalitis or something like that relatively easily.

But where you have got a background noise that is as high as MI, it is going to be extraordinarily difficult to pick that up from that kind of study.

DR. PLATT: Well, in the vaccine field, the large-linked database has been extraordinarily useful for things like febrile seizures after a DPT immunization, and that is a relatively common event. So, I don't take the point that you can't make reasonable observations about even relatively common events.

DR. WOOD: Bob, do you agree?

DR. TEMPLE: Well, just to make the same distinction you were making. You can look for introsusception or something that basically is very unusual, but how to find an increase in the rate in the rate of MIs requires a structured study and a plan to do it, and you sort of have to have a hypothesis or you don't know what to look for.

It is totally different from liver, you know, from gross hepatotoxicity, which comes in

through the AERS pretty well actually, maybe you could stimulate those, but it is totally different when you are looking at a change in something that has a high background rate.

DR. PLATT: The fact that it's challenging doesn't mean that you can't learn something useful, and it is pretty clear from the observational studies we have that we can learn something useful about that.

DR. TEMPLE: I was reacting to what you said, should we have the capacity or have the ability to get people to do studies once something emerges or once a question arises, or once you know something about the drug class, I am not challenging that at all, that's fine, but to have it in place as a mechanism for sort of automatically putting stuff up, I guess I don't know what that mechanism is.

There has been talk about encouraging places to report, and we have an arrangement with some liver centers, and those things are fine. Those might be ways to find hepatotoxins maybe faster than we do now, but that still doesn't answer the question of a change in the rate of a common event, which is a fundamentally different problem, requires a study, not a report.

DR. PLATT: Well, the model of the large-linked databases I think gets around the idea of having to have active reporting. I think that there is a lot of ability to capture the outcomes that are of interest.

Obviously, you don't look for every outcome for every drug, but you can make up the list of things that you care about for certain classes of drugs, and it is possible to use automated systems to take you a long part of the way in understanding whether there is a problem that needs serious analysis. DR. TEMPLE: Can I propose an alternative? I think what you are really saying is the thing you are worried about with drugs, where there is a high background rate of something, is always cardiovascular outcomes. So, I think what you are saying is you might want to look for any chronically used drug at cardiovascular outcomes, and that you could probably put in place.

DR. WOOD: Wait a minute. Are you suggesting that we insist on a cardiovascular study for every drug that we get approved? I mean that would make it prohibitive to approve any drug.

DR. TEMPLE: No, no. We used to fund more of them than we do now, that's a problem that other people will discuss, and certainly I won't, but we have access to databases, whether it's California Medicaid or whatever, and one can do that. It doesn't seem inconceivable to me--and I am talking about something that other people know more about than I do, so I should probably shut up, but I won't--I can imagine that a couple of years into the approval of a drug that is widely used, you could ask the question at certain sites, can we see an increase in cardiovascular risk.

I am not sure how many other high background events it is that are common in the population that we are really that worried about. Maybe that is something that we could think about.

DR. WOOD: So, if we could just sum up where we are, what the committee is saying, I think, is that we are impressed as the primary data source, and that the primary data source should be randomized and controlled trials, and observational studies may be good for hypothesis generation, and I guess the third point is that the AERS database is of almost no value in detecting adverse events that are common in the background in a situation.

Is that sort of fair for what we have sort of got out of this? Do people disagree with that? Yes, Dr. Farrar.

DR. FARRAR: There is one specific point to this question, which is that all of the non-experimental studies that have been presented here, I would certainly suggest, and I would hope people would agree, are hypothesis generating at best. Every single one of them is confounded by indication.

The best example is the indomethacin one where it is only used in people who are sicker than people who aren't. So, I think there are clearly examples. What I was hearing before was a discussion about what we might do, and I just wanted to be clear that what we might do is very different than what we have right now.

DR. WOOD: You put it much better than I did. That is what I was trying to say.

Yes, Dr. Jenkins.

DR. JENKINS: I found this discussion to be very interesting because I think you all know there has been a lot of Monday morning quarterbacking about what FDA has or has not done in this class, and a lot of that has been based on observational study results, many of which fall into the range of what we have been calling small to moderate, I think, at best.

I don't think we need to revisit that here, but I think the questions we have going

forward, first of all, we have to look at the data set we have today, and you have to look at the data set you have tomorrow on answering the questions about what do we do now, and observational studies are part of that data set. We have controlled trials that are part of that data set also.

I think we are also interested in hearing your thoughts on going forward. I suspect that this going to be a mining exercise for everyone who does observational studies in the world probably. They are going to be looking to do another COX-2 or another NSAID observational study.

We are going to see more and more studies published, and as I think someone said, it often becomes attractive to say, "Oh, look at that, you have got a very small p value, yeah, the relative risk is only 20 or 30 percent or 40 percent, the p

value is very small, the study was very large, FDA, you should take regulatory action, you should take this drug off the market, you should restrict its use, whatever."

You are telling us you view them primarily as hypothesis-generating, and that they should lead to controlled clinical trials. The reality is even if we have the authority that we might like to mandate those trials, it is going to take years to get those controlled clinical trial data, and there is the pressure between people wanting you to act based on the observational data versus the scientific desire to wait until you get better controlled clinical trials.

I would be interested in having the committee say a little bit more of your thoughts about, you know, what do we do in the future in this class when we get the next observational study that is touted as wow, this really shows something, FDA, you should take action.

DR. NISSEN: Can I suggest some courses of action? One of them is that as people have pointed out, the strength of the association, I mean the hazard ratio is really important, and if somebody comes up with something which suggests 2 or 3, that is very different from a 1.3.

The other obviously is to have a rigorous process for looking at the quality of it. One of the things I have learned from several of you is that there is observational studies and then there is observational studies, and some of them are done very well, and some of them are not done so well.

The FDA has the expertise to evaluate that. Now, the problem is, of course, if it gets into the political arena, you get a lot of political pressure, but what we would want you to do in the public interest is look at the strength of association, look at the quality of the study, and make a decision on whether there is enough there to put a warning out. We have seen some strange things go on, like the warning around naproxen, that was clearly based upon pretty weak evidence. So, I think having a good standard is where you have to kind of hold your ground.

DR. WOOD: The other thing, in response to your question, is if we walk through the scenario here, the first signal was from a randomized clinical trial, and the question I guess then is what would we need to strengthen that observation because it wasn't against placebo and all the problems there were with it.

It would seem to me that we don't need is a bunch of observational trials. That hardly is going to convince anyone, it seems to me. What we do need is an appropriately powered randomized trial that looks at the issue directly, and I am not so sure how long that would necessarily take.

It only took 2 1/2 thousand people and approved to get the data. The question to which we don't know the answer, in fairness, is would it have taken less time if we had done a larger study, and I don't know the answer to that, no one knows the answer to that, but it is certainly potentially possible that we could have gotten the data quicker if we had done a larger study and the effect appeared faster.

We don't know the answer to that, but that is one approach. I guess, responding to your question, it certainly seems to be in the public interest that you should have the power to ensure that that kind of a study gets done, and that is something certainly people should hear and hear loudly, I think.

