FDA Q & A Regarding Vioxx and Its Safety Concerns

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

Committee Questions to the Speakers

DR. WOOD: Great, and thanks for going through that so quickly. Kimberly tells me that the committee on breast implants went to eleven o'clock so we have a bit to go yet before we beat them. Anyway, we will take questions for the last group of speakers. Curt?

DR. FURBERG: A couple of comments, one regarding Bextra. I applaud the FDA in the effort to standardize myocardial infarction, but to apply the standard criteria of myocardial infarction to patients undergoing bypass surgery doesn't make any sense because you are opening the chest so the whole criterion about pain doesn't make sense.

The other one is that many of them have increases in their enzymes. You cannot apply the regular criteria to myocardial infarction to the population. So, I just think that reclassification is not valid.

The second point is related to the ADAPT. you can add to your list of limitations of the study that there is no prespecified outcome for cardiovascular events. The investigators looked at a number of them and it is not clear which one they decided to put their money on. And, there is no adjudication of the cardiovascular events. They were all self-reported--very, very soft data.

DR. WOOD: Nancy?

DR. NESSMEIER: Well, just a comment about the CABG study, the criteria were different in that it was diagnosed either by autopsy or by CK-MB level of more than 25 ng/mL within the first 72 hours after CABG, or an excess of 10 ng/mL if more than 72 hours had gone by, or a peak troponin of more than 3.7 mcg. So, those are more rigid criteria than would be used for a non-surgical study.

DR. WOOD: Right, and there was a control group so it should have shaken out. Right?

DR. NESSMEIER: Correct.

DR. WOOD: Yes, Dr. Hennekens?

DR. HENNEKENS: I have two comments and a question. First of all a comment about the CABG surgery data, in terms of benefit to risk assessment, I would believe that a priori any drug, regardless of its class, that would increase blood pressure, fluid retention and risk of heart failure, if given during or after CABG, would pose very difficult research and clinical challenges. I would say to Dr. Shafer, regardless of the mechanism that is proposed, this is far beyond the powers of aspirin.

The second comment to Dr. Huber as regards his reassurances from the observational comparisons, I am concerned that for small to moderate effect there are biases confounding by indication, and uncontrollable confounding inherent in all case control cohort studies, no matter how large or how well designed, as well as their meta-analysis. They can either produce false evidence of benefit or harm or false evidence about lack of benefit or harm. I just think the randomized data are far more important, which leads me to my question to Dr. Huber. In VIGOR, do you believe the overall randomized findings are attributable to a hazard of rofecoxib, benefit of naproxen or some combination of the two?

DR. HUBER: I don't know. DR. WOOD: That is a surprise! Other questions? Dr. Shafer?

DR. SHAFER: I just want to re-echo what Dr. Nessmeier said. The CABG population is very different, very much a pro-inflammatory population. In anesthesia we do very poorly at treating postoperative pain, particularly in the first 24, 48. Multimodal therapy is what we are looking for and certainly if you say the CABG population is very different and you look at the data in the acute surgical setting--brief administration--it is an area where we do need improved therapeutic options and I would just encourage the committee to keep that in mind.

DR. WOOD: Other comments? Yes, Tom?

DR. FLEMING: Just looking at the nature of the data that we have been provided here, slide 10 where we looked at naproxen exposure data with millions of doses and the sponsor basically said there is no safety signal for cardiovascular events or MIs. I guess if we were looking at rare events, Stevens-Johnson's rash or something like this, this kind of evidence could be reassuring. But how is reassuring when we are looking at MIs and strokes where you expect to see a certain rate of these in natural history? How do we rule out a doubling? So, essentially it leads me to really wanting to focus on the randomized trials as having a sense.

Looking at slide 17, I am worried about how little of this information is longer term exposure. So, if I am understanding correctly, we really have TARGET and VIGOR and ADAPT as maybe the best bases for making an assessment over a longer term in a truly controlled fashion for effects on cardiovascular-related major events--cardiovascular death, strokes and MIs. Two of those, VIGOR and TARGET, we don't have a placebo control. The questions that were just raised I think by Charlie Hennekens are in VIGOR--basically how do you make an assessment there without a placebo control? ADAPT is a placebo control.

