International Workshop on Minor Use and Minor Species (MUMS): A Global Perspective

KEYNOTE: “---” denotes inaudible in the transcript.
“*” denotes word was phonetically spelled.
P R O C E E D I N G S
(8:35 a.m.)

Welcome and Workshop Overview

#Dr. Stephen Sundlof

DR. BABISH: Good morning. We will be trying to clear the halls in the back. My name is John Babish. I am the national coordinator for NRSP-7, the minor species and minor use program here in the United States. This morning it is my pleasure to begin the program. First I would like to make sure that everyone in here is interested in attending the International Workshop on Minor Use and Minor Species. If you don’t have a booklet and you are not interested in this topic, you are on the wrong flight. I mean you are in the wrong room. You see I have been traveling way too much.

My purpose here this morning is to introduce a fellow that I have known since 1982 and have had the pleasure of working with and knowing since that time, and I believe there is no one single individual that is more qualified to begin a program on this topic. From 1982 to 1984 Dr. Sundlof participated the NRSP-7 program as the southern regional coordinator, and in that capacity he developed enormous practical understanding of the problems and issues in minor species. Whether it was touring in the alligator farm in southern Florida or listening to game bird stakeholders lament about the situation in game birds, Steve has a practical knowledge of minor uses and minor species. Since 1994, he has had experience in the regulatory aspects of minor uses and minor species. So for a 12-year period and a 10-year period respectively, Steve has been participating in and understanding the national and international issues of minor species. So before I digress into some rather ripe old stories about nights in Gainesville, I would like to introduce Dr. Stephen Sundlof.

(Applause.)
DR. SUNDLOF: Thank you, John, for the introduction and the trip down memory lane. I just want to welcome everybody, especially our international guests who have traveled so far to come and be with us today. This is to my knowledge the first symposium of its kind where we brought the world together to address these varied issues that are common to all of our nations. Also we want to welcome the representatives from the pharmaceutical industry because without them none of this would work; government representatives, not only from the US government, but from other governments as well; producers of minor species, and all of the interested citizens who share our passion for this issue. As John was talking about this, it is evident that this particular issue, the need for drugs in minor species and the need for drugs in minor diseases has been more than just a professional interest. It is a profound and personal interest of mine, and I am very happy to see that we have come as far as we have, that we can also get together and talk about the needs.

This workshop is jointly sponsored by the Food and Drug Administration’s, Center for Veterinary Medicine, which is my organization, and the US Department of Agriculture’s National Research Support Project No. 7, or NRSP-7. Both of these groups have a strong interest in the development of new animal drugs for minor species, the FDA being the ultimate regulatory agency which approves the new medications so that they can be legally used. The NRSP-7 program is designed specifically to fund the studies that are needed to generated the data so that FDA can review them and approve those products for minor species.

The purpose of the workshop today is to provide a global perspective on drug needs and drug approvals for minor species and minor uses. Now a number of countries are struggling with these same issues that we have here in the United States. These are animals and diseases that do not have sufficient numbers to provide economic incentives for drug development. Sharing information about how different countries address this problem should be helpful to all of us as we develop policies and methods for assuring the legal availability of safe and effective treatments for minor species and for minor uses.

So I want to thank all of you once again for coming and introduce our next speaker, Dr. Mac Lumpkin, who has been a true friend of the Center for Veterinary Medicine. Just a little background, he told me to keep this very short, so I will. Dr. Lumpkin is a physician and is currently the Acting Deputy Commissioner for International and Special Programs of the United States Food and Drug Administration within the Office of the Commissioner. He is responsible for overseeing the Office of International Programs, the Office of Pediatric Therapeutics, the Office of Combination Products, and for coordinating the FDA responses to several national public and health issues that cut across several programmatic areas in the FDA; and we have lots of issues, so Mac is a very busy guy. Mac, please join us.
(Applause.)

Welcome
Dr. Murray Lumpkin

DR. LUMPKIN: Thank you, Steve, and I am only going to take a few minutes here because I know you have got, just looking at the program this morning, a tremendous amount of interesting material to cover today. But I do appreciate the opportunity just to be able to have a few minutes on behalf of Commissioner Crawford and myself to welcome you here and to say how appreciative we are that you have taken time out of your schedule to come and join us to have these very, very critical and very important discussions.

As Steve said, one of my portfolios right now is the international portfolio for the US Food and Drug Administration, and I am extremely pleased to see the very, very broad international participation that we have here. I think we have got people literally from all of the continents here talking about what they are trying to do to address the issue that is the major theme of this conference. As many of you know, back in 1983 the US Congress passed what became known as the Orphan Drug Act of 1983, and this was the first time that our Congress looked at the issue of how one can create incentives for a public good when the normal market forces do not present those incentives to the private sector. I think as we look back on the human drug side of our experience and see what has happened with orphan drugs over the past 20 years, we can look at the decade of the ‘70s before the Orphan Drugs Act. I think as we have gone back and looked at the data there were less than 10 drugs that were developed and brought to authorization in the United States for diseases that are called orphan diseases on the human side of our responsibilities. If you look at the 20 years since 1983, we have had 1,300 different human drugs designated as potential orphan drugs in the United States, and 250 of those have been fully developed and have been authorized for sale and use in the United States for treating human orphan diseases.

I think we have also looked at other issues such as pediatrics and how we could address the need we have in this country for developing drugs for children. Again, an area where the market forces did not give us the incentive that we needed. We have also looked, for example, at the development of agents to be used in situations were we to have a bioterrorist attack of some kind. Again, a situation where we all hope and pray we never have to use the products, so there is clearly not a market-driven incentive for people to develop those kinds of products, and you are in the same situation here. People looked at minor issues and minor species, and I think we were all delighted particularly with the work of people like Steve Sundlof and people in our Center for Veterinary Medicine within the USA and within the larger animal drug community to work together to put this particular piece of legislation into effect. I think we have all the high hopes for this piece of legislation as we have seen manifest on the human drug side of the house with the Orphan Drugs Act back 20 years ago.

So with that, I don’t want to delay any further you getting into the crux of your work here. It is extremely important work, and we are extremely pleased to have you here and thank you for coming. I will now turn it back over to -- yes, right there. Coming up. Thank you very much.
(Applause.)

DR. WEBB: Well, welcome to our workshop. Just some preliminary information. In case the speakers look nervous, it is because they have been threatened with all sort of death and torture if they exceed their time. What we are planning is if they finish early they can take questions. Otherwise the questions will be rolled over to the group discussions, which we think will be far more interesting because it is an interaction of the workshop, not a conference. That is the first thing. Second thing, warning to the speakers, this program is being recorded. Every word you say will end up in proceedings or transcripts that will eventually appear on the web after you have had a chance to delete your explicatives, and we will then have them available. There will be a CD produced which all of you who attend and sign up will receive. Don’t hold your breath, but it will come eventually.
(Audio difficulties.)

The first speaker this morning is not Dr. Babish. We are going up the agenda. Okay. First speaker this morning is Dr. Andrew Beaulieu or FDA/CVM. Many of you know him as well. He is currently, and I have got in parenthesis Acting Director of the Office of Minor Uses and Minor Species. He may be acting, but he is probably one of the prime people who have
worked with the coalition for MUMS and it is for this he has accepted our invitation to speak and to talk about the bill and to talk about FDA efforts in minor species. I think he has been employed at FDA since 1974. I tried to glean this
background information. The good thing is he came from the University of Miami. He was blown up here in a hurricane back then after getting his baccalaureate degree. He went to Ohio State University for Veterinary School and he was, as I said, very significant in the MUMS work, but also in the Drug Availability Act, which actually set the stage by telling FDA that they should be looking for a solution for minor species and minor uses. I don’t want to take any more of his time, because I don’t want him to get nervous, so I will ask him to come forward.
(Applause.)