DR. O'NEIL: Could I say something relative to a point that Janet Elashoff had brought up? The general process for the review of randomized controlled trials, such as the ones we have been reviewing, is we have the data in, there has been a strong movement for prospective specification of events, even blind adjudication, we look at the protocol very seriously. We actually have the data in hand. We actually can re-analyze, regroup, adjust, stratify, do many things.

We are normally not in a position to do that on observational studies. We don't have the same level of process review for ran observational study. In fact, it is not even clear what the prespecified hypotheses were, even if you wanted to say the best that the observational study could do is to generate a hypothesis. However, there are many of them that have confirmed important things for us, the last of which was a protocol that we played a heavy role in, and that was propanolamine and its association with CVAs.

That was a five- or six-year prospective case-controlled study that was done, that we reviewed the protocol. We had a heavy hand. In fact, David had a heavy hand in how that was designed, and that turned out to essentially support a regulatory conclusion.

The point I am making here is that if we do open the door for observational studies, we have to have a different way of actually having access to the data, the quality of the data, and give it the same level of attention that we do in the review of randomized trials but for the fact that it's not randomized.

Right now that is not in place, so we are talking about trials being balanced against observational studies where the standards for the trials are dramatically higher than the standards for the observational studies, not that they couldn't be better balanced, but I think that is an important issue.

There has been a society, ISPE, the International Society for Pharmaco-Epidemiology has tried to put good principles in place to sort of say these are how you would do these studies, but we really don't have a process that would require that along the same ways that we would in these IND type studies or the larger randomized trials that we are seeing for the safety.

DR. WOOD: Tom.

DR. FLEMING: Just to reinforce some comments that Bob was just making, and Larry Friedman was making earlier, and Steve Nissen, as well. Not all studies are the same, we know that is true of randomized trials in terms of their quality, it is certainly true in observational studies.

Stuart Pocock more than 20 years ago put forward criteria for what you would want to do if you were doing an observational study that would be as reliable as possible.

Essentially, it is just like a randomized trial, it is very complicated and takes considerable effort to ensure that you are putting in the structures. You can then have the sensitivity and specificity issues assessed or addressed by independent committees. You can do your best to try to define time zero cohorts.

You still don't have randomization, though, and ultimately, the level of reliability is increased, but it still doesn't match the reliability of a randomized trial, as Charlie Hennekens was saying, until you are persuaded that the signal exceeds the potential magnitude of the bias, you can't be confident that the result is reliable.

So often what we are looking at are effect sizes that aren't, in fact, larger than the magnitude of the bias, so that leads us down the pathway of needing randomized trials.

John, getting back to your point, if you have a profoundly low p value, this may be obvious, but it doesn't mean we know the truth. There are two fundamental aspects around the truth. One is variability and one is bias, and I can have 100 trials put together and give me a highly precise estimate. I mentioned yesterday, you just end up with a precisely biased estimate, and that is my concern in the absence of randomized trials.

I believe these are very useful clues, we need these results, but just because you have profoundly low p value doesn't mean we got at the truth.

DR. WOOD: That is what happened with the estrogen studies, of course.

DR. HOLMBOE: I just want to make one point because we keep hearing about the estrogen study. There is one very important fundamental difference here. Estrogen had been posited to have a positive effect on cardiovascular mortality in observational trials, so it made a lot of sense to use randomized controlled trials to prove that hypothesis.

The hypothesis here is that COX-2 inhibitors are harmful, therefore, you are doing a randomized controlled trial that in investigating harm, not benefit, and I think we have to keep that in mind.

DR. WOOD: Good point.

Now, we are going to move on, Steve, to the next question. The next question is discuss the available data regarding the potential benefits of COX-2 selective nonsteroidals versus non-selected nonsteroidals, whatever they are, and how any such benefits should be weighed in assessing the potential benefits versus the potential risks of COX-2 selective agents from a regulatory perspective. DR. JENKINS: Dr. Wood, could I make a comment about that as you get started about this particular discussion point? We put this in here for a reason, because clearly, we didn't want a three-day meeting to just focus entirely on risk, because the decisions you need to give us advice on have to be balancing risk and benefit.

I think here we are particularly interested in hearing your views about benefit in a wide range of categories.

You know, this class of drugs was developed for the GI effect, so we are interested in hearing your conclusions about the benefit of these drugs on the GI toxicity, but there is also other areas. Any input you have on their efficacy for pain relief for the treatment of inflammatory conditions will be useful.

I am also interested in hearing your comments about the value of choice. We heard that from some of the people in the public hearing today, that, you know, don't limit my choices, and we hear that a lot from physicians, we hear that a lot from patients, but we often are also hearing a competing view that if you have got one that looks like it is safer than the others, then, you don't need the others, but that is at odds with the idea that people like to have choice, because people don't respond the same to every drug, they may be allergic to one drug or whatever.

So, in this context of benefit, I would like you to cover a lot of different areas, and not just to gastrointestinal benefit, but that is clearly one of the major focuses of benefit here.

DR. WOOD: Okay. Dr. Nissen.

DR. NISSEN: A couple of things. One is I haven't seen any compelling evidence that in terms of pain relief, that the drugs are actually more effective, and if such data is available, I would love to see it, but I don't find it there, so I think that is a little easier for me. I don't think we can minimize the importance of the GI aspect. There is actually two things, one of which was talked about interestingly by the public, but not necessarily by us or the companies, and that is, you know, patient quality of life and patient preference.

Any of us, I have certainly taken NSAIDs and gotten gastritis from them, and it is not fun, you know, having your stomachache, and people who have that every day, you know, there is a suffering related to that, that we heard from the public, and that has to be taken into account as we think about these drugs.

In addition, I would be the first to say that a GI bleed is not a benign event. If these drugs were drugs that were better for treating acne, and they caused cardiovascular harm, that would be one thing, but the events, the GI events always'>

507 here are serious events.

They are not as life-threatening as a stroke or a heart attack, but they can be, and they don't produce the permanent disability that a stroke or an MI does. You know, I take care of people with heart failure, and if you have had a big MI, and your pump doesn't work, your life is changed, the rest of your life is going to be different.

Most people with a GI bleed recover, and so as I weigh these events, I don't discount GI benefits, but I have to give them less credence than the kind of hard, permanently disabling effects of MI and stroke, and I also think we absolutely have to factor in here the sort of suffering of patients who just don't tolerate the conventional NSAIDs, and I think that compassion has to come into our decisions.

DR. WOOD: Dr. Fleming.

DR. FLEMING: A great deal of the focus on the data we have had presented to us relates to the cardiovascular risks and relates to the confirmed complicated upper GI events, so if I start by focusing on that, it looks as though in a crude estimate that we might be having the rate of these events using the COX-2 inhibitors rather than the non-selective NSAIDs.

It looks as though that might be, in 1,000 people, preventing 5, 6, 7, 8 events, something on that order. If we took a relative risk of 1.4 as the relative risk for the increase in cardiovascular events, that would be about 4 events.

So, coming back to what Steve is saying, when you look at it in that context, yes, these ulcerations are important events, but 7 per 1,000, how is that up against 4 events that are strokes, MIs, or cardiovascular deaths, I don't think it adds up.

