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U.S. Department of Health and Human Services

Animal & Veterinary

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MUMS Forum I

Effectiveness and Target Animal Safety
Dr. Art Craigmill, Moderator

DR. CRAIGMILL: And a little more in private. I will just start. One of the questions that we have always had and raised many times over particularly with respect to efficacy, is the acceptability of published literature to fulfill the efficacy requirement. Are there any countries where that is possible?

(No response.)

DR. CRAIGMILL: Well, so much for that one.

(Laughter.)

DR. BABISH: I would like to add an historical perspective on that, Art. When the NRSP-7 program began between 1982 and 1985, NRSP-7 was able to submit published and peer-reviewed reprints as part of the data package. In fact, some of the early approvals would contain that stapled in with several other pieces of information required. So at the beginning of the program that was allowed, and that was discontinued through the ‘80s.
DR. GRIFFITH: Art, I would make one comment: in a recent submission to CVM, we did go back to some older data. We were just trying to see if there was equivalence between two-week-old calves and six-week-old calves, and the reviewer did accept the old papers. I mean, we had to go through and prove that again to some extent because we had to verify that the two-week-old calf was roughly equivalent to the older calf, the feeder calf. But they were willing to look at that data, so there was at least a modification or a softening if you want to call it that.

DR. CRAIGMILL: And that was Dr. Ron Griffith.

DR. GRIFFITH: Right. Sorry.

DR. CRAIGMILL: Are there within the EU, are there any portions of the efficacy which can be addressed using public papers, or does everything need to be GLP studies at this point? Is there a mic up here for Dr. Jones? Maybe I should keep one up here. You can stay up.

DR. JONES: Thank you. Our legislation provides for what we call bibliographic submissions, but they are specifically used when the applications are for generic projects, and that is when you submit published data which is in the public domain to support your application. For submissions for new product applications, the efficacy package indeed has to consist of studies run to GCP, although we don’t have GCP legislation. We have the CVMP guidelines which we expect applicants to comply with. I would think it would be perfectly reasonable. I don’t speak on behalf of the member states, but certainly the legislation would allow for published references in peer-reviewed journals to be submitted in support of efficacy studies run within EU territory to show that all the requirements that one would have for concerns of epidemiological patterns, if you are talking about anti-parasitics the right parasites and so forth, so that you could have a mixture of published and studies run through GCP. So it is two sections. You have the bibliographic applications, peer-reviewed generic applications where you show bio-equivalence and then you submit your published data. But there has to be a for a new application a core base of efficacy data which justifies the dose selection, the dose confirmation in the field studies, but that can be substantiated and supported and complemented by published data.

DR. MITEMA: Thank you very much. Again from the African perspective, normally we would accept published data for generics.

DR. CRAIGMILL: Would you identify yourself?

DR. MITEMA: For generic products, because the patent would be over to begin with and there would be a lot of people who have been working on the same product. So if the study is well done and well documented is published in a peer-reviewed journal, it would normally be accepted. Nonetheless, if let’s say a company, let’s say an American company was trying to export a product to let’s say one of
the African countries and the pathogen is similar. The work is done maybe in the US or in another temperate country. There would be an indication for a lot of trial, but that must be generated from within the same geographical region whereby the conditions are pretty much what would be expected for that particular disease. So we do accept published data, especially in peer-reviewed journals. But for new molecules they have to come up with their own protocols and studies, et cetera. Thank you.

DR. CRAIGMILL: Yes. Professor Errecalde here.

DR. ERRECALDE: Yes. I won’t speak in the name of the national authority because I am not an officer of Argentina. This is a personal opinion.

But now with the experiments being run with good veterinary practice and good documentation practices, this is becoming more objective. So some kind of extrapolation could be done. Anyway, this could be used as preliminary data. Efficacy data I think is necessary for reformulations, even in the case of generics when you can present good document peer-review papers. At least you should present bioequivalence data to show that you are speaking about the same thing. Then you can present papers.

DR. CRAIGMILL: Any other comments? We are going around the globe. Phil Reeves, Australia.