MUMS - US Situation
by Dr. Andrew Beaulieu

DR. BEAULIEU: Wow. I am impressed by the attendance. I am going to have to say I am also somewhat conflicted by the size of the audience. As a long-term advocate of minor-use, minor-species issues, I am extremely elated by the size of the audience. As a generally nervous public speaker, I am severely depressed by the size of the audience.
(Laughter.)

I will try to proceed without letting this conflict discomfort me too much. I, as Alistair mentioned, am under severe warning not to go over time. I have a significant amount of factual information to share with you this morning, but I find that I cannot speak to this topic without first sharing some feelings with you about it. As Steve pointed out, there are number of CVM members, and I am one of them. This issue is more than a job; it’s a heartfelt issue. I have been working on this issue for a long time, and I need to thank a number of people for assisting me in my efforts.

First of all, I want to thank the organizers of this meeting. I have played virtually no role in bringing this meeting together, but I have been in a position where I could observe the work that went into it, and I can attest to the fact that it was enormous. The amount of effort to get this many people from all around the world together in one place to talk about any issue is extraordinary, and I want to thank everybody who helped to make that possible. I also need to thank a whole lot more people, many of them in this audience and others beyond.

I need to thank them for their support in helping to make the MUMS legislation a reality. We have been working on this -- many, many people out there, as well as folks in the FDA -- have been working on this issue formally since as Alistair mentioned since about 1996 when the Animal Drug Availability Act passed. Some of us were working on the issues even before that time. The ADAA did set the stage for this legislation.

The same concern for MUMS that levied the support for and the final enactment of the Minor Use and Minor Species Animal Health Act also supported a long history of NRSP-7 work and it supports the reason and is the reason why we have all gathered here for this meeting today. Personally, I have actually 32 years of government service. I just this summer passed that mark. I could not have wished for a better place to spend those 32 years than the Center for Veterinary Medicine in the Food and Drug Administration, and I couldn’t ask for a better cap to that career than working on the issue that I now have a chance to work on. It was hard to get the legislation enacted. It is also going to be difficult to implement that legislation. I promise you that I will do everything in my power over the course of the next couple of years, over which I have pledged to remain in government service, to do everything that I can to implement this legislation effectively and efficiently.

I thank everybody that has worked on this bill and worked on getting the legislation passed. On behalf of all the minor species of the world, you have done a wonderful thing in getting this legislation enacted. All right. Having gotten those feelings off my chest, I can now turn to some of the facts of the case.
(Slide.)

First, a very superficial overview of the way animal drugs are approved in the United States and where minor species approvals get into that process. The US system basically requires that before a product can be labeled, marketed, and promoted for any particular use, that particular use must have the approval of the Food and Drug Administration’s Center for Veterinary Medicine. That approval is based on a lot of information that is generated by animal drug sponsors and submitted by those drug sponsors to the agency for review. That review process when it is
successful culminates in the submission of a new animal drug application and the approval of that application.

What you see on the screen are the major components of a new animal drug application. All animal drugs, including minor species animal drugs prior to August 2nd of this year, had to go through this process in order to be legally marketed in this country. Where minor species generally fit into this overall process is as supplements to major species approvals that were gained previously. The reason for this largely is because a good portion of the work, particularly I should say major species food animals -- major food animal species approvals,- virtually all of our minor species approvals in the United States are for drug approved for a major animal species.
(Slide.)

With respect to food animal species, a major portion of the work, particularly the basic toxicology work, a lot of the manufacturing information, and to some extent environmental information, has already been done with respect to the major species. So the minor species folks have a leg up in that regard.
(Slide.)

Unfortunately, this leaves major components of the NADA which still need to be supported with new information. Particularly the target animal safety and effectiveness information associated with the minor species, as well as residue depletion studies for that minor species for food animals. This is not necessarily an easy burden to meet. It becomes clear after 30-some years’ experience with this process, which came into existence by the way officially in 1968 as the Animal Drug Amendments to the Food, Drug, and Cosmetic Act, that while this process works quite well I think -- the industry might argue not as well as it might, but generally quite well for major species

-- it does not work very well for minor species, with a few exceptions. For most minor species it simply hasn’t worked at all. There never have been any approvals and probably never will be any approvals for most minor species under this process, and the reason is very clear. The markets for those species simply will not warrant the cost of going through this approval process.
(Slide.)

This is pretty much the way things stood in the mid 1990s when a significant effort was put forth with the support of the Food and Drug Administration to modify the existing process, this process we just described, in various ways to enhance the availability of animal drugs. Now most of those changes were going to have the most significant impact on major species, but we couldn’t propose a Drug Act a bill called the Animal Drug Availability Act, (ADAA) without clearly recognizing that one of the biggest problems associated with animal drug availability is associated with minor species, and the bill that was initially presented clearly did that. The bill contained at least one solution, or potential solution, to that problem, but it was a narrowly-focused solution and it addressed the existing animal drug approval process only. A number of folks, including some in the Food and Drug Administration, felt that while this was a good start and clearly agreed with the principles and the issue as it was described in the Act, didn’t think that the proposed solution in that Act was sufficient. We thought that the uses were too complex and the animal species too diverse for the issues to be addressed by the proposed solution in the initial ADAA, and we recommended strongly that the ADAA not try to solve that problem itself, but that it have Congress direct the Food and Drug Administration to thoroughly study the issue to comprehensively evaluate what the problems were and to enumerate some potential solutions to that problem. That is what the language was in the Act when it finally was enacted in October of 1996.

At that point, the Food and Drug Administration, Center for Veterinary Medicine took on the task of forming a large taskforce to deal with those issues, got public input on a number of occasions, drafted up a whole series of recommendations, mostly involving statutory changes that would help relieve the situation, fought hard to get the Food and Drug Administration itself to agree with all of those recommendations because some of them were frankly relatively radical –and many probably still considered so now by some parties -- and managed to get these recommendations published in draft, got public comment on that draft, and ultimately submitted a final report to Congress about two years after the ADAA had passed. In other words, in October of 1998.

At that point, a coalition of interested parties many of whom you are aware, God bless them, picked up virtually every one of those recommendations of the FDA and had them incorporated into statutory language to put them into effect. That probably happened in 1999 or so, and from that point on that coalition of folks, the FDA and others, worked together to refine that language to the satisfaction of the coalition members and the FDA, and ultimately various members of Congress and their staffs, and various consumer groups and public interest groups who those members of Congress represented. All of this, after five or six years of hard work, finally culminated in enactment of the Minor Use and Minor Species Animal Health Act on August 2nd of this year. Again, thank you to everyone why participated in that process.
(Slide.)

All right. To the Bill itself, the Act itself now. The provisions, the major provisions in the new law provide some definitions. That looks like it was pretty straightforward, but it wasn’t quite as straightforward as one would think. These definitions already exist in the regulations more or less. They got tweaked a little bit in the process of making them statutory. We got a new kind of study, a residue depletion study, which is a key study for the minor use food animals, and we got additional exclusivity associated with those kinds of studies. We put language in the statute to try to alleviate concern on the part of sponsors that major species applications would be put at risk by the submission of minor species supplements.
(Slide.)