If that is the whole picture, I would have a concern, but in a number of settings, it isn't the whole picture. We have heard about the oncology setting. We have talked about, truly, we haven't talked about efficacy. We have only had a number of comments stated that the pain relief seems to be about the same.

Well, if it is the same, then that balance that I was saying concerns me as not being a favorable balance, but we heard a lot of people testifying, and I will be the first to say open sessions at these meetings are not random samples of the entire public, but we still heard a lot of comments that reflected the fact that there seems to be some differential protection or pain relief in certain patients.

Can we quantitate that? Can we, in fact, more scientifically, rigorously establish certain subpopulations where there really is a differential relief? Then, the benefit to risk shifts, or in the oncology setting, the benefit to risk shifts.

The bottom line here, though, is to me the issue isn't so simple as choices. The issue is informed choices, and it takes the kind of scientific studies to reliably identify what are the true benefits and risks, so that patients are in a position to make an informed choice, and part of the challenge to this, as one of the speakers at the public session pointed out, is it is not always the case that what might be learned by those people doing the studies is being effectively transmitted to the bedside or to the patients and their caregivers, and that is the other aspect, as well.

So, it is critical to follow a strategy here that allows us to reliably address benefit to risk and allow patients to make an informed choice.

DR. WOOD: Dr. Hoffman.

DR. HOFFMAN: I think for the last two days we have been hearing appropriate angst about damning a class of agents for which there is a measure of efficacy, both in regards to pain and GI events because of newly-discovered adverse events, but I feel like we are walking on eggs in trying to get away from a consistent observation that is the dose-response effects, relative risks that we are looking at in terms of cardiovascular endpoints.

We have heard this from experts at the FDA, independent investigators. We have even heard it from the thought leaders of industry, there seems to be a consensus to the effect that there is a class effect.

I do take Steve Abramson's point that all of these drugs are not pure in their effects in terms of COX-1 or COX-2, but this is the data that we have, and it seems like there is a consensus about a class effect, and there also is a consensus in acknowledging that the patients that we enter into randomized controlled studies are probably the people least at risk that we may not see in our practices, who come in with 3 or 4 comorbidities that may have excluded them from being in this trial and actually having seen even a clear signal.

The data, of course, that we would like to have is something that we don't have, and that is, the old standards of treatment for pain, whether it's the arthritis pain of OA/RA or postoperative pain, with NSAIDs plus PPIs over a long, extended period of time.

We would all like to know the data for that over 2 or 3 years compared to the COX-2s, which I don't think any of us are saying should, as a class, be taken off the market, but certainly should be used at the lowest safest dose.

Now, at the lowest safest dose we don't even know their efficacy qualities. We don't know whether at the lowest safest dose we have the same benefits in terms of preventing peptic ulcer disease, treating pain effectively, decreasing inflammation effectively, and that it seems is the data that we need to have.

I am a little concerned, as a footnote to that, about the issue of choice. I think it is our obligation to provide patients choice within the realm of relatively safe medications, but most of us would not give as a choice a narcotic analgesic to a patient with, say, fibromyalgia.

I don't think we should keep drugs on the market because of public pressure if we have a signal that we feel is a very strong one. We shouldn't give people a choice if we think that choice is uninformed and potentially does harm.

Now, I am not saying that for the class of COX-2 inhibitors, I am just saying that we need more data to be able to provide for ourselves adequate information to make that choice and give our patients informed choice.

DR. WOOD: Dr. Cryer.

DR. CRYER: We were asked to kind more widely consider the potential benefits. As I see it clearly, one of the benefits is GI, and I will comment on it, but I do want to reiterate some of the comments that I personally don't see the benefit with respect to efficacy.

I think the clinical trial experience to date has pretty consistently indicated that the efficacy is similar to the traditional NSAIDs. We did see some provocative data with etoricoxib today suggesting greater efficacy in one trial than naproxen, but that wasn't replicated.

So, overall, I have to think that the efficacy is the same as we have with the traditional NSAIDs. I appreciated the testimonials of the patients about their individual efficacy responses, but my conclusion about that is those are anecdotes and it is consistent with the clinical experience that we have with efficacy of NSAIDs, which is that there is variable and idiosyncratic, unpredictable responses between patients, and it is very common that you will have one patient who responds to one NSAID and does not respond to another.

I do think that we would still be giving these patients a wide range of choices given that there are 20 other NSAIDs available in the U.S. among which they can choose.

The benefits clearly I think are in the GI tract, but I will say that my conclusion is that the GI benefits are less than previously speculated.

If you look at the three outcome trials which we have, that looked at GI benefits, we have VIGOR, CLASS, and TARGET. The results in the VIGOR are clear, but I think that was clearly also of a manifestation of the comparator, and one of the things that I would like to be remembered is that the comparator NSAID matters.

One sees a greater degree of GI benefit when one compares against naproxen than when one compares against diclofenac, so I do think there is value from the CLASS trial. I know that there was a GI benefit shown against ibuprofen.

In the TARGET trial, those GI estimates are overestimated primarily because they enroll a low risk group of individuals and in a lower risk. We have consistently seen in trials that when you have low risk GI group, the relative risk is higher although the absolute risk in a low risk population is very low.

So, the benefit is going to depend on the comparator. It is probably less than the 50 percent that you suggested it to be, because that 50 percent is based upon the VIGOR trial. It is probably closer to maybe a 30 percent benefit that I would estimate.

It also narrows when you consider low dose aspirin. In the face of low-dose aspirin, there is no apparent GI benefit. So, I think we also need to modify our estimates based upon the population that would be using or not using low-dose aspirin.

So, my conclusion about the GI events is that, yes, there is a benefit, it is not as large as we thought, the appropriate target population is smaller with respect to the target group. It could be low risk people not taking low dose aspirin, but this event doesn't happen very commonly in low risk, and when you look at the high risk people in whom these drugs were originally targeted, several data sets suggest that the high risk people do not, in fact, have any appreciable benefit of GI risk reduction from a COX-2 specific inhibitor.

Final comments about other areas of benefit. Dyspepsia isn't one that is very convincing. When you look at the dyspepsia data from the clinical trial experience, it is only a few percentage points reduced. Dyspepsia, I consider mostly a nuisance symptom for which we have other very safe therapies to effectively deal with this.

Finally, from the GI perspective, the polyp story could be another potential benefit, but with regard to the polyps, we have to remember in every trial we have seen, we are only modestly reducing the polyps and ultimately, we don't reduce cancer risk unless we eliminate adenomatous polyps, so it doesn't really change our algorithm in terms of how we would manage these patients, which would be colonoscopy and polypectomy.

DR. WOOD: Before you finish that, there are only two drugs on the U.S. market now, celecoxib and valdecoxib, so let's review the upper GI safety for them first.

Is there a study that you are aware of with valdecoxib looking at complicated ulcers that showed in randomized fashion that there was a safety signal?

DR. CRYER: No. Wait, what do you mean by safety signal?

DR. WOOD: GI benefit. Is there a VIGOR trial for valdecoxib?