DR. REEVES: Yes. The situation in Australia is that studies presented in peer-reviewed journals can certainly be considered in support of efficacy. We are particularly interested in seeing raw data. We do follow the VICH guidelines with respect to GCP, and residue need to be done in accordance with GLP. Getting back to efficacy, we have concerns regarding climatic factors. That would apply probably more to external parasiticides where we are very concerned about rate of vaporization of solvents for example, because that is going to have effect on dermal absorption and residues. We are very interested in the genetic strains of poultry for example that are used in studies, because we have shown in the past that they are very specific to particular operations and they have quite marked effects on some of the efficacy. The third one of course is residence status of parasites in terms of both endoparasiticides and ectoparasiticides.

DR. SUNDLOF: Now we are going around the globe. We also accept published literature studies, and again we like to have access to raw data if possible. But just as I think most of the other countries have responded, we look at those primarily as supplementary information. Right now in the United States there is a large discussion. Some of the arguments behind this question, why FDA wouldn’t accept peer-reviewed publications, because the medical journals do, et cetera. Right now there is a large discussion in the United States about the fact that many of the studies that are published in the open scientific literature are only those studies that show a positive response and the studies that are conducted that don’t show that response never make it into the journals for one reason or another. Either they are never submitted, or journals aren’t as likely to accept negative studies as they are the positive ones. So there is at least the perception that there is a bias in the open literature toward those studies which tend to show a positive response.

One classic example of that has been the trend at least in the United States, I don’t know about other countries, over the past 20 years or so to supplement menopausal women with hormone replacement therapy. That was never an FDA-approved indication, but the literature at the time and over the years had indicated that hormones were protective against such things as heart attack, stroke, cancer, and senile dementia. It wasn’t until large clinical studies were conducted that it was found that it actually had the exact opposite effect. So now we are experiencing the consequences. So those kinds of historic legacies tend to make us in regulatory agencies think a little bit more conservative in how we look at peer-reviewed public literature.

DR. CRAIGMILL: Any comments, questions?

DR. WEBB: Alistair Webb. I would like to pick up on what Dr. Sundlof said, and that is when large-scale trials take place I believe the efficacy ability in the MUMS bill for that come after the safety aspects would show us more information, because I think it would be done on a larger scale than what is done now. Now it is done on a very limited group of animals to show the efficacy. If we allow it to be used in a wider-based group of animals, diverse geographically, age, and so forth, we may get a lot more information.

DR. CRAIGMILL: Any questions? Other questions, topics related to efficacy? Or I will just work down my list if you want.

(No response.)

DR. CRAIGMILL: I will go ahead with this then, and please pipe in with others as the come up. Under the MUMS legislation it appears that there is an indexing provision for establishing I think it is primarily efficacy, isn’t it? Steve?

DR. SUNDLOF: (Nodding head.)

VOICE: Risk benefit.

DR. CRAIGMILL: Risk benefit, possibly efficacy as well, and I am just going to ask a loaded question. Are there any veterinary drug indexing documents currently available or provided by any bodies within the world? I thought there was somebody here from USP, so I asked the question. I believe the US Pharmacopeia produces a drug index in which they do peer-reviewed indications for a lot of veterinary drugs. They recently published a couple of volumes, one on NSAIDS and another one on -- do you remember the other?

VOICE: Antibiotics.

DR. CRAIGMILL: Antibiotics I believe. So there actually are some documents available with this information that might be a great starting point for establishing efficacy, recommended doses, and things like that. How many of the other countries or places in the world have that indexing provision? EU, no? Australia? There is an indexing provision? Phil Reeves again.

DR. REEVES: The situation in Australia is different. I described in my talk minor use permits that in many ways there are similarities between that and indexing as I understand it. In terms of the minor use permits that I spoke about I made the point that minor uses permits were not a method to bring products to market, but rather a means of making animal drugs assessable to a particular producer group for an indentified need. With that the time frame on that could actually be extended out. So it wasn’t really a matter of saying this is for three years during which time you got to generate data for a full approval. Rather it was for an undefined time. It could stretch from 12 months to five years, and at the end of that time or during that time it could be terminated. Alternatively, if the producer group thought there was an important need for the animal drug, it could actually be extended. So a whole lot of conditions can be on that sort of minor use permit to the point that we can still satisfy the legislative criteria in respect to things like quality, and safety and efficacy, et cetera. As I said in my talk, it was not something that goes on a label, but rather it is a permit which is issued to the applicant. What we have done there recently is consolidated those lists because it got to the point where the left hand didn’t know what the right hand was doing with respect to different applicants. By making that information freely available, different applicants within the same industry will not apply for a permit which already exists.