In terms of new initiatives, we developed a conditional drug approval process, and I will talk more about all of these issues in a few minutes. Maybe the most novel thing that is in the statute is an index for legally marketed and unapproved drugs. We borrowed heavily, stole actually, from the Orphan Drug Bill the concept of designation, and we brought along with that a number of increased incentives similar in nature to what is provided in the orphan drug statute. We made it easier to remove unapproved drugs from the market. Why? Because they constitute a disincentive for people to get an approval. If they are going to spend all that money only to have to compete in the marketplace with people that didn’t, obviously that is a disincentive to drug development. We created an Office of Minor Use and Minor Species Animal Drug Development in the Center for Veterinary Medicine reporting directly to the Center Director. I have the great pleasure of being the Acting Director of that office at this point.
(Slide.)

Major species, minor species definitions. These are essentially what is in the regulations now. These are very straightforward. The minor use definition is slightly tweaked. You may notice that the language appears a little bit strained in places. This is the result of the kinds of compromises that need to be made when you are trying to get legislation passed. We tried hard to come up with a more specific definition for the statute. We could not do that given the diversity of the species involved and so on. So that remains to be worked out in the regulations and/or guidance.
(Slide.)

This new exclusivity provision may be a little bit arcane for some in the office, but the current statute provides for three or five years exclusivity, depending upon the conditions of approval for drugs, on the basis of the sponsors of those drugs generating certain kinds of information. We added another kind of information, residue depletion studies, with respect to minor species to that list for which exclusivity can be granted.
(Slide.)

The scope of the review. The purpose of this change was to alleviate comments that we got during the development process of the proposals from sponsors indicating that they had some real concern about the possibility that submitting a minor species supplement might be used as a basis for CVM opening up the underlying major species applications to additional scrutiny. There is language in the statute that indicates that this will not be done.
(Slide.)

Conditional drug approval. This doesn’t change the approval standards in any way, but it does change the sequence or the timing of how those approval standards are applied. What this provides for is that after all of the components of the new animal drug application that you saw previously, except the effectiveness component, are completed to current standards -- and the sponsor has established a reasonable expectation of effectiveness for the product -- a it will be possible to get a conditional approval and the product may go on the market. It would be identified as a conditional approval, but it could be marketed on an annual renewal basis for up to five years while the full effectiveness data are being generated in accordance with the current statutory standard of substantial evidence based on adequate and well-controlled studies. This gives the sponsor an opportunity to start getting some revenue out of this product while it is still generating a major component of the application. We hope this will provide an incentive to further development.
(Slide.)

All right. MUMS indexing. This is the most novel and arguably the most controversial aspect of the legislation. We would not have gone this route if there had been any other choice that we could see. But 30-some years of experience under the animal drug provisions and the approval process we have just talked about has demonstrated that if you seek approval for certain products under that system it is just too costly relative to the markets for those products, and most products for most minor species fall into that category. So we developed a system whereby products could get legally on the market without having to go through that formal approval process. They would be legally marketed, but not approved. Admittedly, the standard of safety and effectiveness associated with this process is somewhat lower than the standard associated with the full approval process. But we believe that this sort of half-a-loaf approach to getting products legally marketed for these minor species is warranted by our experience.
(Slide.)

It is a two-step process. CVM, must be requested by sponsors to allow their product to be indexed initially. This is the step in the process where the CVM assures that there are no food safety issues, and by the way, this process is generally restricted to non-food animals or early life stages of primarily aquatic species. So this is the stage where CVM makes sure that there are in fact no food safety issues associated with the proposed use of the product, that there are no environmental issues of concern, that there are no user safety issues of concern. In essence, that the only thing that is of concern at this point is target animal safety and effectiveness with respect to the product.

If that is the case, then FDA will authorize the second step of the process, which is for the sponsor to take all of the information available, pro and con, regarding the target animal safety and effectiveness of the product that is to get indexed to an expert panel, that is essentially approved by the agency as an appropriate panel to review the drug that is involved. If the panel is satisfied with the amount of information that the sponsor has produced to the extent that they can determine that the benefits of using the drug for its proposed use outweigh the risks associated with that use, taking into account the harm caused by the absence of a legally-available drug for that use, then they may recommend -- they may write a report recommending to the Food and Drug Administration –- that the agency index that product and permit its use. They would also develop a label that reflects as well as they can the information that they have reviewed.

CVM would give great deference to the recommendations of such an expert panel. Only in rare cases, I think, would the agency second-guess the expert opinion of such a panel. So most of the recommendations are going to end up being indexed.

Now it is clearly easier to get a product -- and it is less costly as a result -- to get a product legally on the market through this process than through the normal approval process. It is correspondingly also easier to get a product off the market in this process. If problems emerge after the product has been indexed, it is relatively easy to get that product off the index.
(Slide.)

As I said earlier, we think that this approach, while not perfect and subject to some criticism perhaps from a scientific standpoint, is on balance the best thing we could do to benefit all of the people that we see, organizations and so on that we see on this slide.
(Slide.)

Designation is restricted to essentially unique MUMS products, and what unique means in this context basically is that we can designate a drug provided the same drug in the dosage form for the same indication is not already approved, conditionally approved or designated. This process does not apply to indexing. It only applies to approval or conditional approval. It is modeled on the human orphan drug law. It provides for –- once designated and subsequently approved -- extended periods of marketing exclusivity, seven years in this case, and this is absolute exclusivity. The other kinds of exclusivity currently in the statute are associated with not being able to be copied on a generic basis. This exclusivity provides that no one else can market the product for seven years in competition with the person who has gotten the initial approval.

It provides the opportunity for the agency to award grants to support such approval. Those grants can be either for the conduct of studies or to defray manufacturing costs associated with the investigational process. Not in the current law, but hopefully in an amendment coming up shortly, we will see potential tax breaks, major tax incentives for developing products under designation. As far as removing illegal products is concerned, I think the slide tells you why we think that is important. We have made it easier to do that by making it clear that if a product does not fall into one of these four categories, either approved, conditionally approved, indexed, or the subject of a regulation published by FDA indicating that the product is generally recognized as safe and effective, it is statutorily -- by definition -- a new animal drug and is immediately subject to regulatory action.
(Slide.)

The current language, the current definition of a new animal drug leaves some room for discussion. The proof of what general recognition is and isn’t and so on it is difficult sometimes to establish. No longer.
(Slide.)

Finally, the statute provides for the creation of a MUMS office, the purpose of which is to facilitate everything we have just talked about and serve as a general liaison for the MUMS community and the regulated industry.

I have a few more slides, but I will stop there in the interest of time. I will be here all day today. Meg Oeller who is working with me in the Office will be here today and tomorrow. Our numbers, email addresses, are in the packet. Call us. Thank you.
(Applause.)

DR. WEBB: Thank you very much. Our next speaker is Peter Jones. He got his veterinary training in Liverpool, so I guess he is Liverpudlian and may personally tell you anecdotes about the Beatles. He was general practice in the United Kingdom and Canada, and then he jumped to the pharmaceutical industry working with regulatory areas in multi-national countries in both Europe and the United States. He then jumped to the dark side and became a regulatory and is currently the head of the Veterinary Unit of EMA, and we welcome him. Thank you very much.

MUMS - EU Perspective
by Dr. Peter Jones

DR. JONES: Thank you very much, Mr. Chairman. I am not a Liverpudlian. I’m a Welshman, but there is no Welsh veterinarian school. Liverpool is the closest I could get to it. It would serve me well I think.

First of all, I would like to thank the organizers for inviting me to this very important workshop. For everyone who feels strongly as I know we all do about animal health and welfare, this is a most critical issue, and I am really glad to be here to speak, but also to learn.
(Slide.)

