The FDA March 2003 meeting regarding Gemifloxacin (Factive) and severe rashes.

DR. MAXWELL: Just two point. I think that the sponsor did a nice job in showing histopathology. That was really helpful. On the other hand, I think that the way we were taught I don't believe that I have any time rechallenged a patient, and most of my patients don't want to be rechallenged. I feel that when you weigh in the balance this severity, let's say, of acute exacerbation of chronic bronchitis it is probably not worth it and most patients and physicians will feel that way because the patients that developed the rash felt that it altered their life significantly. So, one way perhaps to handle this would be in the labeling and also intense provider education.

DR. LEGGETT: Dr. Proschan?

DR. PROSCHAN: So, is this largely a psychological problem?

[Laughter]

I ask partly because I get rashes sometimes for no apparent reason and I just ignore them and they always go away.

DR. LEGGETT: That is why the rate in men is lower in these studies!

[Laughter]

DR. PROSCHAN: What are the doctors and patients worried will happen if they just don't do anything? What is the concern?

DR. ADKINSON: It is worth pointing out that the rash for placebo treatment in the 344 study was 3.9 percent. So, just hyper-surveillance for rash will produce a fairly high rate of them. I think in this 344 study we have seen large numbers because people were looking very carefully and observing something that might otherwise in many cases have been ignored and certainly never have come to medical attention.

DR. LEGGETT: Dr. Cross?

DR. CROSS: I practice in a cancer center and I just want to bring up a point which perhaps is slightly off the point but related, and that is that perhaps most abused drugs in a situation of, let's say, neutropenic host are the quinolones. The practice has been that as long as a patient remains neutropenic, if they are on antibiotics, they remain on the antibiotics until they cure their neutropenia. We have lots of patients who resolve their fever; they are stable and are sent home, off-label, on quinolones and stay on that. I have a real fear if it is used in this way, although it is not with the blessings of the sponsor or the FDA. Is it possible to even have something in the insert that this drug is approved for CAP; that it is not to be used for prolonged treatment of neutropenia in immunocompromised patients because these are the ones where I am sure you will see skin reactions triple and all the other complications. I am not sure we have ever had in a package insert that a drug is not to be used for a certain indication, but in view of the prevalence of the problem I think it is worth considering.

DR. LEGGETT: Dr. Drake?

DR. DRAKE: Who asked the question about any group of patients where you would not use it? Was it you? I started to say something very respectful and say lawyers--

[Laughter]

--but I do think that the legal issues become very, very dicey in this arena. On the other hand, I think as professionals it is our responsibility to do what is right for the patient and to be thoughtful about how we make our decisions. That is why I have said what I have said, that we shouldn't just automatically be reactive and say they should never have the drug because they had a rash once because that is not an indicator in my opinion.

But the second thing I wanted to be sure and mention is in terms of Phase IV studies, if it should go that way. I don't think there was a lot mentioned about mucus membranes. You know, Stevens-Johnson and TEN often appear initially, I mean sometimes it is your first clue. Frankly, when you are dealing with diseases of the eye, they can go south pretty quick. You know, two or three days and you can have some visual impairment. So, I would like to have some special--I am sorry there weren't pictures or biopsies of mucus membranes in this wonderful study that they did, but I would like to strongly recommend that special attention be paid to people who might have a mucus membrane reaction. I can tell you that in that group I would be particularly cautious about rechallenging.

DR. LEGGETT: Before we leave the rash, between the lines I got the impression that none of you were very worried about what has been manifested so far so could I have you speak about definitely showing an increased rash risk that you could identify from the data, recognizing that the numbers are small?

DR. BIGBY: I would say that the rash that has been manifested is not one that I would worry about.

DR. LEGGETT: Dr. Drake?

DR. DRAKE: And I would say that too with one exception, and that is the patient who had the fever. I would pay careful attention to that type of thing.

DR. LEGGETT: Dr. Rodvold?

DR. RODVOLD: Most of these people are going to have fever if they have an infection.

DR. DRAKE: Details, details, details! Picky, picky, picky!

[Laughter]

Probably not by day seven or eight.

DR. LEGGETT: John?

DR. BRADLEY: I have a question for Dr. Poretz. I have mostly a hospital-based practice and, as a pediatrician, certainly don't take care of many women under 40. But as someone who is trying to give recommendations for treatment, what I would like to do is to ask someone who is actually in an office, writing these prescriptions every day, how the incidence of rash in the under 40 women would impact his prescribing practices, assuming that the drug does get approved.

DR. PORETZ: I will try to answer that. You know, medicine is never black or white. We always have to make decisions every day. We see people all the time for whom, for various reasons, you want to use certain drugs. For example, sulfa-trimethoprim is a commonly used drug. We like to use it because it is inexpensive. I realize it has a significant amount of drug eruptions associated with it but, you know, many times prescribe it anyway because it is good; it works under certain circumstances and it is cheap. So, you realize that X percent of people develop a rash.

Well, this particular drug has a higher incidence of rash in certain populations. So, to be crude, I would probably not use it in women on birth control pills commonly and use it in older guys who smoke a lot. Okay? I mean, it seems to have a nice niche for people who have chronic lung disease, people who smoke a lot and people who have community-acquired pneumonia. Maybe that will be patients in nursing homes and maybe it will be people in extended care facilities. I am not sure you are going to use this drug that much in the hospital, in all honesty, because of the reason we said before, people tend to be on parenteral medications.

But in answer to your question, in selective groups of individuals it looks like, because of the MICs--and people can argue that--it will be a very nice drug to add to our armamentarium to treat community-acquired pneumonia particularly.

DR. LEGGETT: Dr. Epps?

DR. EPPS: Just one last brief group for education would be the pharmacies, particularly when they go to the pharmacy and they get a page-long explanation of what the complications are and what your potential side effects could be and it may not agree with what the prescriber believes.

DR. LEGGETT: Go ahead, Keith.

DR. RODVOLD: Actually, on the slide it really only said educating physicians. I would broaden this way up because the triage is lots of other healthcare people. So, when you look at this educational program, once you get to it, it is going to have to be huge, in my mind, and I mean lots and lots and lots of education and lots and lots and lots of people.

DR. LEGGETT: Jan?

DR. PATTERSON: I was just going to say before we leave the rash issue, regarding postmarketing or Phase IV studies, I had some concerns that Dr. Epps brought up earlier about people of color. At least, in that 344 study there were a fair number of Hispanics, about five percent, but there were only two African-Americans, or 0.2 percent. While there wasn't a difference in the overall studies, I think that would be something to focus on in postmarketing.