DR. CRYER: No.

DR. WOOD: So, confining our discussion to the two drugs that are on the U.S. market, there is no VIGOR equivalent, if you will, in valdecoxib, right?

DR. CRYER: Correct.

DR. WOOD: Now, for the other drug that is on the U.S. market, celecoxib, the published study didn't show the full data set. For the full data set for that, there wasn't benefit either.

DR. CRYER: Correct, but we did have the benefit of--

DR. WOOD: I understand, but there is always a benefit--I mean there is mortality problems halfway through, too, that disappear, that we ignore when we get to the end of the trial.

So, for the two drugs that are on the U.S. market now, we have no clear randomized data that show GI benefit given the endpoints that were predefined and the end of the trial, not the trial that was published without the complete data set.

The TARGET trial looks at a drug that is not on the U.S. market. So, our job is to evaluate the two drugs that are on the U.S. market, it seems to me.

DR. CRYER: So, I agree with your comments about the fully published results in JAMA for the class, however, we did have the benefit of reviewing the full class results in the FDA hearing four years ago, and it is based upon that evaluation that I am deriving my conclusions of the full data set in which there did appear to be a demonstrable GI benefit when compare to ibuprofen in people who were not taking aspirin, certainly not when compared to diclofenac.

DR. WOOD: But the trial was not--that was a subsequent analysis taking out the aspirin. That wasn't the predefined endpoint.

DR. CRYER: Point well taken.

DR. WOOD: So, I mean just summarizing the point again, we have a benefit in a trial for a drug that is not on the U.S market, but we are not prepared to extend a class effect to cardiovascular risk necessarily, so I don't think we can just sort of step back and say that we are going to give a class benefit to GI benefit either extrapolating from studies of drugs that are not on the U.S. market.

DR. CRYER: Just because they are not on the U.S. market does not reduce the validity of the observation, for example, with lumiracoxib, and just because this was not absolutely predefined, and the benefit was recognized in, let's say, a post-hoc perspective, I still think there is recognized benefit in the data that we see in terms of assessing the GI benefits of celecoxib versus ibuprofen, and lumiracoxib versus its comparators.

DR. WOOD: But the non-aspirin group also had a cardiovascular risk, right? DR. CRYER: Absolutely.

DR. WOOD: I mean as we are doing Tom's sort of analysis, when we take out that aspirin group and say, wow, there is a GI benefit there, when we take out that aspirin group we find there is a cardiovascular risk. So, you know, we can't have it both ways.

DR. CRYER: Well, I would say that the cardiovascular risks extend to both groups, aspirin and non-aspirin.

DR. WOOD: Right, but it was clear in--okay, Dr. Fleming.

DR. FLEMING: Just to pursue a bit further, Alastair, what Byron is saying, there are two aspects that I hear you saying that are really critical to the comments that I had made earlier.

One is that I might be overestimating the actual GI benefit when I say you are having maybe it's a 30 percent.

DR. CRYER: It depends on the comparator.

DR. FLEMING: But the other, even more important thing to me that you are saying is that in spite of what might appear in the open session, which we know is anecdotal, the scientific data you are saying repeatedly are showing in the RA, OA, CABG settings where we have done studies, that there is not a difference in the pain relief and the efficacy.

I would like to get more sense about that. If that is even close to true, then, there should be an incredibly low threshold for what you would accept in additional cardiovascular events, because the only thing you are getting relative to nonspecific NSAIDs then would be a very small GI.

So, it seems like the efficacy here about the pain relief is a key issue.

DR. WOOD: I think the company wants to say something.

DR. KIM: Mr. Chairman, if I could, I will just make a comment, please. As I said yesterday, at the time that Merck withdrew Vioxx from the market, we based that decision on the available data that was available to us at that time, and we also stated that we thought that it would be possible to continue to market Vioxx with a labeling change that incorporated the results of the APPROVe trial.

But we decided and we concluded that the most responsible course of action to take, given the information that we had at that time, and the availability of alternative therapies, was to voluntarily withdraw the drug from the market. We have heard over the past two days new data and we have seen in the New England Journal new data on some of these alternative therapies. Merck's interpretation, as you have heard, of these data are that we are dealing with a class effect, and the major question on the table right now is how large is that class.

We are a data-driven company. If this committee and the FDA agree that what we are dealing with here is a class effect, then, I think it would be important for us to take the implications of that conclusion into consideration with regard to Vioxx, particularly given the unique benefits that Vioxx provides, one of which you are alluding to.

So, I just wanted to make that point.

DR. WOOD: So, just to understand, what you are saying is that if we think the cardiovascular effect is a class effect, you would consider putting Vioxx back on the market.

DR. KIM: What I am saying is that at the time we withdrew the drug from the market, we did so because of the availability of alternative therapies and the science that was available at the time. That science has progressed. We are now engaged in a discussion around that science.

There are unique benefits to Vioxx, one of which is it is the only COX-2 inhibitor with proven reductions in gastrointestinal events, another one of which it is the only coxib which is not contraindicated for patients with allergies to sulfonamides, and the third is that we have heard numerous reports, and you have heard a few today, from patients, including patients with chronic debilitating pain that Vioxx was the only drug that relieved that pain.

DR. WOOD: Okay, good.

Dr. Farrar.

DR. FARRAR: I wonder if I could just be very clear that so far I don't think we have talked about benefits. The point I want to make is that what we are talking about with the GI, quote "benefit" is, in fact, a reduction of risk. No one that I know of takes coxibs of any kind for an upset stomach.

I think what we need to do is focus on the benefit to the patients, and we heard some of that in the public forum today, and I want to be as clear as possible about the issue of that benefit.

There are two ways of measuring benefit, and, in fact, in outcome trials, there really are only two summary statistics that are possible. One is a mean or a median or some central tendency with a spread, standard deviation.

The second is a proportion, and it is a proportion of responders, it a proportion of people who die, which is the easiest, and in pain management, we get into all kinds of arguments about how much improvement you have to have to be a responder.

If you look at the data, we are used in most of our clinical trials to looking at means and standard deviations, and if you look at means and standard deviations, it is very hard to find a difference between any of the NSAIDs and acetaminophen, any of them.

If you ask patients about what works for them, in clinical practice, every patient will tell you that one works and that one doesn't. "I get sick with that one, I don't get sick with the other one."

That is not something that we measure typically in our clinical trials. If you look at what level of drug is effective, with almost any NSAID, it is never, it is never above 50 percent in terms of patients who actually go on using the drug in a chronic process.

What we are talking about is trying to identify less than 50 percent of a population who respond to a drug, and I can tell you from clinical practice, as any of you who have taken patients with rheumatoid arthritis know, people like specific drugs because they don't cause side effects and because they do have an effect.

I think choice actually is a very important issue. Granted, we don't want to provide choice if there is an absolutely huge risk associated with that choice, but I think it is really important to understand that pain kills in the same way that the drug potentially can kill.

I think it is very important to understand those two principles, the principles of the difference between a proportion and a mean value. Now, I am obviously talking to the converted here, but I think the issue really is looking at those issues.