There are a number of issues for us in the EU, and I need to speak about the EU perspective. But first of all, let’s look at what that EU is, because the EU itself is an issue. Why? Because it is very big, and this year got even bigger. We had 10 new countries joining the Community, and when you look at the map you can see that we have got countries which are less than 200 miles from the North Pole, and if you go down to the south you see that you have got countries that are less than 20 miles from the north coast of Africa. So that in itself presents problems of regional diseases, different species predominating, and we have to deal with that as well as all the regulatory challenges that we meet.
(Slide.)

What are those issues then? Well, taking the advice of Meg Oeller and Art Craigmill, I need to just tell you a little bit about the authorization procedures in the EU. They are rather complicated, but it helps to put this whole thing into perspective. I want to try to describe what the problem is for us, very similar to what you had here in the US some years ago. How do we define it, how did it arise, who are the parties involved, because this is obviously of necessity a collaborative effort to try and address this matter and to get solutions, and then to come to describing for you what actually we are trying to implement and what actions are underway to resolve it.
(Slide.)

In the European Union there are two relatively new systems for authorizing medicines. New legislation came into force in 1995 establishing the EMEA, or the European Medicines Agency, where I am based, and the purpose of this new agency and the introduction of a new procedure called a centralized procedure was to get around the hurdles that faced pharmaceutical companies before then and needing to go with their dossiers to the then 15 member countries, member states of the EU, and to negotiate individually with all those authorities to get an authorization. Centralized-systems enable companies to get a central authorization or community authorization for the centralized process, whereby the dossiers are submitted to the EMEA in London, and after the assessment process, the scientific committee of that agency, the CVMP, the Committee for Veterinary Medicinal Products, issues an opinion which the Commission in Brussels, which is our regulatory authority, turns in to a decision.

Now this centralized procedure applies to all products which meet the criteria set out in Part A of an annex to the regulation that you see listed there. Those are products derived from recombinant DNA technology, so that all biotech products have to be compulsorily licensed through the centralized procedure, and you have then got a central authorization with in the larger EU in the now all 25 member states. There is a Part B to that annex which lists products that at the discretion of the applicant could still be eligible for that centralized procedure (but it is not compulsory). They are new molecules, innovative delivery systems, innovative medicines, new claims. So that it goes give companies that want to market the products throughout the European Union the opportunity to get community authorization; and the CVMP has judged that a new serotype for a biological not authorized prior to entry into force of the regulation also meets criteria set out in Part B, so they, too, can come through the centralized procedure even though they may not be a biotech product. So this route, as I said, provides for community authorization in all 25 member states.
(Slide.)

The second route of authorization is something called the mutual recognition procedure, and this procedure operates for conventional products, for generics, and at the discretion of the applicant those which would qualify in the Part B of the regulation for centralized procedure, but where the sponsor may feel that they don’t want to commercialize the product in all of the European Union. You might envision a company who is manufacturing and authorizing products for the dairy industry who of necessity wants to get into the big dairy markets in the UK, Ireland, the Netherlands, Germany, France, but not into some of the southern Mediterranean countries. The way that that procedure operates is that authorization is undertaken by one member state, of the EU, the reference member state and the recognition of that authorization by the remaining member states, the concerned member states, where the applicant wishes to license the product.

So you can see the two systems that we have in play, and the problem that comes of this is that while many companies would like to authorize their products through the centralized procedure may be for minor species which prevail in all countries, but not in large numbers, is that that centralized procedure can be quite expensive and burdensome because you have to produce your product literature in 19 languages. We have 19 official languages in the European Union now. So undertaking translation of SPCs, data sheets, packaging inserts and labels is an expensive cost to be considered. So many of these company will consider the mutual recognition procedure to try authorize these products, and it makes sense if you are trying to bring a product to two or three countries where maybe rabbits for meat consumption predominate, or dairy sheep predominate, or reindeer predominate as is the case in Scandanavia. But the difficulty of course then, as we will see shortly, is that there is no harmonized approach by all the member states authorizing these products. They tend to follow their legislation in asking for the data requirements as laid down in that legislation, but there is a lack of harmonization in the approach with which they take that onboard. If a company wants to license a product in one country only, it can do so and that national authorization can continue.
(Slide.)

So the first step is to try to define the problem, and here we have some of the minor species that we have been talking about. They are just examples. There are many more not on here. Deer, different avian species, rabbits other fin fish.
(Slide.)

So continuing to ask ourselves what is the problem, it is very clear. Veterinarians do not have medicinal products available to treat some minor species, and to a lesser extent minor uses in major species, including both food and companion animals. These vets understandable are becoming very angry and very anxious. In effect they are potentially breaking the law when they are using product off label in large numbers of animals; and it is not only a conflict for vets and their duty of care to animals, but of course off label and sometime illegal use of medicines in food animals can result in residues. That is indeed a major problem because it focused attention on this whole problem as being more acute in the food animal sector than in the companion animal sector.
(Slide.)

How do we define it? It is very difficult. Definition of a minor species and to a lesser extent minor uses is a real challenge, especially in such a diverse region as the European Union. You saw on the first map there how big a geographical area it is that we cover, and what may be a minor species in one country can be of course considered a major livestock enterprise in another with widespread consumption of food produced in the latter. So that indeed what might be construed as a minor species, say goats in Northern Europe, can constitute a major species in Southern Europe where these animals are a major livestock sector. Goats are produced for meat and for milk, and that in itself presents a problem with how you agree on definitions. Despite attempts to define minor species, some of them achieve higher profiles than others, and that also presents challenges to resolving matters.
(Slide.)

The reality is that politicians, veterinarians, animal owners concerned with the horse for example seem to be far more successful in attracting attention to this problem than those concerned with these creatures(laying hens). Now you are saying why, are they-hens a minor species? Well, no, they are not. Of course in terms of numbers they would not be a minor species, but we treat them as such because there is a distinct lack of medicines available for laying hens in the community. But when you look at the shortage of medicines, it is the horses that seem to attract higher profile and higher attention, and that has resulted in initiatives being taken in the European Union to try and facilitate provisional medicines for the horse as opposed to some of these other minor species because he who shouts loudest gets the results.
(Slide.)

There needs to be some means or some way of trying to reach agreement between all the parties as to what medicinal products, and part of the problem is if you talk to those that are the interested parties, the vets, the farmers and so forth, is that you end up with a wish list. That is really not very helpful. When we first spoke to the veterinarians in Europe, the Federation of Veterinarians, and said, "Look, you need to help us to try and define where these therapy gaps exist," and the response is that you get a list of 100, 120 products which they say, "This is what we need." In reality, there is no way that we can work on that basis. We have now made progress on that, and I think we all understand that we need to narrow our sights a little bit. So that the reality is that despite the best intent the lack of adequate return on investment by industry -- for industry, is a significant disincentive to research and develop these products, and we need to find a way of overcoming this as well.

In terms of further defining the problem, there is a tendency in the past to censure the regulatory authorities and to hold them responsible for resolving that matters, and I think that is unrealistic. It has to be a concerted effort between all those that are interested, all those that need to resolve the problem, and a collaboration and a coalition is the only way we can go forward. There are no procedures or legislative measures in force to facilitate the authorization of MUMS products. As I mentioned, that is something that would only come about if we have changes in legislation.
(Slide.)

How did this problem arise? Well, to some extent it has always been there. There was never a time when there was sufficient medicines authorized in the EU for minor species. Prior to major legislative changes in 1981 when really the foundation of legislation for licensing medicines in the EU came into being, the veterinarian had the right to prescribe. It was almost as if they had this inalienable right to use whatever medicines the wanted. So there was widespread off-label use for MUMS. A significant step in 1992 was the introduction of legislation to establish maximum residue limits, and this obviously compounded matters.