DR. LEGGETT: Go ahead.

DR. CONJEEVARAM: From the perspective of not treating these patients on a regular basis, a question I have is that it is true that the current standard of practice for most physicians is that if someone develops a rash you don't rechallenge them. You can talk all you want about that this is safe. We do that in our specialty too with some of the medications we give and we go through the rash, but in general, especially with antibiotics, my impression is that if you do treat someone and they get a rash you don't rechallenge it.

If you take the setting of acute exacerbation of chronic bronchitis, which is a recurrent phenomenon, and as we make guidelines would you use this antibiotic as first line knowing that if there is a high incidence of rash you will never be able to use that again in that setting? That might actually be quite clinically important at a later time.

DR. LEGGETT: That was the reason for my comment about the niche of the resistant bugs. Go ahead.

DR. ADKINSON: If we are treating, for example, acute bronchitis and consider using this drug, the expected rash rate will be lower than if one chooses to use amoxicillin. So, I think we have jumped to conclusions about the clinical significance of this that are far beyond what is practically the case when you are in a prescribing situation. I mean, I don't see any particular reason to be concerned about the use of this drug for these two indications. If there are high risk groups that can be easily identified, then one would naturally stay away from those groups but for these particular indications the rash rate is not going to be substantially different from the alternatives, it seems to me.

DR. LEGGETT: Dr. Bigby?

DR. BIGBY: Well, in the actual data in the study in head-to-head trials with amoxicillin and Augmentin the rate that is higher, more than twice as high in the head-to-head studies that they presented. I mean, that is clearly not going to be the case.

DR. LEGGETT: If it is okay with everyone else, it is 3:30 and we have two members who have to leave at 5:00, we will skip the afternoon break. If folks have to skip out, that would be fine as long as they come back. Can we move on to the hepatotoxicity issue? Hari, could you give us your view?

DR. CONJEEVARAM: I think in general, at least from the data presented and from the point of using it for five or seven days, it seems very safe in that it is reversible. None of the findings suggest that they are at risk of going on to acute liver failure, using the Hy's rule.

The only two concerns I have, and maybe Jim Lewis or someone can comment on this, is that if, for whatever reason, you do use a higher dose or you prolong the dosage, if you look at the data from using the 640 mg, it is associated with increased ALT plus increased alkaline phosphatase which is cholestatic hepatitis. So, those patients are not really at risk necessarily of liver failure, which we all worry about but. As we know, there are antibiotics where one of the other potential risks is irreversible bile duct injury where they go on to have prolonged cholestasis, sometimes going on to liver failure.

So, that would be one concern. That is where I think really education about use of this drug for a limited time period might be important and also surveillance post-approval, if it is approved, to really follow these patients, especially patients who are being treated for longer than what is prescribed. Again, I think probably in a certain number of patients it will be prolonged beyond one week or two weeks and really I think it is very important to follow those patients.

The other issue is patients with underlying liver disease. I am not sure if among those patients there were patients with actual cholestatic liver disease included in the studies. We don't have the details on that. Again, maybe someone can help us with that.

I am really not too worried about the fact that there was a higher rate of further increase in these patients because when we see patients who already have chronic liver disease, we are really looking at their baseline ALT which is usually abnormal, two or three times abnormal as the baseline cut-off. You really cannot compare with a normal ALT in that setting. You really have to say, well, what was the patient's baseline and then how many times beyond that has it increased. The data presented here again shows that though you do have a further rise, they all come back to their baseline, if not even better actually. So, I don't have much concern from that perspective.

DR. LEGGETT: Are there any populations that you know of, other than sort of idiopathic, that are at increased risk of severe cholestatic hepatitis?

DR. CONJEEVARAM: As far as we know, no. At least there doesn't seem to be any risk when you look at gender, though in general females are a bit more higher prone for drug-induced liver disease. No information on race, not that I know of.

DR. LEGGETT: Dr. Sjogren, could you please put in your two cents?

DR. SJOGREN: Yes. First I want to congratulate the sponsor and the FDA for the analyses of the data. It made it very easy for my review in terms of liver tests. Looking at the group of people with normal ALT and then the group with abnormal ALT, I can make some congruent decisions and opinions.

I agree with my colleague that it doesn't alarm me. It is something that is not unusual for me in the clinic to see these elevations, the percentages that the drug produced, and I was very comforted by the fact that the abnormal ALTs, when they discontinued the drug, went back to normal in one or two days after discontinuation. So, if people had a normal ALT to begin with I think this situation is not alarming.

For people with abnormal ALT and presumably chronic liver disease, I am also very glad to see that the sponsor took steps to study those kind of patients because that is where we have to use our intuition most of the time because other drugs have not studied patients with chronic liver disease. So, I am very satisfied to see at least an effort in that regard. They had a couple of patients where the elevations were more sizeable and worrisome probably to clinicians at the time, but also when they discontinued the drug the ALTs went back to normal or to baseline, or in some cases improved.

We have no information on the basic kind of diagnosis of those patients but I guess, you know, that may or may not be relevant. The fact that some patients had elevated alk. phos., yes, it points to a cholestatic type of liver condition which in general in our field we call bland cholestasis because it usually doesn't make you think that the patient is going to develop liver failure, which is what worries us the most.

I would think that if a patient develops jaundice, Hari, the clinicians are going to take that patient off the drug. They just won't continue on it, especially when there are other antibiotics that they could use. So, I am not at all alarmed by what I have seen in the data that was presented today.

DR. LEGGETT: Are there any postmarketing studies or any more data that either of you would like to see?

DR. CONJEEVARAM: I would think only if it is being used for prolonged periods, otherwise I don't think so. The other issue is the issue of isolated hyperbilirubinemia, which doesn't concern me at all actually because usually isolated hyperbilirubinemia doesn't always suggest underlying liver disease. Some of these patients can have Gilbert's when they are under stress where, in fact, the bilirubin does go up. I suspect it is most likely that rather than real liver disease.

DR. LEGGETT: Thank you.

DR. SJOGREN: I would make a plea to continue on--especially the FDA--to continue on this path for other antibiotics or these kind of drugs to study patients with chronic liver disease because this was very valuable.

DR. LEGGETT: Dr. Epps, go ahead.

DR. EPPS: Do you have any recommendations about alcohol consumption or other drugs, or anything?

DR. SJOGREN: In hepatology we don't want anybody to drink, of course.

[Laughter]

DR. LEGGETT: Does anyone have any comments on the QTc issue as regards gemifloxacin? It was my take that it sort of puts it right smack in the middle of the other fluoroquinolones. Any dissent? Go ahead.