DR. CRAIGMILL: Switzerland, Canada, any comments on either of these? Any other comments? Rick Clayton.

DR. CLAYTON: Rick Clayton for IFAH Europe, and I have a question on a related issue, and that is the question of “substantial evidence”. I have tried to read the American legislation and the Animal Drug Availability Act of ‘96. It is quite difficult sometimes to get through. I wonder if somebody perhaps could give a brief summary of what was looked at there and try to redefine substantial evidence?

DR. CRAIGMILL: I noticed all the CVM people looking at their shoes while you were asking this.

(Laughter.)

DR. CRAIGMILL: Actually why don’t you stand up this way if that is okay.

DR. BEAULIEU: Yes. It has been a while. I am trying to remember back to the regulations, which -- that particular regulation -- which I haven’t studied lately. The statute said before and says now that efficacy must be demonstrated by substantial evidence based on adequate and well-controlled studies. The agency either published or refined two existing regulations; one to better define substantial evidence, and the other to better define what it considered to be adequate and well-controlled studies. The latter is largely a compilation of and consistent with what the agency has said with respect to human drugs. I mean, the qualities of an adequate and well-controlled study are going to be similar, whether those studies are intended to support human drugs or animal drugs. I think our regulations are now very consistent in both well-controlled studies and substantial evidence with the human regulations. It is very difficult since the statutory standard is the same for human products as it is for animal product for those to be defined in different ways.

Generally speaking, one thing ADAA did change is that it said that it would be possible for substantial evidence to be demonstrated by as little as one adequate and well-controlled study. Then the question arose as to what that really meant. While it is also potentially possible to get a human drug approval with as little as one adequate and well-controlled study, but in both cases both centers defined that to mean it could be one adequate and well-controlled study, but it would very likely have to be a multi-location study.

The problem with a single study in a single location is that it doesn’t have very much power to be generalized to a total population of either animals or humans. If you have a study with sufficient locations and sufficient power, then you can make some reasonable scientific judgements on the basis of that study. A small study in one location is not going to satisfy, in our judgement, the statutory standard for substantial evidence. Yes, it is a single study, but that single study does not constitute substantial evidence. Adequate and well-controlled -- that is, those standards -- I think they can be more objectively defined perhaps in terms of the conduct of the study, the power of the study and so on. We have a regulation that lays those out -- I think as 10 factors that we describe in that regulation -- which unfortunately I cannot recite to you from memory. I am not doing a very good job of this because I simply haven’t refreshed my memory on that particular issue recently enough. I would be happy to talk to you about it later or identify someone at CVM that is more familiar with that issue, and they can talk to you.

DR. CRAIGMILL: Thanks, Andy. That actually is an excellent lead into one of the questions that I also wanted to ask, which I am hoping to engage certain people in the audience for a response, and that is the possibility of extrapolating efficacy data between species. Dr. Carnevale showed a slide that the efficacy portion of a drug application in NADA in the US is probably 40 percent of the cost. It is a substantial amount of money, and if there are ways to reduce fulfilling that requirement for minor species, what are some creative ways that we can use and implement in order to do that? Such as pharmacokinetic extrapolation, field studies? Dr. Sundlof, or would you like me to pass it back to the person who --

VOICE: ---.

DR. CRAIGMILL: Please stand up, too, and face the audience. Let them see you. This is Dr. Sundlof, by the way.

DR. SUNDLOF: Thank you. This is a good segue way because it does address the other question about substantial evidence. In the ADAA (Animal Drug Availability Act) we stated that in addition to target animal efficacy studies you could use surrogate studies, you could use in vitro studies, you could use pharmacokinetic, pharmacodynamic studies in certain cases as a substitute for the actual animal, target animal efficacy study. So that is in effect in the law, and it is possible. There has to be I think some fairly good evidence that he studies that are being conducted are in fact good surrogates for the actual animals, but they are certainly not precluded in the Animal Drug Availability Act.