When this legislation came into force it meant the companies had to establish sfe residue levels and submit an application to establish an MRL at the time of authorizing their product or slightly before so that authorization was dependent on an MRL being established, and there were upward of 1,000 old products in the EU that also had to have MRLs established. Some substances were never defended. Companies just felt that there was an inadequate return on that sort of investment. Applications were made by some sponsors, but they were inadequate and they never really took it any further. Other companies were trying very hard to defend their products and submitted applications which were reviewed by the CVMP. In the end though questions, the incomplete letter I think you call it over here, was too much for them to respond to, too much investment for answering those questions, generating the data, and that also resulted in products being lost. We will hear much more about that from my colleague Kornelia Grein, who is going to be talking about the situation with food safety in the context of MUMS in her talk tomorrow.
(Slide.)

I have mentioned the reluctance by the veterinary pharmaceutical industry to invest in R&D of such products, and of course we all know about the shifts in industry for mergers, the downsizing of some companies, the divesting by some of the larger companies of their animal health divisions, and that basically has a huge negative impact. These MUMS products are no way the blockbuster products that these companies are looking for to really make money. Certain livestock enterprises have grown significantly so that the problem has become more acute. Regulatory requirements have increased. There is no doubt about that, and that results in a higher R&D cost for industry. It is very difficult, I think, for the regulator to balance what is demanded by societal values in terms of consumer, environmental, and operator safety to try to have a predicable, stable, regulatory environment for all licensing of products, let alone MUMS. As I have mentioned before, no specific legislation in the EU exists, and there are no agreed definitions.
(Slide.)

Who are the parties involved? Well, as indeed over there, in Europe there are a number of us. The regulators. The EMEA; the European Commission, which is the regulatory authority in the EU for products that authorized through the centralized procedure and they are responsible for legislation and procedure; the member states of the European Union, 25 of them.

The industry. The International Federation of Animal Health in Europe, IFAH-Europe, and obviously strong links between that federation and the AHI in the US and other industry associations in other countries; the European Group for Generic Veterinary Products and the Association of Veterinary Consultants. They are a very important group in the EU with the changes in company structures and mergers, and so many companies have consultants as opposed to having a strong base of regulatory staff to advise them in their regulatory activities; and these colleagues are often past members of industry regulatory staff, and they are very vociferous and very active in this whole MUMS issue on our side of the pond.

The Veterinarians. Of course the Federation of Veterinarians of Europe, the FVE; and the producers-COGA-COCEGA. That is an acronym for the name of the organization representing farmers. I have to say it has rather been disappointing that we have seen very little push from the farmers. They clearly want and have a need for greater availability of medicines for their animals, but they haven’t played such as an active role as one would have liked.
(Slide.)

So what actions are under way? What have we been trying to do to resolve this? A number of activities have been taking place. There was a big meeting which was a landmark meeting in the late ‘90s between all these interested parties, and following that we convened the taskforce of the EMEA with representatives from across the sphere and we tried to come up with recommendations that we felt could kick this thing into play and really start getting things focused and moving forward. As a result of that, certainly some of the recommendations were taken onboard by the Commission in a communication to our Council of Ministers and Parliament and the references given there making a number short, medium, and long-term considerations.

Extrapolation of maximum residue limits from major to minor species; calling for a review of efficacy requirements so if you have an authorization in the major species to facilitate a minor species authorization from major to small ruminant for example. Relaxation of the cascade. This is part of our legislation that enables off-label use, but in very strictly defined conditions and in very much the control of the veterinarian for small numbers of animals and under his care. This allows a veterinarian where there isn’t a product authorized for an indication in the particular species to use a product used or licensed in another species in that same country and then to set a withdrawal period as defined in legislation. A mechanism analogous to human orphan drug policy is what was discussed in that paper, and indeed the EMEA has prepared a policy and submitted it to the Commission, but there hasn’t been enough impetus and drive to convince our colleagues in Brussels that that is something they want to move forward with on the regulatory front as yet.

Kornelia will talk about extrapolation of MRLs from major species to minor species as I mentioned, and the initiative to extrapolate indications from major and minor species has been focused on in some considerable detail. What has resulted from that is a great deal of in depth review and discussion over the last two or three years at the CVMP with the result that we produced and adopted in July of this year a position paper regarding the availability of medicines, and that is available on our website. This is a pivotal document for us. It is really from the regulatory standpoint an attempt to lay down what the situation is today, an estimate of what can be done, what possibilities exist for it, and to really make strong recommendations on a strategic basis.
(Slide.)

Commission Decision 2000/68 was as a result of a lot of lobbying by member states with regard to the horse. Remember I said the horse seems to attract a greater profile. There seems to be greater impetus to do something about the horse because in the EU it is a food animal, and that decision allows the exemption of particular animals from the equidae family from the requirement of MRL legislative requirements when they are clearly identified specifically marked with a sort of horse passport as not being intended for slaughter, and that is currently in place. That as certainly helped in terms of providing medicines for horses.

We have this year undergone a huge review of the pharmaceutical legislation in the EU, and the Commission, the Council and the Parliament have tried to introduce in the new review, new provisions aimed at helping to resolve the problem. The relaxation of that cascade facility that I talked about means that it is now much clearer so that there should be a common interpretation of that across member states which there wasn’t before, and we have also allowed products to be used when licensed in another country but not in the country where the veterinarian is seeking to use the product. We have also now got a provision for identifying essential products for horses so that they can be used without MRLs and used where there are therapeutic gaps in products that have very much applied and with consulting with the equine veterinary profession to determine what those products should be. There is now provision for greater protection for products that are authorized for minor species.
(Slide.)

The CVMP position paper, I won’t go through this in great detail, but it attempts to define the problem. As I mentioned, that is a major challenge in terms of how you define major species and minor species. I have talked about that. We have used the MRL guideline that has been current for some time now so that the major food producing species are cattle, dairy and meat animals; sheep; pigs; chickens including laying hens; and salmonidae. As a consequence everything else defaults into minor species. We have considered the legislative aspects, and we have certainly made our commentary on that.
(Slide.)

This illustrates really the problem we have got with what is a major and a minor species in the different countries. If you class sheep as a major species and goats as a minor species, then what do you say to the farmer who is going to go round these animals up when they graze together and treat them with a wormer for worms in the summer. Pick these guys out, the goats, and leave the sheep or vice versa? That is the sort of problem we have when we are trying to classify what these animals are.
(Slide.)

The position paper goes into a strategic action plan. It talks about possible use of provisional authorization, and we heard about that from Dr. Beaulieu earlier this morning. The ability to introduce a product on a provisional authorization basis with a legal commitment for followup for data to be provided in order to complete the dossier, and we are evaluating that. We want to provide free scientific advice, I think you refer to that over here as protocol assistance, from the CVMP to encourage companies to come in and seek advice from us when they are thinking of developing these products or extrapolating from major species authorizations. Our Management Board at the EMEA has provided as with the facility to do this and has provided funds, and that is now in place. So the possibilities of extrapolation of major to minor species MRLs is underway, and we will hear more about that tomorrow.

Our CVMP and its working party of experts are looking at adapting the data requirements within the legislation to see if we can facilitate easier pathways to authorization without compromising consumer safety. We need to work with our member states to harmonize the approach, and we also are looking to provide assistance to companies intending to submit for these regional diseases and for minor species. So we hope to help with some of those translations that will be bureaucratic hurdles they face. We are still pushing for more reflection on legal mechanisms. I passionately believe that the only way we will go forward and make significant steps is if we have an orphan drug policy in the EU, and we need to work on persuading our political masters that that is certainly something that has to happen.