DR. GLODE: I wonder if now is the time to ask about a side effect that wasn't reported?

DR. LEGGETT: Perfect.

DR. GLODE: I am just interested and I have to ask this question as a pediatrician and it goes to the beagle puppies and their arthropathy. I am sorry, it is probably here and I missed it but I want to know if the study design was such that the sponsor attempted to capture all encounters with the medical system for some period of time after starting the drug. I wonder if that was 30 days or 60 days. I specifically want to know if there was any tendon rupture or tendinitis that was reported that we didn't hear about.

DR. LEGGETT: Dr. Patou?

DR. PATOU: There were no tendon ruptures or tendinitis in the clinical trial program.

DR. GLODE: And what was the ascertainment for that? How long?

DR. PATOU: I am sorry, the studies followed subjects for 30 days post therapy.

DR. GLODE: Great, and you captured all medical encounters?

DR. PATOU: Yes.

DR. GLODE: Thank you.

DR. LEGGETT: Dr. Maxwell?

DR. MAXWELL: Just in the same vein, I didn't notice anything mentioned about neurologic abnormalities so I wanted to know did you notice anything.

DR. PATOU: No is the answer. Although I didn't dwell on it, on the slide that I showed with the overall incidence of adverse events some of the CNS related adverse events were actually lower on gemi. than the pooled comparator. But certainly in terms of seeing any specific issue neurologically, that has not been the case with the drug.

DR. LEGGETT: Could we spend maybe five or ten minutes at most to think about things on our "want/wish" for further studies that have not been mentioned, or address specifically the blister pack issue, those sorts of things? Dr. Maxwell?

DR. MAXWELL: While I agree that the rash may not be life-threatening, it is certainly morbidity inducing and it is an additional doctor visit, probably several additional doctor visits and unhappy patients. Depending on what the patient does or does not do, it is physically disfiguring to some extent. So, I would like to see more emphasis to look at exactly why women seem to be more at risk, and what is it about estrogen, if it is estrogen, that seems to increase the risk and certainly labeling, if it is approved, should address this really clearly for the clinicians to be able to deal with it.

DR. LEGGETT: Dr. Bigby?

DR. BIGBY: As someone who does not treat CAP, I certainly won't tell the infectious disease people here about efficacy but I am always very interested in numbers with regard to the evidence that something either is or not efficacious. I think that Dr. Alivisatos has pointed out something very important, that the justification for its being efficacious in the treatment of CAP is based on a single randomized, controlled trial of only 228 patients.

DR. LEGGETT: As you can tell from the looks, we have been down this road before. I don't see anybody jumping on blister packs. Go ahead, jump to wherever you want to go.

DR. BRADLEY: I was going back to the under 40 age cut-off. In talking with Dr. Powers when he had reviewed the previous gemi. submission, the 40 cut-off was apparently something that had to do with acute exacerbation of chronic bronchitis so it seemed a natural cut to look at adverse events as well. If, for some reason, it is actually premenopausal women that have this high rate of reactions, then I think if there is going to be some package labeling which looks at adverse events, as per Dr. Patou's last slide in his presentation, perhaps that sort of information would go in rather than just under 40.

DR. LEGGETT: Anything else? Dr. Goldberger, I was just going to ask if you wanted us to say anything more.

DR. GOLDBERGER: Well, we still have all the dermatologists here so perhaps I can get them to do some of our work for us. As you know, if this drug is going to be recommended and ultimately approved, we are going to have to write a label so we have had a lot of discussion. But what I would like, if you don't mind, is if each of the dermatologists could give a line or so on these two questions in terms of what should go in the label.

The first is for the person who develops a rash while on therapy, what the label should say about what should be done. Second, for the patient who has developed a rash on therapy, what the label should say about future exposure to this drug and drugs of the class, keeping in mind that at the end of the day we are obliged to do the best we can to make such information available to both practitioners and patients in a way that is clear to them and, hopefully, something that they can actually use. So, I wonder if we could sort of get each of the dermatologists just to briefly address what we should put in the label.

DR. LEGGETT: Who wants to volunteer?

DR. BIGBY: I think that in the description of the drug for the patient you would have to say that there is a relatively high rate of a mild drug rash that occurs, and you can sort of give a range of percentages based on trial data and also indicate that the rate is much higher in premenopausal women.

I think the management of this type of drug eruption really is just withdrawing the drug and symptomatic therapy. With regard to what should happen to them thereafter, I think that for those patients in whom it is clear that it was a drug rash, I don't think that they should get that specific drug and I don't think we are actually in a position to make a rational statement about the entire class.

DR. EPPS: I agree with those statements. I don't have enough information to say whether or not another drug from the same class could or could not be given. As far as his statements, I think that is appropriate. I might also add what percent were considered severe since they were dermatologist evaluated. That could be helpful.

DR. GOLDBERGER: You would again also say that in a person who developed a rash while on treatment the drug should be stopped?

DR. EPPS: Yes.

DR. GOLDBERGER: Is that what you meant, that this particular drug but not necessarily other drugs of the same class should not be given again?

DR. EPPS: Right. I don't think I have enough information to say don't give one of the others.

DR. ADKINSON: I would disagree. I think it would be a mistake to put anything in the package information about the management of these drugs because we don't have any evidence-based data to make a recommendation, and to put it there makes it become standard of care and really is an impediment I think rather than a help to most physicians. As far as I know, there is no precedent for that. You don't have advice on management of adverse cutaneous reactions to other drugs that are licensed so why bring it up as a particular issue here? The management is going to be the same based on medical considerations regardless what the source of the rash is. I would argue against putting any specific advice if we don't have any evidence to recommend a particular course of action.

DR. GOLDBERGER: Your recommendation then would be to describe or not to describe what was observed?

DR. ADKINSON: Describe the risk factors so far as they are known, but leave the management of the rash to the physician.

DR. GOLDBERGER: And say nothing about what should be done. Okay.

DR. LEGGETT: Finally, Dr. Drake?

DR. DRAKE: I have to think about it for a moment. May I start with a question first? The reason I was thinking about it is I don't recall any other drugs where you dictate--not dictate but make recommendations on management in this particular arena.

DR. GOLDBERGER: We certainly provide information about certain situations with regards to toxicities in general that may warrant discontinuing a drug. How much have we done? We certainly haven't in the anti-infective world had to deal a whole lot with the issue of what to do about the issue of rash.