DR. CRAIGMILL: Dr. Jones?

DR. JONES: Thank you. You may recall from my sides this morning that when we were talking about the position paper, the scientific committee at the agency, the CVMP, as to what we could do to drive this thing forward. One of the bullets in there was extrapolating efficacy data for major species, and it was as a result of reflecting on that and trying to come forward with some real, good, sound proposals that would be acceptable across the board that we actually then moved to develop the whole policy paper, our MUMS position paper which I made reference to. One of the things that that paper has resulted in is that the CVMP, which has several working parties of experts advising it on quality, safety, and efficacy, has said to its efficacy working part "We really want you to go into this in some detail and say what is it you feel would be acceptable in terms of extrapolating from major to minor species."

We have this difficulty of course that from what I am learning more and more through this conference that the progress that you have been able, the excellent progress that you have made within -- hang on a minute -- the NRSP-7, is because you have in Dr. Sundlof somebody who is pioneering this thing. You have an agency who decides policy, who decides on proposals that can influence legislation. We have a slightly different scenario whereby we have 25 sovereign states who all have their own opinions on this, and we have the Commission, which is the executive body in consultation with Council of Ministers and Parliament who make the legislation.

We are in there as a scientific body trying to push this thing along, but if anybody gets a hint that what we are doing is going to jeopardize in any sense primarily consumer safety and secondarily animal safety, they are going to say, "No. You can’t loosen up. You can’t adapt. You can’t be more flexible." But we are trying very hard through our working parties to take a look at the efficacy requirements in the context of minor species, and I hope -- well, in fact, we have had some draft proposals from them, and we are very hopefully that by the end of the year the December CVMP, as late as January we will be releasing some guidelines for consultation that will describe what it is we hope that we can do. Then maybe I can push this back on Rick and say, "See, we are really doing something."

DR. CRAIGMILL: Excellent. Excellent. Do I see a hand from Marilyn Martinez in the back?

DR. MARTINEZ: When you use pharmacokinetic data, there are a number of assumptions that need to be made, and I think the first thing that is really important is to lay out what those assumptions are. Number one, is there an active metabolite? Two, looking at the MICs of the organisms. Three, looking at the expression disease. Four, partitioning of the drug to the site of the infection.

One of the things that really impressed me recently was in discussions with Bill Craig was there were animal models that he was using for human disease, particularly for looking at pneumonia, and recognizing that there was a difference in the partitioning of drugs across the human into the human bronchial secretions versus some of the animal models. That being said, I think it is really important to also recognize that if we don’t have the drugs approved with these animals using pharmacokinetics, many times those drugs are not going to be available.

So therefore, again, what we have to do is, number one, lay out the assumptions. Two, we have to generate the pharmacokinetic data, get the MIC data if it is an antimicrobial. If you know what the disease expression is in the animal, if there are some things that have to be assumed, then you lay out what those assumptions are so that if down the road, you find out that an assumption is no longer valid then additional tests need to be made. But we have to get these drugs on the marketplace, and that is why these data are extremely valuable.

DR. CRAIGMILL: Marilyn, could I continue with that, and could you explain a little further the mechanism you might do when you would compare, for example, cattle pharmacokenetic data for a drug used to treat pneumonia to sheep data?

DR. MARTINEZ: Okay. Well, we have first of all you come to the point that if you have an assay that you use, it has been validated, there is no reason to -- and you already have the cattle data. There is no reason that you have to regenerate all the pharmacokinetic data on the cattle. Now we are saying as long as you have the validation for the analytical method, you can show that you are still running that same analytical method and it is valid, then we reuse the sheep data. We know whether or not there are any active metabolites. We ask for the generation of MICs.

Now the important thing here is to look at the relationship between let’s say if it is a beta lactam, time above MIC for the sheep versus the cattle. So there might be a difference in the C max, but we can see that the ability to maintain concentrations above the MIC is similar. So again, using the assumption that the disease expression is the same, that the partitioning of the drug is the same, there is no active metabolites, at that point -- and the extent of bio-availability is the same. At that point we would say that they are bio-comparable.

DR. CRAIGMILL: Do you think such extrapolation would be possible between pathogens? Currently, isn’t it similar pathogens are the ones that are okay?