We don't have any good trials, any that look at switching behavior within our patient populations, so there is no data that I know of that will help inform us about the need to and exactly how to go about this process, but I do know that in spite of all of our understanding of what goes on with the COX-1/COX-2 pathways and the inflammatory pathway, that when it gets down to using it in the patient, the issue is, is it absorbed, does it cause local effects, does it get to the active site, once it's at the active site, are there enough receptors for it to then cause the effect that we are looking for, a whole host of factors that we really can't measure and haven't measured yet in terms of metabolic process.

My honest sense from the data that we have heard here is that the drugs that we are considering today, the two, perhaps three, has to do with the relative benefit of those drugs.

What is very clear is that there are people, and a large portion of people, who have trouble with the current list of what we call non-selective COX inhibitors, and that there is a very important role for the more selective COX-2 group, however we want to define that.

I think it is also, however, very important to understand that not everybody should be on a COX-2 predominant agent, and one of the problems that we are struggling with right now is the fact that because they were marketed as being safer, there was a very large push to switch people over who may not have needed to be switched.

So, I think that the issues that we need to consider are there is very good data that these drugs are effective at least in some segment of the patients in whom they are tried.

There is I think reasonable data to suggest that the potential risks is not clearly very different between them, at least not the data that we have to date, and that from that perspective it is going to be important that we carefully think about how we then go about controlling those drugs.

I would end with just saying that I agree absolutely it is about informed choice, and that I think that there needs to be a fairly large amount of information in the label and information conveyed to patients and physicians to help them make those choices.

DR. WOOD: Dr. Gibofsky.

DR. GIBOFSKY: I am particularly pleased about the nature of the conversation because as a student of medical history, it reminds me that the first treatment we had for arthritis was, of course, willow bark, and we told our patients to ingest willow bark in order to get salicylates, which, of course, have an anti-inflammatory effect. So, if only our patients could take aspirin, perhaps we wouldn't need the whole class of non-selective and selective COX-2s, but, of course, they can't. There are problems just with aspirin in the treatment of arthritis at the doses they need it.

I am intrigued by the comments that, well, you know, an MI is an MI and you are dead, but a GI bleed, you get up, you get over it with no long lasting effect, and that may be true for the people who survive, but as Dr. Cryer showed us yesterday, and the best data set we have from Dr. Singh, 16 percent of patients who have a GI bleed die, so for them, it's a fatal event and one that they are not going to get up and continue on.

I don't want to get into a discussion of the GI benefit and whether, in fact, it was achieved with one agent versus another, but what is clear is something that hasn't been remarked yet, and that is for patients going to surgery, who are going to require anticoagulation following their surgery, and that is particularly in large part patients who have arthritis and are undergoing joint replacement surgery, the risk of a traditional nonsteroidal with an anticoagulant appears to be far worse in terms of bleeding later on than the risk of being on a COX-2 because of the lack of platelet inhibition.

So, certainly there is a benefit for patients in that group who are going to go to surgery and require concurrent anticoagulant.

With regard to the issue of patient choice, there is several sets of data--and we heard one--showing that when you give a patient two different medications, in one study, the ACDA study, looked at acetaminophen versus diclofenac, another one, the PACES study, looked at celecoxib versus acetaminophen, and you asked patients without knowing which drug they were getting, in which arm, patients expressed a preference for either diclofenac or celecoxib over acetaminophen in the treatment of their arthritis.

The other issue with regard to choice is that we have also recognized, even in the pre-COX-2 days, that not infrequently, patients develop what is called a tolerance to the agent that they were on, that the latest data set we had suggested that inside of 18 months, patient who were taking medication for their arthritis chronically had to be rotated among agents three to four times in that period of time. So, the necessity for multiple agents in our armamentarium, the necessity for agents that allows for this individual idiosyncrasy that we have heard of is quite important.

As was alluded to, there can be two patients in the waiting room on the same drug, one will swear by it, one will swear at it, and so it is for that reason that we need to have, not just one agent in a class, whatever we define that class to be, but sometimes several. Sometimes they are agents of allergy or idiosyncrasy which necessitate having more than one agent available.

I think it is for all those reasons that we have to consider that in the benefit part as long as we are discussing benefit in the last part of the day.

DR. WOOD: I think we have to be really careful accepting this data, this 15-year-old data from Dr. Freis. I mean he has published, he published multiple updates on that, and people keep showing that same data, and that data isn't what is in his latest revision.

DR. GIBOFSKY: Accepted. Dr. Cryer?

DR. CRYER: I would like to comment on that, and I think your point is well taken. While I showed the 16,500 data yesterday, at the same time I said that that estimate, based upon more recent evaluations, is probably an overstatement of the actual mortality risk, GI risk attributable to NSAIDs.

Dr. Singh has showed me more recent data which he has conducted in the U.S., which has shown that the risk has dramatically decreased in the U.S. That is probably related to several factors included in which is the eradication of HP, the introduction of PPIs into the U.S. marketplace, as well as the introduction of COX-2 specific inhibitors.

The most recent estimates that I have seen would suggest that the mortality is about half of what Dr. Singh previously suggested it to be.

DR. GIBOFSKY: Accepted, but even the mortality rate of 8 percent in a population is unacceptable.

DR. CRYER: It is not 8 percent, it would be 8,000.

DR. WOOD: It is much lower than that, and if you look at the curve, the fall occurred long before COX-2s were on the market.

DR. CRYER: You are correct.

DR. WOOD: The data are out to 2000 on his paper, and that fall had occurred by 1998, so that is before any of these drugs were on the market.

My point is that we keep throwing this 100,000 number around, including from the industry people, when the data is 15 years old, and the author has updated it multiple times, and that is not reasonable, guys.

Dr. Singh.

DR. SINGH: As the author of the papers that you are discussing--

DR. WOOD: I am talking about Dr. Freis's paper, which was actually published. Yours is an abstract, I think.

DR. SINGH: Also, the 16,500 was from my paper that we estimated with the Aramis data set, and that, you are right, it is not 15 years old, but that is about '94, '95 data, and now that we have newer data sets, that was an estimate from the Aramis data.

The latest work now is actually on real hospitalizations based on the nationwide inpatient sample, which is a much better estimate of what is really happening than an estimate from a small patient population.

When we go back and look in '93, '94, of what the total number of deaths that the Federal Government said occurred in the United States, we were off by 32, that's it. It was like 16,486. That is how far we were off by, just to let you know in terms of an estimate.

This is also true that now, today, the latest data set that we have available from 2002, that has dropped significantly, and the death rates are more like 8,000.

But the other place where we underestimated was the hospitalizations. We underestimated the hospitalizations, they are not 108,000, there are a lot more than that.

The mortality rates today have gone down tremendously, and the mortality rates today are probably more in the 5 to 6 percent range, and that is where Byron is correct, as well.

Then, as far as the trend is concerned, the data that I showed you today is based on 483 million hospitalizations. We are not counting about 50 hospitalizations and then extrapolating it to the country. There are 483 million hospitalizations and 3.68 billion patient years.