The reason in part why I am asking is at the end of the day, in spite of some of the comments we have heard, it seems to me the majority of the evidence here suggests that rashes, at least in some patient groups who under normal circumstances would be likely to be exposed to this drug are fairly high relative to other drugs. I have heard some people say that there was no comparator in the 344 trial and, therefore, the fact that it is 32 percent--you know, we really can't interpret that. But, of course, there was a comparator, another fluoroquinolone, and the rash rate was six or seven times as high.

So, our concern is if there is likely to be a common adverse event and we are silent, what it does in essence it sort of leave the burden then on the physician and the patient to figure out what to do. Maybe, in fact, at the end of the day, as Dr. Adkinson suggested, that is the best thing to do. Since we are not sure what to say, we just don't say anything and they are left to figure out what they are supposed to do with this, what they are supposed to do in the future, although that is not an easy thing for the average practitioner and patient to have to deal with.

So, I think at the minimum we ought to have this type of discussion and get some feeling from people who at least have either, (a) a lot of experience in the area and/or, (b) at least have heard a lot of the information presented here in detail, and get some sense of what they think about this. Then, if we decide that it is sounds like people think we shouldn't say a whole lot, then at least it was on the basis of a lot of discussion. But I think it would be a mistake to just assume, well, let's not say anything even though we have a concern that some large groups of people might end up having a rash.

Interestingly enough, one of the reasons to say something might be that many people seem to believe that the rash actually is not of that much consequence, and if you were to make a statement in the label saying that, that might, in fact, be reassuring to some people.

So, those are some of the issues that I think should at least be addressed in terms of deciding how to proceed.

DR. DRAKE: If I can get away with not giving my opinion, I am happy to do so.

DR. LEGGETT: No.

DR. DRAKE: I guess I tend to believe that you should keep it as factual as possible. We have observed this rash in a disproportionate amount in women under age 40, etc. Maybe I am coming from my own personal bias because I chaired the guidelines of the Care Committee for the American Academy of Dermatology for so many years and what I have learned is that it is very hard to mass dictate what an individual doctor does with the individual patient and I don't think you should put the physician in the position of not being able to prescribe something they think might really help that individual patient without being there at the bedside and understanding what is going on with that patient.

So, I lean towards just giving the provider of care, whether it is your pharmacist, your nurse of your physician, whoever is providing that care, the facts. These are the factual issues as we know them. Then, I think anything beyond that should be--I would vote for putting in a statement that this level of rash perhaps is--you might even want to mention that this has not been seen in other drugs in this category so that will preclude the use of them. But, at the same time, I would hate to have you preclude the use of this drug when it might have a very important role. So, I think I would just leave it factual and let the patient and the care provider make that decision as individuals.

DR. LEGGETT: Dr. Wald?

DR. WALD: I agree with you entirely. Would it be helpful also to add data about the number of patients in the original clinical trials who did continue to receive treatment despite the fact that they developed a rash? I don't know if you have a number that you could attach to those who continued to receive treatment who did okay, in what proportion of patients that was. And then give the cipro. data because although it may not represent what would occur with any other fluoroquinolone, at least it would be a piece of data that suggests that at least for one the cross-reaction rate was quite low.

DR. LEGGETT: Dr. Reller?

DR. RELLER: Actually, Dr. Wald has probably already brought up perhaps the most important point, other than the relative increased frequency, and that is the data for lack of cross-reaction because the very group of patients who have the highest likelihood of a rash are the group of patients who are most apt to see a quinolone, for example for a urinary tract infection.

DR. LEGGETT: Go ahead, Mark.

DR. GOLDBERGER: I think that was very helpful. That provided us I think with at least enough information to get some idea how we might want to proceed.

DR. LEGGETT: Ken?

DR. BROWN: Mark, I was going to comment that the precedence for such a teaching statement goes back to nitrogen mustard where it says be careful and wear gloves if you are giving this drug and then the boiler plate for all beta-lactams which says what to do in case of anaphylaxis. But I think trying to turn the package circular into a teaching instrument or a Merck Manual would be a terrible mistake.

DR. LEGGETT: But it doesn't have to go as far as the sort of QTc worry.

DR. BROWN: Well, I have drafted some wording but I don't think it is important for me to share that right now.

DR. LEGGETT: You can give that to him later. That would be great. Since it is now four o'clock, why don't we pass on to addressing these three questions? Everyone here at the table, except Dr. Brown, is a voting member. As we go around, what I would like to do is hear your vote and then a brief summary of your reasons for a yea or a nay, understanding that there are many of us and there is only an hour left. Judging by the way the day has gone, I just thought I would make that clear.

Though I do not think we necessarily need a vote for the FDA's purposes on questions two and three, I would like to address both two and three at least in brief terms so they get a better idea of what to do, no matter which way they take our 50-50 vote. John, do you want to write a little longer or do you want to be the one to start?

DR. BRADLEY: I would vote for acceptance of community-acquired pneumonia, except for the severe category where I think that the data are insufficient at this time to give that approval.

DR. LEGGETT: That is a yes for community-acquired pneumonia for mild to moderate?

DR. BRADLEY: Exactly. Yes for acute exacerbation of chronic bronchitis. In terms of adverse events, to have the package labeling somehow document the increased risk of rash so that it is something that is understandable by clinicians for the appropriate age group and sex.

Then, in terms of the specifics for the subsets of pneumococci that are resistant to other antimicrobials, my preference would be to turn the clock back and just go by in vitro susceptibilities but if what Dr. Powers says is true and the cow is out of the barn, then I think simplifying the approval for multi-drug resistant Strep. pneumo. based on criteria that I think we will be working on would be appropriate because it clearly recognizes the fact that gemi. is active against penicillin-resistant, macrolide-resistant, cefuroxime-resistant strains.

DR. LEGGETT: So, that is a yes for NDRSP?

DR. BRADLEY: Yes.

DR. LEGGETT: Dr. Maxwell?

DR. MAXWELL: I vote yes for community-acquired pneumonia, mild to moderate disease certainly, and I echo what John has said about the multi-drug resistant bugs.

On acute bacterial exacerbation of chronic bronchitis I vote no. I think that while the issue of the other two adverse events, the hepatic toxicity profile and the cardiac toxicity, is really not of great concern. For me the rash still is a concern and I believe that it should be evaluated more in depth.

Having said that, I also believe that even though the rash may not be life-threatening in the few patients that we have seen, I think it will impact on the practicing physician. I know that I would be hesitant to do so because most of my patients, once they develop a rash, and this is a generalized rash, develop great concerns. So, I would like to see more studies on why women seem--

DR. LEGGETT: We will get to that later. Dr. Poretz?