DR. MARTINEZ: Right, and one of the problems is do we know that the PKPD relationship for that pathogen and the expression of disease is going to be the same? That is where you start getting into some problems.

DR. CRAIGMILL: Exactly. Dr. Errecalde, did you have a comment? Thanks, Marilyn.

DR. ERRECALDE: I think what Marilyn said is perfect. I only want to add a couple of things. There is an enormous growth in the knowledge of antibiotics in the last years. There are at least two kinds of antibiotics, time-dependent antibiotics and concentration, dependent antibiotics, and this PKPD pharmaco-parameters that could be obtained from this relation. This work can help us comparing the effects of drugs in animals. So for a quinolone for instance you need a large difference between the C max obtaining them and the minimum inhibitory concentrations, and for amino glycoside the same. On the other hand, for penicillins or a macrolide you need persistence of concentrations above the minimum inhibiory concentration.

These pharmacokinetic, pharmacodynamic parameters are compatible between species if the pathological agent is the same. So if we know the value of the parameter in sheep, we can use this value for cows, or for horses, or even for minor species.

DR. CRAIGMILL: Thank you. Any comments, observations on this topic? Elaine, Elaine Jetté.

DR. JETTÉ: Elaine Jetté from Canada. It is a very interesting discussion, and Canada would be interested to participate, but if we are looking for a recipe for equivalence or extrapolation, what type of forum could develop such equivalence -- maybe a checklist?

DR. CRAIGMILL: It is a good question for everyone to think about what kind of forum. One of the things that we also wanted to do was to collect ideas on how we could not necessarily harmonize, but cooperate in obtaining data that would help fulfill requirements in a large number of diverse regulatory climates, which I think is what you are asking. Yes?

DR. JETTÉ: Yes. Because I think it was Peter that was mentioning, at least someone from the EU, that they were looking for a Czar or a leader or a champion to carry on the MUMS file. Or maybe it was you, Rick. You mentioned that? So I think we need a world champion.

DR. CRAIGMILL: Eric just volunteered, Dr. Eric Mitema.

(Laughter.)

DR. MITEMA: I would just like to comment a little bit on the pharmacokinetic data and also the MICs. Of course I know there has been a lot of data generated in the last 20 years, especially pertaining to the pharmacokinetic parameters, especially in normal and diseased animals. If you remember very well, that in the last 20 years there has been a lot of data generated by pharmacologists trying to relate the regimen of treatment in normal and diseased animals. You know, this was due to the fact that, in diseased animals with pathogens being released and because doses in the past were really fixed on normal animals. Then the last 20 years a lot of pharmacologists have been thinking that, gee, maybe in the diseased animals there could be adjustment as really needed, and that also there has been quite rigorous study in the last 20 years.

Nonetheless to say again, I think that when it comes in terms of extrapolation of the pathogens between the species, a typical example, for example if you are dealing with E. coli, let’s say --- maybe causing diarrhea in piglets and also causing diarrhea in calves. You may be dealing with the same strain typically, and the pathology is basically known. If for example if certain key parameters, certain key pharmacokinetics parameters pretty much within the similar statistical significance. I think there could be room for trying to extrapolate that data within the species, and we could use that model maybe in the MUMS so that there could be a change. Because if you are dealing with the same pathogen and the MIC is pretty much within the same range, and the key pharmacologic parameters are also pretty much close, that information in my view would make sense. Especially if you are dealing with minor species in this context, or if you are dealing with animals that belong to the same kind of family background, not too far off, and depending on how the drug distributes itself in the body.

So we have cases like that. For example maybe in North America --- you may be dealing with parasites in sheep and the same parasite or the same type of parasite is found in goats. It is more expensive to generate the same data, because normally in the typical farm administration you will have the same farmer keeping goats and keeping also sheep, and it is probably the same parasite. Thank you very much. That is my contribution to that.

DR. CRAIGMILL: Thank you, Eric. Flurina, Dr. Stucki.

DR. STUCKI: I have no explanation. I have another question to what Elaine said before. When we are talking later about harmonization and exchange of data, I would like to ask are we talking then only about the MUMS subject, or are we talking in general about harmonization? Because for us it is really an important subject to do because we have to harmonize since we are the black hole in the European Union, and I would like to know --

(Laughter.)