We heard just now that the data monitoring committee specifically didn't stop the trial on 12/10/04. By my notes earlier this morning, I thought we were told that the data monitoring committee on that date did stop the trial due to naproxen GI bleeds, cardiovascular and cerebrovascular events. So, I am a little confused about what actually did happen. Is it true at this point though that we don't have first-hand access to what the data actually are in ADAPT?

DR. HUBER: Let me answer your first comment about the randomized clinical trials. Basically what you said was that the TARGET and the VIGOR studies are the large randomized, comparative trials. There is also the Alzheimer's study which is obviously much smaller but it is one-year follow-up.

With regard to the postmarketing data, we recognize the limitations. We were just wanting to reassure you that there hadn't been numerous case reports out there. Also, when we look at disproportionality there is really no signal there. It is something we use in postmarketing surveillance.

I would be careful on the observational studies. Recognizing the limitations as stated, that does give us a large number of patients who have been exposed to naproxen and gives us some, we believe, important data. There are 80,000 exposures in that series of observational studies. So, we do believe there is some weight to that evidence. It shouldn't be completely put aside.

DR. FLEMING: And the weight you are placing on that is you are reassured about what specific outcomes?

DR. HUBER: That for MI, for myocardial infarction with 11 observational studies, we see a consistency of finding that is at 1 or lower.

DR. FLEMING: But doesn't the fact that we have 11 of those give us a more precisely biased estimate? How do you know that all 11 aren't in fact subject to the same type of systematic bias and under-detection?

DR. HUBER: Well, we use multiple databases. There are different comparisons. There are past users in several of the studies. I guess the question is if we take that approach, then we have to question should we even do observational studies for any issue?

DR. FLEMING: Not necessarily. It depends on what you are looking for. My comment was if you are looking for MIs and strokes, which are events that would in fact occur in natural history, unless you are looking for a ten-fold increase, isn't it really difficult for that type of outcome to truly be able to rule out a relative risk of 1.5? I would argue, yes, it is. While there are other things that were reassuring, if we wanted to be reassured about stroke and MI, this is where it is intrinsically the most difficult.

DR. HUBER: I agree you. I don't think we should rule things out on the basis of the observational data, but I think what is important is when we looked at this a priori based on mechanism of action, etc., the data was telling us there was probably not an increased risk. So, when we take that as the first line of evidence and then we put on the additional lines of evidence, at this point in time the only data suggestive of an increased risk, to our knowledge, is the release of the preliminary findings of ADAPT.

DR. FLEMING: Can you clarify that? Because I believe we heard something different this morning about what actually has been stated. Can you clarify what actually has been stated?

DR. HUBER: What we are talking about is the NIH press release. I believe there were approximately 70 cases, and what was stated about it was that there was--I can't remember the exact wording of the text, but it was an increased risk of stroke or MI.

DR. WOOD: Well, we are going to hear about that on Friday morning.

DR. FLEMING: So, we will hear about it on Friday?

DR. WOOD: Yes, unless we keep talking until then, I guess. It is down for 8:10 on Friday morning. Other questions? Yes?

DR. MORRIS: Dr. Huber, while you are there, did any of the observational studies stratify by time on drug? And, was there any different finding by length of time on Naprosyn?

DR. HUBER: I am going to have to look to my epidemiologists? Dr. Thacker is the epidemiologist for Roche.

DR. THACKER: We did an extensive literature review of all the studies that were published up to December, 2004. None of the studies really gave us any data on duration of use. DR. WOOD: Other questions? Yes?

DR. WITTER: I just want to make the point that in the ADAPT trial naproxen was the OTC dose.

DR. WOOD: Any other questions or are we finally getting exhausted? Yes, Ralph?

DR. D'AGOSTINO: Just because we are exhausted, that doesn't mean that what was presented is, in fact, something we can buy. I think the comments that Tom is making are very important. We have all this meta-analysis. We don't know anything about those studies. So, I think we have to wait until we hear from the NIH.

DR. WOOD: Right. Dr. Seligman has something to say?

DR. SELIGMAN: Just a very brief announcement to the Drug Safety and Risk Management Committee. We would like to meet in the lobby at eight o'clock and all go out for dinner if you are still willing.

DR. WOOD: Before we break, do the FDA have any final comments or questions? No? In that case, we will meet promptly at eight o'clock and start dead on time. See you tomorrow.

(Whereupon, at 7:30 p.m., the proceedings were adjourned, to reconvene at 8:00 a.m., Thursday, February 17, 2005)

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