DR. PORETZ: For community-acquired pneumonia I vote yes and for exacerbation of chronic bronchitis I vote yes, and I will explain why for both of those.

I think the data that we are recognizing more and more with the fluoroquinolones and seeing the resistance to Strep. pneumoniae is a real thing. I think the people from Canada showed that in the past. It is happening in the United States; it is happening in other parts of the world, and I think there is probably no reason to believe that it is not going to continue. If we don't approve this drug we could wake up in a year or two and have a significant amount of resistance to fluoroquinolones to Strep. pneumoniae. For that reason, I think it is very important to get this drug on the market and use it for those indications.

I like the concept of multi-drug resistance to Strep. pneumo. I like that as an indication. I think that sums it up very, very nicely.

DR. LEGGETT: Could you address in community-acquired pneumonia where you would include severe?

DR. PORETZ: I think it is going to declare itself, in all honesty, because those people, as I said before, who are severely ill are going to be in the hospital and are going to get parenteral medication. I am not against leaving off the word "severe" but I think it is going to declare itself so I don't feel very strongly about it. That is going to be a clinical decision.

DR. LEGGETT: Dr. Goldberger, if we forget to make sure that you have enough information about the why's or the why not's, jump in, please. Dr. Patterson?

DR. PATTERSON: Based on the fact that there is activity against fluoroquinolone-resistant pneumococci, although it may be small if you consider the area under the curve, I would vote yes for the mild and moderate community-acquired pneumonia indication and for the acute bacterial exacerbation of chronic bronchitis indication.

I would favor the term multi-drug resistant as defined by three classes of clinically used drugs rather than pen-resistant or macrolide resistant.

DR. LEGGETT: Dr. Reller?

DR. RELLER: Yes for CAP owing to mild to moderate Streptococcus pneumoniae. Though it may work for other things, I think the data are insufficient to have a broad claim for all of the other etiologies.

The data are sufficiently sparse in my view for acute exacerbation of chronic bronchitis, especially with the broad number of pathogens listed. In any individual group there are insufficient numbers so I vote no for that. Not that I don't think that it may work given the largely empirical therapy, and I recognize what has been brought up earlier about perhaps the unfairness of going back but I think the data are sufficiently sparse that I would like to see additional studies on this issue, and including a placebo-controlled trial, not in holding someone to a standard that is imposed after the fact but based on the relative smallness of the studies done to date that don't give me confidence especially for the broad range of indications.

In contrast to others, I want to take the opportunity to voice a no for specific resistance mechanisms. Clearly, in the past and perhaps the present and future there may be promotional benefit to a sponsor to have a specific resistance indication. There may be political plus to the agency for doing something about resistant organisms. But I think some of the things we have done in the past are an ill-advised precedent and, despite the past well-intentioned actions on this issue, I think it creates a deepening dilemma for us. The reason I say that is because what is true today can't be assumed for tomorrow.

In support of what Dr. Bradley mentioned earlier, I fail to see why we can't have indications for susceptible organisms and, to the extent that a given compound is active, regardless of whether or not a particular organism is resistant to penicillin, macrolide, cephalosporin or whatever the case may be, it enables one to treat. Indeed, the promotion of a compound could be based on the data in vitro, PK/PD, etc. that a compound is active without regard to mechanisms of resistance and then one has a basis for continued use of a drug based on susceptibility even though the ground may shift in terms of resistance, and even within class.

I think there is pretty interesting information presented to us, both on PK/PD as well as investigator susceptibility, and this drug may well be an agent one would go to for quinolone failure for empirical therapy. We don't have the data to specifically make that claim but as long as one had an isolate that was persistently susceptible, or even in a given institution in biograms where the prevalent organisms were susceptible, one could still use the drug empirically, getting around the argument that in reality you don't usually have an organism in these cases.

So, I think that actually it is an issue that the agency should revisit, and we should emphasize the persistent robustness of some agents versus other agents in the face of increasing resistance and not get into the specific claims that are not apt to hold up for tomorrow necessarily.

DR. LEGGETT: Dr. O'Fallon?

DR. O'FALLON: I want to preface my remarks by saying that I was really impressed by what the company did. I think that this was a good piece of work.

My problem is that when I looked through the information and saw what was going on, I think you have proved or I think the data support the decision that this is not inferior to the things that are out there now. That doesn't mean that any of them is effective. That is what isn't there. But, frankly, that is about as good as it is going to get as far as I am concerned; they are not worse.

But I do think, given the fact that there is substantial toxicity associated not only with this but with any other of the rest of them--they all have their adverse event profiles, if they aren't doing any better than, say, multi-vitamin capsules three times a day, then we are exposing patients to a lot of toxicity for no real benefit and I think that needs to be sorted out by the business here, the FDA and company. I don't think it is right to change the rules on the company because they did what they were told.

I am not happy with the results but I think that there is the problem of treating people with these agents and then we are feeding the resistance. Every time we treat these patients with something they really don't need or even if it is something they do need, we are feeding the problem of multi-drug resistance or beefing up the resistant organisms.

DR. LEGGETT: Judith, yes or no?

[Laughter]

DR. O'FALLON: No, no, you said and I am going to do it.

DR. LEGGETT: I said briefly.

DR. O'FALLON: Well, see, my problem is I can vote yes to saying it is not inferior. I can't vote to whether it is any good, and I think that is the problem.

[Laughter]

And, I think there is just not enough information about whether it works in severe disease. There is not enough information about whether it works in resistant organisms. So, a placebo trial is needed but that is not your problem; that is the FDA's problem.

I suggest though when you go to publish your results, I think it is going to be very important to use confidence intervals. These points estimates are ridiculous. We cannot tell what the real range of values is likely to be. I think it is very important to publish the confidence intervals when you go to tell the rest of the world what happened in this study.

DR. LEGGETT: So, we will take that as a yes for non-inferiority.

DR. O'FALLON: Non-inferiority is a yes. That is as far as we go. No on everything else.

DR. LEGGETT: Keith?

DR. RODVOLD: In community-acquired pneumonia I agree. In the mild to moderate indication I would be willing to vote yes. I agree that the data for severe wasn't there and historically we actually kind of voted for resistant pathogens when you had a very clear picture where there were in vitro models, in vivo models, patients, ICU, bacteremic, everything convinced and lit up so that you were really convinced that bacteremia with resistance, you were going to cover it. So, I am a little hesitant on giving resistance because we don't have a severe indication here.