DR. STUCKI: I would like to know how is the tendency in general with harmonization?

DR. CRAIGMILL: Thank you. Is there anyone who would like to attempt that?

(Laughter.)

DR. CRAIGMILL: It sounded, Flurina, that you were only the black hole with respect to money, however. Right? It just goes into the banks and never comes out, is that it?
(Laughter.)

DR. CRAIGMILL: I don’t see any takers, but I think that is hopefully an outcome that we will eventually be able to address with this. We have about 10 more minutes left in this forum, and one of the things that I know is there are some pharmaceutical company representatives hiding in the audience today. I wondered if any one of them would like to be so bold as to talk a little bit about their perspective from their company with respect to efficacy requirements.

DR. HALEY: Well, I want to speak to efficacy, but I want to say something else. I am Carol Haley from Pfizer Animal Health, formerly of FDA CVM, and I am speaking for Carol Haley right now, not for Pfizer. Okay.

DR. CRAIGMILL: That is written down.

DR. HALEY: Okay. Good. I am looking at the forum topics, and the topics seem to be mostly around gathering data, and certainly gathering efficacy and safety data are topics we should be discussing. I will make one comment about substantial evidence in the US. I seem to remember there is a phrase in all of the preambles to the rule and everything that talks about data sufficient that persons qualified by experience and training would come to the same conclusion. I think I am sort of summarizing that a bit. But that is one issue and I think to speak to our Canadian representative’s point, you know, it might be interesting to get together groups of scientists who sit down and say, "Yeah, this is the kind of data that would demonstrate this is effective," because that really is what -- the reasons for all the regulations we have around substantial evidence is, “do we have scientific data to support the finding of efficacy.” That is, do people qualified by experience and training, would they come to the same conclusion. So that is just my point on that.

But the other point I would like to make is that for industry issues not just around data, but also about things like manufacturing components, about definition of minor use and minor species, because that helps the company determine whether they are going to get a break or not. That is important. Enforcement of things like Andy was talking about earlier, I would be really interested in knowing what it will look like when a company comes to FDA and says, "We would like to develop a product for minor use or minor species, but there is this competitor out there." What does it mean when you say that you are actually going to shut them down so that we can get our drug approved? Does that fall in the enforcement priority list where it may never see the light of day to get done or not, or can we really expect it to get done? So those three areas I think are of interest to us, enforcement, manufacturing, and definitions of minor use and minor species.

DR. CRAIGMILL: Anyone else? John?

DR. BABISH: I also have a question on minor use in major species, and we discussed this yesterday at the NRSP-7 meeting. The definitions that I saw in most of the presentations today were just as unsatisfying as the NRSP-7 discussions. But I did find it interesting in the orphan drug definition that the lack of a possibility of any profit over the foreseeable future is one definition of a minor use in a major species, and I know we have two experts in the room here today that have done a lot of negotiating with the minor species bill. Meg, has that ever come up with this as a possible definition of a minor use in a major species -- the lack of any potential in the foreseeable future for a profit.

DR. OELLER: Yes. That was certainly one of our earliest discussions, because it was part of the Orphan Drug Act at the beginning. What happens then is you end up having to have a staff of economists and accountants to determine that, and, as it was stated today, they actually removed that as an option. It is still something that we will be able to keep in our mind, but we will not be looking for economic analyses to support that something is a minor use. So we are still looking for ideas.

DR. CRAIGMILL: Thank you. Pass it to Rick and then we will go back to Carol. Rick Clayton.

DR. CLAYTON: Yes. I have to speak up now, and from an industry perspective you really have to forget about the idea of, you know, profit for these products. It is just not in the real world, and I am actually expecting these products to come out of the marketing budget in terms of, you know, sponsorship of something like that and forget it. Because, manufacturing has been mentioned many times here today, I know a company like Pfizer have invested an enormous amount of money in their GMP plants, and now we are expecting to go on and tell them to stop their manufacturing runs to get a little short run on a MUMS product. I mean, even just stopping the manufacturing costs them money, and to expect them to do this for a product that has no profit is just not on this planet.

DR. CRAIGMILL: Carol Haley.