Yes, the trend line started going down way before the COX-2s were introduced, but then there are two sharp years of decline. The trend line actually, if you look at my slide, is very interestingly correlated with PPI use, and I showed data to Byron from the same data set, that it also explains it very nicely because the duodenal ulcer rates have gone steadily downward, which would be attributed primarily to PPI use and H. pylori eradication therapy.

The gastric ulcer rates and the gastric ulcer hemorrhage rate have not gone down in the same fashion. They went down when the '94-'95 H. pylori eradication campaign started. Then, they plateaued off pretty much, and PPIs haven't done very much to gastric ulcers until 1999, when the gastric ulcer rate dropped dramatically.

In 1999, there is a 22 percent drop per 100,000 prescriptions sold in this country. I don't know what it is because of. Coincidentally, in 1999, January 1, celecoxib was introduced. I don't know what it is because of.

DR. WOOD: Let's move on. Dr. Dworkin.

DR. DWORKIN: Much of what I wanted to say has already been said, but I just want to emphasize that while there are no differences on average in pain relief amongst these drugs, certainly none that are replicated, as Byron pointed out, that there is a great deal of variability in response, and I think there is every reason to believe that some patients respond better to one drug than another, so you have variability in the pain benefit, and you have to consider at the same time there is variability in the tolerability of the drug.

So, there are two sources of variability in patient response, which at least to my way of thinking provides a really solid basis for there needing to be a choice amongst several drugs, because you have the variability in the pain benefit amongst patients and the variability in their tolerability.

DR. WOOD: Dr. Cush.

DR. CUSH: I prefer to say that these drugs are equally potent between the COX-2 specific and the non-selective drugs. I think there is a variability, but that speaks to the need for choice.

Every rheumatologist at this table will tell you they cannot manage in any effective or compassionate way osteoarthritis or rheumatoid arthritis using just Tylenol and aspirin and ibuprofen. That would be a gigantic step backwards.

So, they are equally potent. I think when it comes, however, to the risk, thankfully, this risk is incredibly low, but we would like to make it lower, and what we need to put forward is that we need a strategy for risk modification that is going to extend to all these drugs that we are

examining here, much in the same that occurred with GGI, I think that we can start with some recommendations and then make it the responsibility of the manufacturers to come up with studies that will further define how we can best reduce the risk in people who may need to receive these medicines.

DR. WOOD: Dr. Morris.

DR. MORRIS: Let me focus on the question that asks about the weighting, because what we have is--I guess everybody interprets this question differently, but what I interpret it as is how do you look at these non-comparable outcomes and how you trade off a TIA from a gastric ulcer or something.

I think what we can do is we can describe the effect and we can describe the probability of the effect, but what we don't know is what is the right way to weigh those things, and I would make a plea that probably the right way is to try to involve in some way the views of patients in that decisionmaking.

I don't mean that qualitatively, I mean that quantitatively, is in quality of life type data where people have looked at various outcomes, looked at it on a single scale, and apply some of those ways, so we understand how patients view it, and go beyond just medically what we think patients should evaluate it, but how they actually do evaluate it, and try to use some of the input of those data.

That literature suggests that we get it wrong, that there is things worse than death, and we always think of death as the worst thing to happen in a medical outcome, but yet from a patient's perspective, being paralyzed by a stroke is perceived as worse, and we need to understand patients' evaluation of these outcomes, so we can make those weightings better for them.

DR. WOOD: Ms. Malone.

MS. MALONE: Obviously, this is complicated. I agree with most of what the previous speakers have said especially Dr. Cush, Dr. Gibofsky.

A big problem is like Dr. Gibofsky had said about having choice and trying different drugs, and having a period of time when they would work, and then they wouldn't be as effective and you would have to try something else.

That is why the need for choice is there. I have spent the last 35 years probably on each of the NSAIDs that are still available, and went through that, and the frustration and the pain, and just--it's very difficult, so when people give this anecdotal information and say that they have found something that works for them, they are going to fight for that.

We have to be able to prove to them that the risk far exceeds the benefit, and we have to be able to show that, and we can decry anecdotal evidence as not being sufficient enough, but, in reality, it all comes down to anecdotal evidence. It all comes down to the personalization of it, what happens to me when I take this drug, what happens to me when this drug is not available. But I think behind everything is the whole element of trust, and they place their trust in us, in FDA, and we can't give in to pressure, okay, but we can't give in to pressure either way. We have to keep an open mind about it and realize what they are going through and try to put yourselves in their shoes.

DR. WOOD: Dr. Platt.

DR. PLATT: In the spirit of supporting informed choice, it seems to me we could do a very much better job than we do by using the existing data that FDA already has to provide good information to patients about the risk stratum that they inhabit.

Saying that there is an overall 1 1/2 or 2 percent difference in the risk of a GI complication or myocardial infarction is not doing the best service to most people who take those drugs.

I would imagine that those data can be used to support predictive modeling that would allow a fair amount of discrimination so that individuals could be told that people like them can expect a risk of 1 in 1,000 or 1 in 100 or 10 in 100, and that would make it a lot easier, I think, for individuals and their doctors to make thoughtful decisions about the tradeoffs of the benefits and the risks.

It seems to me those data are there and it would be a straightforward thing to make them available. We do that with breast cancer all the time. The NIH did a tremendous service I think to the public by providing good predictive models that let women know what their risk of breast cancer is to help them decide whether to take preventive action. I think we could do it with these drugs.

DR. WOOD: Dr. Bathon.

DR. BATHON: It is interesting that you would say that because that is, in fact, what most of us rheumatologists have been doing for the past four months with every single clinic visit, is weighing the benefits and the risks based on the data that exist right now, and it is a difficult endeavor.

I think that we are really hearing from our patients, and we heard this today, we are in a different era of patient-doctor relationships, and patients want to be a collaborator in these decisions, and they want to know the information.

I think that the way I am thinking about this problem right now is that these drugs, whether they are selective or non-selective, are another risk factor in the GI complications and the cardiovascular complications that we have to weigh along with their blood pressures, their diabetes status, their BMIs, their family history, and everything else to come to a final decision about what we recommend with their input.

Until we see an unequivocal cardiovascular risk that outweighs all those other factors, I always'>

545 think that is the appropriate approach with the patient is to put the drug in with all the other risk factors and try to come up with the best benefit-risk ratio that exists for that individual.

DR. WOOD: Dr. Hennekens.

DR. HENNEKENS: I find Question 3 extremely complicated in a number of dimensions. I am attracted to Tom's formulation of benefit to risk, but I think we also have to consider these arthritis patients with regard to the use of selective coxibs.

As a group, they are at maybe a double the risk of heart disease of their non-arthritis counterparts. They are also suffering terribly with pain. From that perspective, the data we saw over the last two days on naproxen was somewhat reassuring to me, but for the patient who has gastroesophageal reflux disease or an allergy to aspirin or non-selective NSAIDs, I think there the benefit-to-risk obviously shift although even here, I think they have to have their cardiovascular risk factors managed aggressively, and I would add three more dimensions.

One is I am not reassured at all by the data that are available on the short-acting non-selective NSAIDs with regard to risks and benefits, and I think we need a lot more data there.