With that, I would also like to make a comment about the aspect of the cefuroxime-resistant pathogens. I don't even see that that language is needed because that is not a drug you put up in CAP that much at this point and penicillin is predicting a resistance anyway. So, I think that doesn't need to be there, or second generation cephalosporins. I think the penicillin data tells you that.

The multi-resistant labeling, if you do go to it, my comment would be I would not list five or six drugs. I think that is going to be way too confusing to people. I would probably try to stay with penicillin and macrolides only but, again, I am not voting for that.

The second indication of acute bacterial bronchitis, actually I am going to vote yes for it but if I was going to hold back on that indication and wanted more postmarketing safety data, this would be the one I would tell you to hold and get more postmarketing safety data if you thought you needed to do that, and then release it later on as we got convinced. You have done that before with other drugs that you have approved. You have held an indication waiting for more data to come. But I would approve it based on the basis that you followed the trials that you were told to do and you did it. The data could be more though. I think you need more data there and I think it needs to be done better but I think you did what you needed to do.

DR. LEGGETT: I vote yes for mild to moderate; yes for exacerbations of chronic bronchitis. I see no reason from the MIC and other data to believe that this fluoroquinolone, which is a lot like other fluoroquinolones, should not work for H. flu. in CAP but I have a lot of worries about community-acquired pneumonia due to E. coli and Klebsiella pneumoniae and I would definitely not allow the name Staphylococcus aureus to go on the label for community-acquired pneumonia with this drug. I might have a little worry about even putting aspiration in there because I am a little worried about the anaerobic coverage. The reasons for all of the things are basically what everybody has stated so far.

Regarding the fluoroquinolone multi-drug resistance, I like the concept at least how we have talked about it in the last couple of meetings. While scientifically I definitely agree with Dr. Reller, I think the cat is out of the bag, as he sort of mentioned, and I think that while we can sort of try to stay pure scientifically, this is a world of political and capitalistic compromise so I think that, given that, eventually I would be convinced that this is a multi-drug resistant drug because it is exactly in that small population of folks that I might use this drug, that have seen a lot of fluoroquinolones, that I am worried at least from what we have seen so far. I do not, however, think the numbers for all the different subgroups are big enough yet. So, I would put a yes vote contingent on how many sick, bacteremic, drug resistant folks in the 287 come in. I would also make a caveat not for long use.

DR. WALD: I would vote yes for acute community-acquired pneumonia and yes for the acute exacerbations of chronic bronchitis.

I would agree with some of the others in terms of multi-drug resistance. I think we can feel confident recommending the drug for the empiric management of community-acquired pneumonias. Most or at least many of those are viral. There is a relatively small proportion that are bacterial. Of the bacterial, there is a very small proportion that are really multiply drug resistant and we never know which those are when we begin therapy. So, I think what we are saying is that this is a drug that can be used comfortably for community acquired infections of the lower respiratory tree that can be managed as outpatients. That is sort of where I would draw the line.

I don't know if this committee can exert any pressure on any AHRQ, NIH or CDC to fund the study that we are talking about, which is a placebo-controlled study, because it would be very brave for any of the drug companies to undertake that and I think really, in the end, if it turns out that most of the drugs we use are no better than placebo that would really be a tremendous advantage to the insurers and to the government. So, I think it really should be a government-sponsored study.

DR. LEGGETT: Dr. Cross?

DR. CROSS: I would vote yes for community-acquired pneumonia. I agree that there hasn't been a lot of data on severe pneumonia. There hasn't been anything on Staph. aureus and I would also agree with Jim that we have no basis for actually including that.

I think it does fit a real niche in terms of the increase in quinolone resistance. I think each of our locales ought to have some information on the degree of resistance. So, I think the idea of having an approval for multi-drug resistance is instructive if you know what is going on in your community. It gives a certain reassurance.

In terms of the exacerbation of chronic bronchitis, I have mixed feelings about this. Seeing the long list of drugs that are already approved, this certainly doesn't appear to be any better or any worse, although I do have some doubts as to whether or not it is efficacious. But the thing I am concerned about is if any patients, by getting this for this indication, do have a rash and in practice once a patient does have a rash--most physicians haven't had the benefit of the excellent dermatologic consultation we have had here and the reassurance and I think what will happen is that a patient will not get quinolones in the future. That is my main concern. Having said that, I don't think we can hold them to a higher standard although I wouldn't use it myself.

DR. LEGGETT: Dr. Proschan?

DR. PROSCHAN: I am teetering on the edge with respect to community-acquired pneumonia because I still believe that, you know, on page 69 of the blue book, it is no means a slam dunk. That confidence interval, by the way, for study 12 if you look at the intention-to-treat analysis, is actually minus 12.-something, not minus 10.-something. I tend to believe the intention-to-treat analysis more than per protocol anyway. So, it looks to me like the supportive evidence shows that it is better than at least one currently used drug. So, I guess that would tip me ever so slightly for voting yes.

For chronic bronchitis, I agree with the FDA that multiplicity issues were definitely an issue here. I think when you are writing the results you have to be careful about some of those multiplicity issues. In particular, when I look, for example, at page 64 of the red book and you see the results at all these different visits, I think it can be explained by chance. But overall I felt like the evidence was pretty conclusive that it is at least as good so I would vote yes on that as well.

DR. LEGGETT: Mike, could you give us a yea/no on severe community-acquired pneumonia? You can also abstain.

DR. PROSCHAN: Yes, I think I probably should abstain because I don't know that much about the severity.

DR. LEGGETT: Dr. Glode?

DR. GLODE: I would vote yes for mild and moderate community-acquired pneumonia, again understanding this was designed as a non-inferiority trial. I think the data support non-inferiority but I accept your comments certainly.

I would just have the caveat that I agree with 19 strains of Staph. aureus, and who knows whether that was even the causative organism. That data is inadequate for staph. or M. catarrhalis, possibly even for Legionella with 14. So, the numbers are small when you do the subsets.

I would also vote yes in terms of non-inferiority for acute bacterial exacerbation of chronic bronchitis. But I am persuaded by Dr. Reller's comments and his reluctance to allow a specific claim for multiply resistant Strep. pneumo.

DR. LEGGETT: Dr. Drake

DR. DRAKE: Well, I feel completely inadequate. I learned a long time ago you don't get in the way of the ID guys or the pediatricians when you are a dermatologist.

[Laughter]

But I must tell you I learned a ton here today and I did read all the stuff you sent me, which is unusual. I read it better than I read the derm. stuff because I actually felt I had to read it because I didn't know what I was doing.