DR. HALEY: Yes. I would like to speak to what Meg just said a little bit. Having been involved with regulation development for some time, I went back to the law and read what the committee report had to say about the definition of minor use. It is actually interesting because on one hand the committee report does stress the fact that minor use has to be limited to a small number of animals, but then goes on several pages later to say that the definition of minor use will be left up to FDA CVM. They are allowed to have a rather broad interpretation. Then it goes on to talk about something they don’t exactly call a standard, but they do talk about saying, well, it is a minor use if the company can’t expect to get their money back on getting the approval. So I think there is some confusion; there is either some confusion or some conflict certainly within the intent of Congress. So I don’t know if FDA will decide that they have to have economists on staff to decide whether to make that decision or not, but certainly the legislative intent seems to imply -- or at least what they have written seems to imply that that is a factor that FDA can take into account.

DR. CRAIGMILL: Thanks. I wonder if we could call on Dr. Randy MacMillan to make a comment with respect to this since he was quite heavily involved with getting the MUMS bill through, probably one of the major backers.

DR. MACMILLAN: In the United States I was the MUMS coalition chairman, and the issue of profit is an interesting one. Many of the companies that in addition to AHI that were working with the coalition were very small companies. They were niche marketers. Those that were involved in aquaculture or potentially involved in aquaculture, they were interested in things like 17 alpha metuyl testosterone, which is not currently approved or under consideration under the MUMS bill or MUMS provisions. But they were looking at that type of compound for brood stock or for hormonal regulation of spawning using hormones to induce spawning. It was that kind of niche market that these smaller companies were really interested in pursuing. The AHI type of companies, the larger, Pfizer and all, our impression was that they intend to look more expansive than these smaller companies. So we just kind of muddled through that, that whole issue of profit, and we were so interested to get the MUMS bill approved that some of the key issues that have been identified here today were not focused on all that much. We were trying to get as much flexibility in how FDA deals with the approval process for minor animal species and minor uses in major species that then we just kind of glossed over some of those particular issues. It was a small step for fish so to speak --

(Laughter.)

DR. MACMILLAN: And from our perspective, it was a good move. We also acknowledge that the proof is in the pudding we will probably see if there is really benefit to the MUMS legislation in the next five to 10 years perhaps. It is going to take that long to sort things out. The other thing about the MUMS bill of course is the drug index, and that may not require quite the level of scrutiny that you need for the conditional approval. Those details still need to be worked out. We will go through the rule-making process, and I can assure you that industry will be an active participant in those as best we can in the rule-making process. Again, trying to insure that there is just as much flexibility as we can possible achieve with that.

DR. CRAIGMILL: Thanks very much, Randy.

DR. BROWN: Jenaay Brown with Smart Drug Systems, and let me just make one comment on this profit issue. I agree with the fellow from EU. If there is no profit, there is going to be absolutely no product. Period. End of discussion. But one thing you may want to consider, and I have worked for about four or five different companies, and different companies have a different percentage of profit that they want on a product. Maybe some of the smaller companies are much happier with a smaller percent profit. They can keep the lights on for a little bit less money. That is what I found out anyway, but that is just something. There does have to be some profit, but the percentage of profit varies, you know, company to company. It may interest, you know, a minor use, a minor species product, may interest one company where it wouldn’t another; but there does have to be some profit.

DR. CRAIGMILL: Dr. Jones.

DR. JONES: If I can come in on this from a European perspective. I think we have got to work through this a bit more, too. Certainly if we talk to our colleagues in the Commission who make the decisions ultimately about whether they are going to go for new legislation that would support MUMS initiatives, the argument always is of course on the human side we have got state medicine, reimbursement for medications pertaining to human health and so forth, and drugs. It is an entirely different picture, because even though you are putting public money into invest in a product that is designated as an orphan drug, because that product when it reaches the marketplace is still going to be reimbursed by state health service funds. That will never happen on the veterinary side. I am not sure about the US. I don’t know how the system works over here.