Community support for research funding, we are looking at that as well. So the question now is who goes next and what goes next, and I think I want to wind up with a real message here as to where we are struggling. That comes down to responsibilities and actions.
(Slide.)

What has been the case up until now is that there has been a great deal of focus on the regulators to do everything. Whilst we regulators have to facilitate the regulation of these medicines, it is only now that I think in the last 12 months, 18 months or so, that we have come to realize that there has to be a coalition of all parties. There has to be collaboration, and the driving force that will take this forward to persuade our political masters to persuade the politicians to persuade the executive are the people who need these medicines. The producers, the veterinarians, the member state competent authorities who do, after all, have responsibility for making sure that there is provision of safe and effective medicines for all animal species. I think we have learned not to aim to high. We need to focus on what is essential and work on those. We are really trying very hard with our collaborates to try agree on a list of essential products, and I was very interested in the meeting that I sat in yesterday to see how much progress you have made in the U.S. in identifying what is essential and really focusing in and not having a wish list of hundreds of products. We need to therefore continue to work together I think if we do that we will make some progress.
(Slide.)

I hope we can catch up to where you are in the US, and I guess we have talked a lot about MUMS. Let’s hear it for the DADS as well, because I think this will help us.
  (Laughter.)
  Thank you.
  (Applause.)
  DR. WEBB: Thank you. Our next speaker is Flurina Stucki. She is Swiss. She has a bag of Toblerone outside to give to everybody.
  (Laughter.)

She comes from Bern, which is the home of Toblerone. She got her veterinarian training there at the University of Bern. She even did better. She studied veterinary anaesthesiology, which I am very pleased to see. She practiced with she says farm animals and pet animals, and I think farm animals in the Bern area has got to be dairy cattle. Ten for the last three years she has been with the Swiss Agency of Therapeutic Products as a veterinarian reviewer, and in her work there she specializes in the minor use of minor species areas. Thank you.

MUMS - Swiss Perspective
by Dr. Flurina Stucki

DR. STUCKI: Good morning, ladies and gentlemen. First I would like to thank the organizers for arranging this meeting and giving us the opportunity to speak about the MUMS program in our countries and to discuss together later on. Our institute called Swissmedic is situated in Bern, which is the capitol of Switzerland. The institute is doing drug authorization and marketing surveillance for human medicine and also for veterinarian drugs. So we are about 300 people, and the department for the veterinary drugs is only about 10 people. I can tell you something about the aspects of MUMS in Switzerland.
(Slide.)

The bear, you can see him on the slide here, is the heraldic animal of Bern. You can find him everywhere in town, but in his living form he presents a minor species in Switzerland.
(Slide.)

The marketing authorization in Switzerland contains the three minor requirements, quality, efficacy, and safety. The safety factor for veterinary drugs includes of course the food safety aspect. The regulation of the authorization is based on the new law of therapeutic products from December, 2000, which includes both human medicines and also veterinary medicines. Several guidelines are taken into account for that authorization procedure.
(Slide.)

If a drug is already approved in a foreign country with an equivalent medicinal product control it is fixed in our law that this circumstance is considered. Vice versa, Swiss medic decision are recognized in several countries .
(Slide.)

Last but not least, the increasing requirements for quality, efficacy and safety cause a lack of available veterinary drugs. Like in other countries, different known reasons are involved in this problem. The demand of vets to have a wide range of veterinary drugs available, the adoption of the regulation which is demanding MRLs for all active substances applied in food animals, and of course the small market share of veterinary products. Just to say the most important ones. You can imagine that this market share is even smaller in Switzerland, and so Switzerland as well is concerned by the MUMS problems. I will speak to you about our situation and especially about our efforts to handle this problem.
(Slide.)

The lack of authorized veterinary drugs for MUMS has been recognized to be a major reason leading to misconduct in that field. As a result of the availability problem there is still observed an increasing off-label use of veterinary drugs. Legal standards to avoid the procedures are not always followed. When drugs authorized for small animals are applied in food producing animals the food safety is not granted. Due to the strong concerns of food safety as well as the requests belonging to animal welfare and animal protection, the Swiss federal authorities decided to act. Improving the availability of veterinary drugs can actively promote the compliance in this field.
(Slide.)

So what we have done, under the lead of Swissmedic a taskforce group was created in May, 2002, to pay attention to the availability problem, especially in food-producing animals. In this group were representatives of different federal authorities as well as of cantonal authorities, but also veterinary organizations and various livestock breeding organizations. The first step was to find resources to deal with the existing situations. The goal was predicted to work out methods and solutions to minimize the shortage of veterinary drugs.
(Slide.)

One of the first measures was to evaluate the lacking substances. Together with veterinary organizations and experts, lists have been required with the lacking substances for ruminants, pigs, poultry, farmed fish, horses, and rabbits. For the selection of this substances in the relation to “must have” -- against “nice to have” the absence of an alternative treatment was an important factor. A risk assessment took place in the meaning that we stopped going on, with substances without MRLs because there we saw no chance for a solution in the near future because of the high cost. Some examples, for cattle there is no imidocarb to treat Babesiosis, and there was at this time no Halofugihon known to treat coccidiosis. For goats, a short time ago as anthelmintics if there were only benzimidazole substances available. There was a strong demand for eprinomectin, and further in goats we don’t have any antibiotics to treat mastitis. In pigs as well as in all other species there is no doxapram available at the moment, and since the loss of phenylbutazone for food producing animals there is no oral NSAID to treat these animals. In farm rabbits there is no authorized antibiotics at all. Also in farmed fish there is a strong demand for drugs to treat infectious disease. Only since several months Bronopol is authorized in our country, but all other drugs are still missing. For horses doesn’t exist, an authorized penicillinfor intravenous application as well as for example thiobarbiturate for anesthesia. On the basis of the resulting substances and with quite a large view of the experience of the FDA and of course of the NRSP-7 program and the propositions of the EMEA we heard before, we started to develop some standards in our country.
(Slide.)

The following solutions are either already implemented or are in development. Since the beginning of September, 2004, we have a new veterinary drug decree which regulates the use of veterinary drugs in food-producing animals. It has nothing to do with the authorization of drugs. In this decree the Swiss cascade is implemented. I will come back to this in the next slide. Implemented in the same decree is the exceptional rule for horses, but next to that there is still a lot to do. In progress is the MUMS decree, in a certain way comparable to the FDA bill we heard before. Other tools underway are the limited permission and a notification requirement for special animals. There are the five subjects I will talk to you.
(Slide.)

The Swiss cascade is very similar to the cascade in the European Union. The veterinarian decided in his own responsibility if there is no other treatment in a first step to change to another indication, and then if there is still no drug available on another species. Then there is a possibility to switch human medicine authorized in Switzerland. And at last if there is still no product such as referred, a pharmacist can prepare a drug according to a veterinary prescription. The import from abroad was allowed before the cascade was enforced, and is still possible if there is no other alterative. For food animals it needs a permission from Swissmedic for each single case. So it is not a very comfortable way for the veterinarians. To allow the cascade also for food-producing animals there is a regulation for food safety which is valid for each single step. Only substances with defined MRLs are allowed to use for this purpose. That means that either they have MRL or they don’t need anyone because for the protection of the human health it is not necessary to establish an MRL. Also the withdrawal periods are laid down in this cascade. The harmonize with the determinations in the European Union.

Now the regulations for the horses. This exceptional rule for horses, and horse -are in our country also fixed in the law as food animals -this rule means that horses can be kept for non-food purposes. But then the passport has to signed: “with this horse is not intended for human consumption.” For these horses the range of veterinary drugs is of course wider. These sport horses are considered as pet animals and can be treated also with substances without an MRL, including the forbidden substances for food animals. All the horses which are still considered as food animals can be treated with substances without established MRLS, but then except for the forbidden substances. But this requests a withdrawal period of six months. In these horses all treatments have to recorded in an individual file.
(Slide.)