I am also not reassured by data we haven't reviewed that acetaminophen is either sufficiently efficacious or much safer, and then finally, the problems with high doses of aspirin are real.

I do point out, though, the UK TIA trial of 2,400 people that gave aspirin 1,200 mg in a placebo-controlled design for 5 years, the rate of GI side effects attributable to the aspirin was 14 percent, significant bleeding was 3.3 percent, but this flies in the face that 25 percent of the people on placebo had GI side effects and 1.6 percent of them had a significant GI bleed, so I think nothing is straightforward here.

DR. WOOD: Dr. Nissen. DR. NISSEN: Just one brief comment, and that is, one of the things I am struggling with for all of you, and maybe some of those that either deal with these diseases can help me with this, is that the people at greatest risk for GI bleeding are the older and more frail individuals who are also at the greatest risk for cardiovascular disease, and so finding the sweet spot for the drugs becomes a little bit harder.

There obviously are certain populations where it is obvious, but the big populations where there is risk, is it not true--I think I heard from Byron that older people are at greater risk for GI bleeding, and I can assure you they are at greater risk for coronary disease, so the question is how does it tilt in any given patient. It is not so easy to figure it out.

DR. PLATT: But you can quantitate it. I mean it seems to me you could tell the patients what individually, approximately what they could expect on both dimensions, and for a lot of patients, they would be high on both, but at least they could make an informed decision about that.

DR. CUSH: But it's the same situation as the GI problem. We know what the risk factors are, and age is a risk factor, and we counsel patients, and we probably should tell the ones who might be willing to accept some small risk, because they don't seem like they are at risk just because of their age, but they don't have any other factors, and the same thing can happen here with regard to the cardiovascular risk if we have some appropriate guidelines.

DR. CRYER: Steve Nissen, I think you have got it exactly right and that there seems to be a great degree of overlap in those who are at GI risk tend to be, not uncommonly, the same patients who are cardiac risk. They are older, they may have a previous history of cardiovascular disease, and other risk factors which are common to both risk considerations, GI, and cardiovascular.

DR. WOOD: Ms. Malone, do you want to say something?

MS. MALONE: Yes, I do. Just what Byron has said, all of that brings in the importance of the doctor-patient relationship, and today, with the health care climate that we have, I have heard patients say how difficult it is to go in and get an amount of time when you can talk to your doctor, have a relationship with him, and especially, as people become older, and where I live... there are many elderly people who do not have family around, so they are going to their doctor by themselves, and they are dependent on that doctor's viewpoint.

They will say, "Well, what do you think?" I used to say if I were your child, and then it was if I were your wife, now it is getting to be if I were your grandmother, you know, with the age of everyone, and I hope I live to say if I were your granddaughter.

But that is very true, and again it is not a simple situation, and whether we need some sort of health educator to assist the doctor to be able to explain this to the patients, so that they are not taking valuable doctor-patient time, but something needs to be done.

DR. WOOD: Thanks.

Dr. Ilowite.

DR. ILOWITE: I wanted to talk to a few pediatric issues about these agents, the granddaughter. First of all, about choice, there are far fewer choices in pediatrics. There is only three NSAIDs approved, only two liquids and none any longer that are available as once-a-day dosing regimens.

The second issue is about tolerability.

Certainly, children have fewer serious gastropathic events, but they do have a lot of symptoms, and it is often difficult to get children to take medications that give them even bellyaches.

Third, is the risk of cardiovascular disease, which is very low in pediatrics. A new clinical research network called CARRA, Childhood Arthritis and Rheumatology Research Alliance, organization polled its 130 members of whom 92 or 71 percent responded, and there were no events of myocardial infarction or stroke that couldn't otherwise be accounted for easily that were attributable to these agents. Lastly, is the issue of exposure. It is likely that children with chronic rheumatic diseases are going to be on these agents longer even than adults, and the cumulative risk is of great concern.

I think it would be very important to try to get some insight into the pathogenesis of this, not just the frequency, so that early markers could be explored in children who are exposed before they exhibit the clinical endpoint. MR. LEVIN: I haven't spoken for two days, so now I may go on. A couple of thoughts. One is I am all about informed choice, but the question is how informed is the choice, I think, as others have raised, and I want to point out that I think we have this sort of mythology of a changing environment which is patient-centered in which there is this sort of partnership.

With all due respect to the clinicians around the table in the room, I don't think that characterizes most people's experience in the health care system today. I think it is totally unrealistic. We have 45- to 50,000 people who are uninsured, who have very haphazard access to care, certainly don't have an ongoing relationship probably with a practitioner who is going to sit down and run through the benefits and risks in the alternative therapies and help them make an informed decision.

We know from studies of how much time physicians have with patients and what they convey when they prescribe a drug, that is far from the role of the learned intermediary that is sort of I think mythic, and we need to get over.

I agree with Lou that we need to ask patients what they want and what their experience is, but on the other hand, we have a regulatory context here. We have 1906, we have 1938, we have 1962. For better or worse, the Congress has decided that there is a role for government to play in protecting the public from harm.

So, I don't think we can just sort of slide this all off on patients and physicians supposed in this Nirvana good, up-to-date information, making intelligent choices through this very difficult, complex issue.

The Government does have a responsibility, and that is why we are here. We are being asked for I think advice on how government can best meets its responsibilities under statute to protect the public health and to do what it has to do.

We all recognize that there are lots of things that need to be improved, I believe, in the way new drugs come to market, because I have sat through this before when we are chasing the train. The train is out of the station, folks, it is going down the track very fast, and we are trying to catch up to it and figure out what do we do.

You know, it is heading for the crossing, there is a car on the track, how do we stop the train. It is too late. We are always going to hear from patients no matter what the drug, "This drug worked for me, it's wonderful, it changed my life."

I believe them, I certainly empathize with them. There will always be that appeal. So, I guess we have a complex task, the train has left the station, but we can't abrogate our responsibility, and we can't pretend the Government, through the FDA, doesn't have a statutory responsibility here to protect the public health.

We can't just say put information out there, make it transparent, let this mythical doctor-patient relationship sort of bubble up and make things all right, because it's not going to happen that way.

DR. WOOD: Helpful comments from our consumer representative.

Dr. Manzi.

DR. MANZI: First, I would like to congratulate the members of the panel who I thought have brought some very relevant points to the table, and I agree with most of them, but it is interesting to me how many times I have heard the term "safe alternatives" used.

I look at our first question about weighing the benefits of the COX-2s versus the non-selectives, and I think the assumption, as we are trying to deal with the coxibs, is that there is, quote "safe alternatives" in the non-selective agents that we would feel comfortable having our patients turn to in the event that these other COX-2s were not available.

My question would be, or I guess my challenge to my other panel members would be to provide data that has been obtained with the same rigor and had to undergo the same scrutiny as the drugs that we have just looked at to prove that the other non-selectives are safe alternatives.

I don't think we have it. I think we have signals actually to the opposite potentially. So, I just think we have to keep that in mind as we are making decisions that patients are going to have to turn to something, and do you feel comfortable saying that the alternatives are safe.

DR. WOOD: Another way to think of the same thing, though, is that if we were sitting here thinking about approving these drugs right now, would we approve drugs with a clear cardiac risk in randomized clinical trials.