But I think we are getting mixed messages, Rick, and I think from your industry fortunately some of those messages are quite positive. You and I were in that meeting in Paris where I can’t remember the company representative, but it certainly wasn’t one of the smaller companies, that said, "Guys, don’t shut off the idea because we won’t profit." Some of these things, I think the term can be “loss leaders” in the sense that if you have a blockbuster drug that is --- well into major species, you want to really get in well with the farmer clients that maybe have enterprises with minor species as well, and to go that extra mile and reformulate -- or not even reformulate, but maybe just repackage because you want a smaller multi-dose vial, is something that they are ready to consider. So I think like the colleague from the back just now was saying, there is a possibility that even some of the larger companies are prepared to take low margins in these products because it can work in the marketplace to a commercial advantage for them.

I think the other point to make is in the real world -- again, the experience in the US may prove this differently. If we make progress on this in the EU I think it is going to be salvaging what we have got and extending it into minor species. I think the chances of developing de novo, new products for minor species is a step too far, and so hopefully we can do that even with the low profit margins. I think the biologicals -- and we often forget biologicals and there is a definite need for those in minor species as well -- some of the discussions that we have had with the head of regulatory agencies from the member states is that if you are never going to see profit margins sufficient to stimulate companies to develop vaccines for minor species, maybe there has to be state intervention. There has to be government intervention that says if we have a responsibility as a national government to provide vaccines for disease control in a minor species which makes up a livestock enterprise that is important to our economy, the government has to step in. So I don’t think we should just close the door when we say profit and there is no hope. I think we need to discuss this. Certainly in the European forum I think we need to discuss it further.

DR. CLAYTON: Just to finish, I mean, I support everything that Peter said, and I didn’t explain myself terribly well towards Meg just then and I don’t want to leave the wrong impression. As Peter said, it is not a question of no profit, nothing will happen; the point is it shouldn’t be a criterion and the company should have the choice. As Peter said, companies are interested in having the opportunity maybe to have loss leaders. If you have some fish products you may want a complete range, and you are prepared to carry one or two products perhaps, but it has to be the company’s choice how it handles its economics.

DR. CRAIGMILL: Meg Oeller.

DR. OELLER: It is me again. I just wanted to say a little bit more about this profit issue. The MUMS law does not replace anything that already existed. It was intended to add more incentives and more flexibility and more options, specifically to help the pharmaceutical industry do this, because we have had to rely a lot on altruism of drug companies in the past. Each one of the provisions benefits different groups. When we are talking about ornamental fish, then the indexing provision is the best thing for them. When we are talking about a big drug company, we are usually talking about supplementing a product they already have, and we are mostly talking about a label change. We understand that the administrative costs and the labeling costs are not free, but we are looking at issues like grants and extended periods of exclusivity and earlier marketing through conditional approval to help lower the costs for the drug companies, get them on the market faster. But not everybody is going to be able to take advantage of every one of the provisions.

It is sort of cherry-picking around to get some kind of extra incentives, and we never expected anyone to do this without making some money. That is why these provisions are put in, but there is something like an example would be to add -- well, right now we have NRSP-7's latest Public Master File for tylosin for American foulbrood for bees. That will not require a new product to be developed. It will not require a new manufacturing chemistry package. It will be a new paragraph on the label to add the new indications. So that is the kind of thing we are looking at, maybe, from the larger drug companies. For the smaller companies, the grants and the marketing exclusivity and incentives like that may be the things that they need to bring some of these niche products into the marketplace.

DR. LYNN: My name is Randy Lynn. I am with Idex Pharmaceuticals. I have been lurking here today trying to find out what this MUMS thing is all about, and I guess the only thing I would like to say is almost more of a comment and not as a question, and that is the devil is in the details. Obviously the legislators provided FDA and CVM with enormous flexibility in how this law will actually be enacted, and again from the perspective of a licensed veterinarian and also from the perspective of an employee of a pharmaceutical company I guess I would just hope that CVM would take a very proactive, very cooperative approach to find a way to work within this flexibility to make drugs available that are safe and effective without encumbering this process with unreasonable expectations for safety and efficacy.

DR. CRAIGMILL: Thanks. I think the red light has been on for about five minutes, but it is okay. We set the timer.

(Laughter.)

DR. CRAIGMILL: Ron Griffith is now going to lead us in a standup as we change moderators, a standup stretch. Dr. Paul Bowser is going to come up and talk about probably one of the least contentious of all the issues, the environmental assessment. That was supposed to be a joke.

(Laughter.)