I am going to vote yes on the community-acquired pneumonia but I would like to support what Mary said and what you said and what others around the table said. I think it is mild and moderate. I am not convinced it is adequate for severe. It may be; I just don't think we know.

I am going to vote yes on the chronic bronchitis, and that is based mainly upon what I have heard here at the table, and I hesitate to cast that vote. It might be better to abstain because I don't think I have the depth of knowledge to comment on that.

DR. LEGGETT: Dr. Bigby?

DR. BIGBY: I guess my comments would be that I think that the drug will have a relatively high rate of producing drug rashes. I think these are predominantly of a minor type and that shouldn't preclude it from being marketed. I think it should contain some warning especially about high rates in premenopausal women, and I don't think I am going to vote because I don't treat patients with community-acquired pneumonia or with chronic bronchitis.

DR. LEGGETT: Thank you. Dr. Epps?

DR. EPPS: From what has been heard and what I have read, I guess I would be in support of mild to moderate community-acquired pneumonia, as well as the bronchitis indication. Certainly, I think clinicians need options. I would support many of the comments regarding facts regarding the 344 study, the brevity of the course as well.

DR. LEGGETT: Dr. Adkinson?

DR. ADKINSON: I would vote yes on both indications, largely deferring to what I think is a consensus of my infectious disease colleagues and I certainly accede to their views on the issue of multiple resistance, about which I know very little.

My yes vote certainly includes my own assessment that I don't think this rash problem is sufficient to deny approval for a drug that otherwise has a clinical niche. I think that is especially true for the bronchitis indication where the expected rash rate will be very low.

DR. LEGGETT: Thank you. Dr. Hilton?

DR. HILTON: I feel that the high potency of the gemi. drug works strongly in its favor for me, and I feel that if I were the patient being treated getting over my community-acquired pneumonia would be much more important to me than experiencing a bout of rash. So, I vote in favor of the CAP but with the restriction on stage V of the Fine criteria.

On the chronic bronchitis, I feel that the youngest patient studied was 34 years of age and I feel that there is essentially no data in young people and it should not be considered for approval for young people. The average age was 60 and higher for the patients in those studies.

I also feel that even though the standards may have shifted and the drug company wasn't previously requested to do placebo-controlled trials, given what we know now, they are very important. So, I vote no on the chronic bronchitis.

DR. LEGGETT: Thank you. Dr. Conjeevaram?

DR. CONJEEVARAM: I would vote yes for community-acquired pneumonia, mild to moderate. I would vote yes for the acute exacerbation, but I would favor giving it as a second line, especially if they fail other regimens.

Again, my concern is that this is a recurring disease and, to me, the risk of rash is still concerning. I would favor multi-drug resistance labeling. I would also, as some of my colleagues have already mentioned, really discuss on the label about the predictors of rash, who is at actual increased risk. I think that is very important for the physicians who are treating with this drug to know. I would also strongly emphasize the long-term use, that this is really for five to seven days.

DR. LEGGETT: Dr. Sjogren?

DR. SJOGREN: Yes, I am guided here by the comments from my colleagues, infectious disease colleagues although, you know, I have heard both sides, some pro and some against, and also based on my own opinions as a clinician at a hospital.

I think I would like to vote yes for the community-acquired pneumonia and for the acute bacterial exacerbations of chronic bronchitis, mild to moderate. I think for the severe cases there is little data.

About the drug resistance, I do feel that there is so much drug resistance nowadays that the drug has shown, at least in microbiology, to be quite good about it. I don't know why we have so much resistance to approve that label. For I think for the Staph. aureus I am concerned that there was not enough data but for the rest of the organisms I thought it was adequate so I would vote yes for that as well.

DR. LEGGETT: If I could make one sort of last point for the FDA, there was mention made, regarding this multi-drug resistance status, of substituting one drug to boost something else. But what we don't know from the data that was presented is how many of these bugs were actually the same bugs so we are seeing the same 12 all over again. If it is really 12 plus 10 plus 6 and we are coming up towards 50, that is one thing. But if it is the same 15, just in different ways, then I think our numbers are not as big as we would like.

Instead of going to question two, since it is now 4:35, can we jump to question three? Let's just assume that our answer to 1(a) and 1(b) is no, what kind of things would people around the table think necessary to be done? One of the things that I would sort of throw out is that I, for sure, think that we need to finish 287 and increase the number of pneumococcal isolates and resistant data. I will shut up and let somebody else throw in their two cents. Barth, you were another hold-out.

DR. RELLER: Well, I think additional data for 3(b) is a placebo-controlled trial, funded by whoever's arm can be twisted to do it for its potential benefits to the taxpayers, third party payers, consortia thereof, brave pharmaceutical philanthropist, anybody who is willing to do it, Bill Gates.

DR. LEGGETT: There was mention made already of postmarketing studies and a study looking at photographing mucus membranes. We already talked about better data for AECB. Someone did mention, in terms of resistance gemi., rash, gemi. again, if more things can be done in that sort of subset. Then I think, of course, if the answer is no or approvable but, I think we would all like to see more cases of severe bacteremic community-acquired pneumonia in terms of that. John?

DR. BRADLEY: In some of the earlier derm. presentations the risks of rash with the drug and the risk of Stevens-Johnson/TEN were listed, and the Stevens-Johnson is always less frequent than the regular exanthem. I am wondering if there could be any systematic way postmarketing, if we could track the incidence of Stevens-Johnson syndrome to see if it throws into the category of sulfa or phenytoin or whether it is something very, very small. I don't know if that is possible but that would be very helpful and would fold into this rash AE story.

DR. LEGGETT: Dr. Reller?

DR. RELLER: Another thought occurred to me. The 344 study has been lauded by many. I wonder if it would be possible, since our dermatology consultants were of divided opinion on the importance of this rash, as well as the probability of it happening again and, if I recall correctly, some diversity of viewpoint about whether a reaction was for life or for a period of months, is there any possibility of going back to the participants in the 344 study who had a rash to gemifloxacin and giving them a five-day exposure to gemifloxacin? Because if it is 100 percent, that is one thing. If it is five percent, like it was with ciprofloxacin, or ten percent that would be very useful information. Given the general consensus that no matter whether you should or shouldn't ever give the drug again and all of the other things for which I think there was consensus that it was not a serious reaction, certainly not a life-threatening one, nor was the exanthem, Dr. Bigby emphasized, necessarily a prelude to some more serious consequence.

DR. LEGGETT: Dr. Cross?