Now to the MUMS degree itself. The next three subjects I talk about are suggestions, we are only at the beginning it is in development. It is not implemented yet. It will take some time for it. As we know, the cascade can’t solve all availability problems, and additional, the long withdrawal periods after using the cascade are not feasible for all situations. The goal has to be that the missing drugs can be authorized one day. That is our idea. At the moment we are working out a simplified marketing authorization for MUMS drugs. This MUMS decree is from the idea similar to our human orphan drug regulation.

The three main points have to be discussed. What is the definition of MUMS? That means which products are considered to profit for such a simplified authorization; and in which field and in which extent are simplifications available, and what can be the grant of the authority?
(Slide.)

Some words to the definition of MUMS. We don’t have the same problems like in the European Union of course because we are only one country. It is much more easier for us to do this. So which animals are considered as minor species? Also we define only our major species. It is proposed that cattle, dairy and meat animals; pigs; sheep, but only the meat animals; chicken; horses; dogs; and cats are major species. All other species are minor species. This is in particular, for example, goats; sheep, but then without the meat animals; laying hens; rabbits; fish; honey bees, and so on. This list of the minor species of course can’t be final.
(Slide.)

So what is our definition of minor use? Seldom occurring indications or limited applications in major species. What means that? As a minor use are regarded special applications in major species for diseases which are occurring rarely or which are treated in a circumscribed scope. That can be, for example, a geographical limited incidence of a disease like babesiosis, or a treatment which is reserved to a specialized clinic. Also this definition is in discussion. What is sure is that the applicant of such a marketing authorization has to demonstrate the minor use of his product when it comes to an authorization.
(Slide.)

Now some key words to this MUMS decree. The attainment of the food safety requirement is a high goal which assumes the existence of defined MRLs. Especially in these products, the possibility of the pharmaceutical industry to put money into research is very limited as we all know. For us that means that nearly only substances with an established MRL are possible candidates for a marketing authorization. That means further that an enlargement or an extension of an already-existing product for MUMS application is one of the most important ways to go for us. Or at least it should be a product with a known substance respectively with a known MRL. The extrapolation of MRLs from major to minor species is a tradition in Switzerland and is therefore not a limiting factor for MUMS authorization. The simplifications we are planning concern mainly the part from the efficacy and sometimes the part of the safety. Whenever possible, data from literature can replace our studies. But this decision will be done case-by-case. Swissmedic will provide its knowledge. It can give advice and evaluate special study designs or extrapolations before the submission of an application. The fees for the authorization will be waived.
(Slide.)

Just some words to the limited permission. This, too, will make important veterinary drugs against dangerous disease available in a short time. It should be also a part of this planned MUMS decree. This limited permission normally should end up in a MUMS marketing authorization. It should give the company or the involved groups more time to collect the missing data.
(Slide.)

To the last factor is to say that this notification requirement is not at all an authorization. It is more a listing of drugs for special exotic species like ornamental fish and birds and so on. The requests will differ clearly from a simplified authorization. It will include only a special veterinary products and, for example, no antibiotics.
(Slide.)

In the meantime, that means until the presented tools are enforced, and this will happen approximately in 2006, some projects are in progress. On the basis of these projects, we can see if our approaches are working. In goats, as I mentioned at the beginning, the situation with
anthelmintics was worrying because there were only Benzamidazoles available with a rather high resistance rate. With the extension of an existing drug for cattle, the substance eprinomectin could be made available. The cooperation between Swissmedic, the Swiss goat association and the pharmaceutical industry was necessary. With pharmacokinetic data from literature and a monitored release field study -- that means a field study has to be done -- the marketing authorization could be done.
(Slide.)

For farm rabbits there is as I said no authorized antibiotic at all. There is a strong need for substances to treat pasteurellosis and diarrhea. Also in this case the basis was the extension of an existing product, but in this case are no data available to define efficacy and target animal safety. Because of that, the few Swiss farm rabbit breeders and producers we have in Switzerland team up to the first Swiss farm rabbit association to put power and money together and to support the needed studies. This is so much amazing because they are normally in big competition, and they team up only because of the availability problem. The study is under the head of a department of our university. These studies are in progress at the moment, and we hope that it will work.
(Slide.)

Let me say some critical points at the end. Is the pharmaceutical industry willing to cooperate? We will see it only when the MUMS decree is enforced and can be really used. The funding is a problem for us, because authorities don’t have money to support research and studies. You might know in Switzerland the money is safely locked up in banks and is not available for our MUMS projects.
(Laughter.)

Sometimes the money has to come from the user itself or the breeders or the animal owners. Strongly connected with the funding of money is the problem of the substances without an established MRL. There we saw nearly no chance for a marketing authorization in the near future. The example I mentioned before of these motivated Swiss rabbit breeders and producers is unfortunately a single case until now. We need a stronger cooperation between all the involved groups, especially the veterinarian, the breeding association, and also the university. Only then there is a chance to make these lacking veterinary drugs available. Thank you.
(Applause.)

DR. WEBB: Well, that brings our first session to a close, but before you know we always have housekeeping comments to make. The first is that this meeting has been in large part funded by FDA, which is a government organization. It is a public meeting, and we require and welcome public comments at certain sections of the meeting. If anyone has a public comment they wish to make that does not relate to MUMS or anything like that, if they let the front desk know so we can a lot them a time in that session, those sessions. If there is nobody making a public comment, we will make private comments and continue the meeting.

The second part is those of you who are wondering what NRSP stands for, and I can never quite remember, it is National Research Support Project No. 7. No. 6 is for potatoes, so you can see how we rank with that.
(Laughter.)

For members who have badges on, it is not so you can be identified by security. It is so that any of you who have a question you want to ask about NRSP-7, people who wear this badge should know the answer to that.

Anyhow, to something much more important, friends of NRSP-7 have sponsored a reception this evening at the end of business from 6:00 until 7:30, and it is the gazebo or whatever you want to call it. That little house in the middle there on the upper level at that time, and we would really like to see you all there because it allows us to talk and you to talk to each other.

The final thing is you be back on time on you suffer the same fate as the speakers if the run over. You didn’t see any bloodshed this morning. We don’t want bloodshed from you. Thank you.
(Whereupon, a break was taken.)

DR. CRAIGMILL: Ladies and gentlemen, we are going to attempt to remain relatively on time. So if you could please come in and take your seats, we are going to go ahead and get started. My name is Art Craigmill. I am from the University of California at Davis and I am one of the NRSP-7 regional coordinators. I am the only original one left. When John and I started we were both young men.
(Laughter.)

Just a little greyer and a little more worn at the edges. I am delighted that we have so many in attendance as Dr. Beaulieu said. Once again, in an attempt to remain relatively on time, I am going to introduce our first speaker of the second session this morning, Professor Eric Mitema. Dr. Mitema received his veterinary degree. He also holds a PhD in a field near and dear to my heart, pharmacology and toxicology. He is currently a professor in Nairobi, and he has two other very important distinctions here. He serves on his country’s pharmaceutical registration panel, so he does drug evaluations, and he has also been a member of JECFA* since 1995. I introduce Professor Mitema.

MUMS - African Perspective
Dr. Eric Mitema

DR. MITEMA: Thank you very much. I would like to thank the organizers for inviting me over and to be able to share some experience with you. I know it is quite an interesting thing being here, you know, in Rockville. So it is nice to be part of this meeting and to be able to share some experience and be able to compare some notes. But as you say most of the regulations in our country, there may be a little difference, but in this workshop I will use Kenya as a case study for Africa, and most of the things that take place in Kenya are fairly the same.
(Slide.)