I think that is an important question for the committee to address because if we don't address that, we will either not be able to address it for drugs coming up in the future and/or we are going to apply a different standard to drugs that are on the market, and I understand all these points, but I think it's--maybe I am wrong--I think it's highly improbable that the committee would have approved any of these drugs given the safety signal we have got right now.

I think it is highly improbable that the FDA--I am talking about from randomized clinical trials--I think it is highly improbable the FDA would have approved drugs if they had had all the randomized studies they have right now.

That doesn't mean they wouldn't have approved them eventually perhaps, but they certainly wouldn't have approved them on that basis. Is that fair, Bob?

DR. TEMPLE: I think it varies depending on how you view various collections of data, but some of them I think probably would not have made it.

DR. WOOD: All right, some of them we would not, but that is a fair comment.

DR. MANZI: Could I just comment?

DR. WOOD: Sure.

DR. MANZI: I would argue that that would depend on the need for the drug, and it would also depend on the alternatives available, and so I think it is hard to look at it in isolation.

DR. WOOD: Fair point.

Dr. D'Agostino.

DR. D'AGOSTINO: The Framingham study has generated many risk assessments. They are in the cholesterol guidelines. Cardiac risk assessment tools do exist. Would the physicians use them? I am not sure that cardiologists use them, nor other classes of physicians to automatically use them and sit with the patient and go through that, but they do exist, and if you could build a scenario for that, it would be possibly very useful.

But one of the things I wanted to really mention isn't just the existence of these tools, but there seems to be something synergistic about taking the drug and your cardiac risk, so it is not just a matter of telling you you are diabetic and how likely you are to have a heart attack. This drug seems to double that or triple that, and so forth, so you will be presenting very high risk to the subjects, and I am not so sure how easy that is to do, but it should be kept in mind that there is an elevated risk beyond the normal cardiac risk.

DR. WOOD: Unless someone else has a burning question, I am going to give Ms. Malone the last word.

MS. MALONE: I feel the need to speak up for rheumatologists. I had been on this panel I believe starting in 1995, and as a consumer rep. I filled someone's term, and then I had my own term. So, I was on it for five years, and then I came on as a patient rep intermittently.

From my 35 years dealing with rheumatologists and being on the panel, I have to say that rheumatologists, on a whole, are a unique set of doctors. They are in there for the long haul and I have always felt that when I was on this committee, if I were not here, that the voice of the patient would still be heard.

I find that I don't think there is one rheumatologist on here who would not spend time with their patient, who would not spend time educating them and listening to them albeit it it's not a half-hour, but I think they do have the ability to form a relationship with them, and I applaud them for that, and I disagree with Arthur on that point.

DR. WOOD: Stephanie, I will give you the last word and then we are stopping.

DR. CRAWFORD: Thank you so much, Mr. Chairman. I simply can't quite leave without at least attempting to address this stunning near cliffhanger that we were given about 40 minutes ago.

I am going to ask, if I may--and please forgive me if I get your name wrong, it's not listed on my papers--I think it was Dr. Kim from Merck. Thank you.

Yesterday, I asked the question to Dr. Braunstein about what was or were the deciding factors in the extraordinary step that Merck made in deciding to voluntarily withdraw rofecoxib. I am not sure I heard a clear-cut answer, so I am going to ask you something very related to this last question we have been addressing from the opposite side.

Tonight, what considerations would you weigh or would you ask this committee to consider when we deliberate tonight or tomorrow in determining the benefit of potential re-introduction of rofecoxib, or if you wish to say this class, where the benefits would far outweigh any issues of safety concerns?

DR. KIM: Thank you for that question, and I will say that it has certainly been a very educational and informative day, two days actually, listening to these discussions. I think the issues are complex, and I think that all of the complex issues are being brought up.

As I said, Merck believes, based on the new data that has just become available, that what we are dealing with here in terms of cardiovascular risk is a class effect.

The thing that we are struggling with, which you are all struggling with, is what does that mean in terms of the size of the class, and, in particular, is it limited to just inhibitors of COX-2 or does it include inhibitors of COX-2 that also now have an effect on COX-1.

The only point that I was trying to make was that at the time that we decided to withdraw Vioxx from the market, we did so based on the information that was available to us at that time, knowing that there were alternative therapies and that there were questions that were raised by the APPROVe trial.

Now, where the science has progressed to, where we see, we think, and we look forward to your decisions, but we think we are dealing with a class effect, then, I think we are no longer dealing with a situation where Vioxx is unique in its cardiovascular risk, but instead is a member of a class.

Then, I think it is important for us--again, we are looking to you, this committee and the FDA, for your evaluation of whether or not you agree with our interpretation that this is a class-specific effect, but if that is the case, then, I think we need to take a look at the unique benefits that Vioxx provides, which I mentioned, and actually a fourth benefit which was already mentioned, that is, that Vioxx is the only COX-2 inhibitor which has been proven to reduce the events, serious GI events, as compared to naproxen.

Vioxx is the only COX-2 inhibitor that was approved that is not contraindicated in patients with allergies to sulfonamides, and Vioxx was the only COX-2 inhibitor with approval for juvenile rheumatoid arthritis in addition to the fact that we have heard numerous reports from patients, some with very chronic debilitating pain, that Vioxx was the only drug that worked for them.

With that, I will leave it to the committee. We really await your decision on this issue.

DR. WOOD: Okay. It's never the last word, is it.

DR. STRAND: May I finish the answer to a question that I was asked yesterday?

DR. WOOD: Who are you?

DR. STRAND: I am Dr. Strand and I responded to you yesterday about the use of COX-2s in patients, the benefit-risk profile. I simply to say that with Dr. Hochberg we authored an editorial in 2002 after the introduction of the data from CLASS and VIGOR to point out that there is benefit with these COX-2s, which is at least numerically preserved from a GI point of view, both from TARGET and CLASS data, with a baby aspirin, and, in fact, most of the cardiovascular risk may be abrogated by co-administration, and we certainly don't have to then worry about the potential interaction as has been demonstrated with ibuprofen.

So, I think it is important in your deliberations to consider that point. Thank you very much.

DR. WOOD: Kimberly tells me the committee has to meet in the lobby in 15 minutes. I think that is pretty optimistic, but good luck.

(Whereupon, at 7:00 p.m., the proceedings were recessed, to reconvene on Friday, February 18, 2005, at 8:00 a.m.)

Weitz & Luxenberg is no longer accepting Vioxx cases.

see also:

Lumiracoxib/Novartis Your Bextra Side Effects Lawyer - Vioxx, Celebrex & Bextra FDA - Lumiracoxib/Novartis
Bextra side effects lawyer - the complete transcript of the FDA meeting

Epidemiologic Studies Your Bextra Side Effects Lawyer - Vioxx, Celebrex & Bextra FDA - Epidemiologic Studies
Bextra side effects lawyer - the complete transcript of the FDA meeting

FDA Transcript - Day 2 Vioxx, Celebrex & Bextra FDA Transcript
Your lawyer provides the complete transcript of the FDA meeting.