DR. CROSS: Barth, I like that idea. I think it is worth doing. I would just like to reemphasize the point made by Dr. Maxwell in terms of looking at the incidence of rash in minorities, especially African-American. I think there were only two subjects in the large study.

DR. LEGGETT: Sorry, I forgot to include that. Yes?

DR. ADKINSON: I was going to say I found it very intriguing and would endorse the proposal of the sponsor to try to manage the rash problem by packaging the drug in five unit doses so that extended courses of therapy cannot easily be given.

DR. LEGGETT: Dr. Rodvold?

DR. RODVOLD: I agree with the aspect of packaging but the problem I have with that is no one was proven to us that it works. I constantly hear about Z-packs being re-prescribed and ABC packs being redone, but I think I would also like to see data that proves this works because it is constantly coming up--we are going to package it this way and this is going to be the save-all of this problem. So, I think that is something that really needs some science put behind it. I don't have a solution how to do it but I think it does tell us something with or not that is a really legitimate reason to put on the table.

DR. LEGGETT: In that sense, could we have question number two flashed up? Keith, you already talked about information for everybody, especially the front office and the folks answering the phone, and you talked about the Z-pack. In my notes I didn't really notice anything except how long the treatment should be and what to do about repeated courses and how to handle the rash, that sort of thing, in terms of the packaging. Do you want to address that again?

DR. RODVOLD: One of the other things that comes up that I would think could happen is that if, say, you developed a rash but you still wanted to use a quinolone, if you switched to another quinolone do you go into a problem? It goes away? I think there are going to be scenarios where people get into that. They are going to be up against the wall and they are going to switch out of this quinolone and go to the next one, and that would be very valuable information, to know whether or not you can or cannot do that. It is not going to happen a lot but it is going to happen.

DR. LEGGETT: Working in a managed healthcare plan, I can tell you that we don't get the chance to choose any fluoroquinolone we want. So, that is going to come up again too. Go ahead, Hari.

DR. CONJEEVARAM: I suspect that if this drug is used, especially for community-acquired pneumonia, and if it works for that particular patient and even if they do develop rash it might be used again for that patient. So, I think I would favor for the drug company to really keep track of that data. You are getting your rechallenge data, especially with the rash, in that setting. It will be very important. At the end of the day you can actually show that the drug is beneficial but the risk of rash is not that high or the same.

DR. LEGGETT: Thank you. Any other comments before I ask Dr. Brown to read his statement? Go ahead, Ellen.

DR. WALD: I would like to ask the dermatologists. A rule of thumb that I have used for alleged penicillin allergies when I am treating someone with amoxicillin or ampicillin is that if the rash doesn't itch and it is non-urticarial I use that as an indication to keep going, or if I get that history I feel comfortable repeating or using it again. Is that sound or crazy?

DR. LEGGETT: Or does it just sound crazy?

DR. BIGBY: Do you want a vote? I mean, I would say that there are lots of drug eruptions that don't itch and aren't urticarial and, under those circumstances, if you continue to give it the patient may or may not get worse, and if you let them clear and gave it again the rash would come back, not necessarily that it is a terrible thing. I mean, there are lots of drug rashes that are due to a drug that don't itch and are not urticarial.

DR. LEGGETT: Mark?

DR. GOLDBERGER: Just to ask again, similar to what I did before, about another issue, what kinds of statements--some people have touched upon this already--would you like to see in the label, ranging from very little to a lot, about duration of therapy and avoidance of re-prescribing, and even any comment about multiple courses over time? Some people have touched upon a few of these issues but it is another thing that is important in deciding what kind of information we ought to put in labeling. In other words, the duration and there has been a proposal for a five- or seven-day pack. Linked to that is how strong a statement about really discouraging re-prescribing and, finally, does there need to be any comment about multiple courses over time?

DR. LEGGETT: I would think in the absence of data it would be better to keep our mouth shut. Is it possible to start off a label that sort of mentions the risk while these other studies might be pursued, and then go back and modify the label specifically at that point? I don't know if that is even plausible but that might be one approach to sort of not say too much until we at least have some data and then readdress it, just as the QTc wasn't put on the packages until we had some data, or the drug interactions with the macrolides and those sorts of things.

DR. RODVOLD: I think when we did some of the other agents, linezolid and moxifloxacin, when we did that we really told people not to exceed the dose and do not exceed the duration. That was pretty much where we stopped at that point. But here you may want to say that longer durations of therapy were associated with a little bit higher risk in selected types of patients. You put it in the inserts because I was the one that made these comments during those times and Jim jumped in with me at least on one situation. We made them at that time because we only knew this amount of information at this point. If you can put it in multiple places in the insert so, hopefully, it gets read at least once, that is the best you can do.

I would agree with Jim too that eventually you may end up modifying that. That may be a goal that the sponsor and the agency may want to work to be able to change this with time.

DR. LEGGETT: I would also remind the sponsor that what they heard today about physicians being very reluctant to re-prescribe a medication to which there was a rash might be, in itself, enough of an incentive to try to sort out this question if they wanted the drug sold the second time around.

The final point in terms of packaging things, linezolid was approved for 14 days but we now have people using it for months at a time and developing peripheral neuropathy. So, anything is possible. Dr. O'Fallon?

DR. O'FALLON: With respect to the duration of treatment, there is a lot of evidence here. You provided us with a good bit of information about how the rash rate went up anywhere from five days to 15 days of treatment. I think you can simply explain that the rate, you know, tripled over that period of time. It is a statement of fact based on a very good study and I think you should put it into the label.

DR. RODVOLD: In designing and implementing a clinical trial we typically take many safeguards to minimize the bias and estimate treatment effect.

DR. O'FALLON: But the warning should be to let the physicians know that this rate is going to go up rather substantially over time.

DR. LEGGETT: Yes, Dr. Glode?

DR. GLODE: I would just think as opposed to trying to capture in a Phase IV postmarketing study retreatment episodes and hope you got them, I would think if the dermatologic opinion is split or somewhat divided that maybe it would be worthwhile, in a sort of sequential phase, to take the patients from the study and take ten women who had rash, who had mild to moderate rash, and rechallenge those ten. If ten out of ten get a rash, at least you know. If it zero out of ten, you could proceed sequentially. You don't have to offer it to hundreds of people initially.

DR. LEGGETT: Good thought. Unless you can think of anything else for us, Mark, I think we are done. Thank you, everyone, for coming and for sitting through a long day. For the committee, I believe tomorrow we start at 9:00 a.m.

[Whereupon, at 4:50 p.m., the proceedings were recessed to be resumed on Wednesday, March 5, 2003, at 9:00 a.m.]

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