We use the drugs just to, you know, take care of some of our animal diseases, and also we can use them as an aid, and their regulation is done by Pharmacy and Poison Board of Kenya. In today’s talk my main objective is to review some of the scientific requirements for MUMS and also to enlighten some current concerns about these compounds. For example risk analyses and the risk of use in animal products and also antimicrobial resistence.
(Slide.)

Now I would like to -- this is more interesting. I would like to define what I mean by minor species in our terms so you get me right. The minor species depends where you are, even within Africa. If you are from north, northeast and the north part of Africa, I list there the camel as a minor species. But if you are in Egypt or you are in Saudi Arabia, or you are in Somalia and certain parts of north Kenya, the camel would be considered as a major species, because there it is very, very common. That goes all the way up to the Middle East. So in terms of Kenya, the minor species includes camels, rabbits, bees, and of course donkeys. Now the major species includes cattle, sheep, goats, pigs, poultry. There is also dogs, cats, and horses to some extent, because the horse industry is not very advanced, but those would constitute the major species.

There, as I say, you see that the goat is also very, very popular in most parts of Africa. Again, if you look at the northern part of Africa, which is a desert there are somehow that the drier parts, the goat becomes a very, very important animal species because the goats are very hardy. They can survive everywhere. They can literally live anywhere and just nibble and just survive, and by nature they have been able to survive that region. That also extends to up the Middle East.

Now we also have the exotic animals. Some of you are very familiar with game ranching. Here we put a little game ranching. Now we got the big game ranching. We have got the eland. We have got the wildebeest. We got the zebras. Some of these animals are herbivorous, and we have a problem whereby they have cropped. Some farmers really have certain big ranches. They can be able to have these game animals within the ranches, and the government gives them the license to keep these animals. The animals don’t belong to them, but once they are fenced within their boundary the government gives them the authority, and then the government can give licenses as well where these animals can be cropped at certain time intervals. So we also call them game ranchers, but nonetheless these animals can only be slaughtered at specified outlets, and also the meat can only be sold in specified restaurants. So you have to go to a very, very affluent restaurant to be able to be treated to game meat, and you pay dearly for it because of the risk of cutting it and, you know, trying to get it and even treating it. It is not easy.

Now we also have the crocodiles. We have one big crocodile farm near Mombasa. Probably maybe 2,000 animals, or 2- to 3,000, and crocodile meat is quite a delicacy. It is a taste between chicken and fish.
(Laughter.)

I always make a joke to my wife and say, "Look, I’ll eat the crocodile before it gets me, because it is not staying." Then the ostrich farming is also becoming very, very popular.

As you know, the BSE and the cholesterol. We have got about four big ostrich farms, and also that also extends even in South Africa. So we have a lot of ostrich farms, and the ostrich meat is kind of like a red meat, but very low cholesterol. So it has been getting a lot of popularity.

So we have these animals, and most of the time the drugs that are used, you know, we use off label. Now, when we talk about the minor uses, now this is very tricky as for every country. What Americans would call minor uses would be major uses in our case, and I’ve given very good examples here. Now we have three let’s say East Coast Fever theileriosis, then tick fever babesiosis, anaplamosis. All those are protozoic diseases. Those diseases could be considered minor. I know you have Red Water in Texas, the southern part of Texas near El Paso, and maybe anaplamosis near down the southern part of Texas, but in our region these are really major diseases. So whereas Americans may want approved imidocarb as a minor use, in our case we consider it as a major use. So I will come back to that as I proceed. The next slide will probably show a little bit more of that.
DR. MITEMA: Oh. Thank you.
(Slide.)

Now, again, I have some specific treatments which you can consider. You may consider them as minor. Now in your context we have theileriosis, which is East Coast Fever. We have at least three drugs that have been approved for use, and these include parvaquone, buparquone; and then for babesiosis, which is a tick fever in dogs or Red Water in Texas or whatever -- I mean Red Water in cattle, we have diminazene. Also we have imidocarb. All those have been approved. Some of these products also have been reviewed even at the National level. Then you have anaplasmosis. We have imidocarb and also we can use tetracyclines as indications for these conditions.

Now as far as Kenya is concerned or our country is concerned, the data requirements, these will comply to CAP 344 of the Pharmacy and Poisons Board which was established as a law in ‘82. So all drugs in Kenya have to be registered if they are intended for either food animals or companion animals. The law has been there since 24 years ago, and any product that claims that it has got a therapeutic claim either in livestock or in companion animals must be registered. Data requirements are basically the same for all drugs, whether it is for minor use or for minor species. The only difference in the case is if the drug is orphan, which you can borrow that from the human term, but we also have that. If the condition is such that we see very little of it, the drug can be approved fast because the cost involved in the review and the condition of data may not warrant it, and therefore there is also a waiver of fee as far as that is concerned.
(Slide.)

Now regulation of drugs for MUMS drugs, one of the conditions, one of the aims, just like any other country, is to assure that the product is of high quality and also to make sure that there is proper distribution and storage. Also one of the conditions is that efficacy data should be available. Any claim must be able to be substantiated by proper efficacy data. Also safety data must be available for target animals, and also safety for the human consumer and also environmental safety; and insure prudent use, especially for antimicrobials. In the case of antibiotics, we have to insure that they are properly used so that there is no transfer of resistance which can be able to compromise human public health.
(Slide.)

Good drug quality is important from the viewpoint of animal health, that is in terms of efficacy, and also animal products intended for human consumption. There is a need for GMP, harmonization of GMP. For example, I know currently that in the US, EU, and Japan there is a very strong attempt to harmonize. That is the VICH, to harmonize the requirements either for GMP or most of the requirements. So most national laws should insure good quality, good assurance during manufacture. So basically in quality, we are trying to emphasize the fact that the drugs should be of high quality so that the human consumer or the target animal is well protected.
(Slide.)

Now we can have mutual recognition of manufacturing or import authorization should be encouraged. In our case if a product is registered or licensed in another country and this is really important in our country, one of the requirements is that the product should actually be registered in the country of origin. Especially the label claim is such that the clinical indication is available in that country. The only exception is that if that disease is not available in the country and most people, the reviewers, they are familiar with the various conditions. Then they can be able to exempt that. So certificate for sale is a requirement for most drugs if they are imported from other countries. Raw materials should be sourced from approved and reputable outlets. The distribution of these compounds should conform with the national and international law, and we encourage veterinarians to continue to prescribe to insure proper use. The OIE code of practice requires that all veterinary drugs are registered with respective authorities.
(Slide.)

Now I am trying to review the data requirements for efficacy. One of the fundamental objectives in efficacy is that the label claim must be supported by adequate scientific data, and because of that for new molecules data should be generated by sponsors during pre-clinical and clinical efficacy studies. For generic compounds, bioequivalence studies should be done. In certain cases, clinical efficacy data can substitute bioequivalence studies, and all the studies should be done according to good clinical veterinary practice. Some of the requirements for the GCPV requires that there must be a qualified or competent investigator, there must be a proposal in place, data must be properly audited and properly documented, and there must be verification of clinical trials. The investigator must be able to show high level professionalism, including the welfare of animal’s under trials.
  (Slide.)

Now in terms of safety assessment, some of the requirements to test the product is that GLP must be in place and the studies include the tox data, which is basically the same. It include some acute or chronic studies, especially if it is a new molecule. Also if it is a new molecule, long-term study data must include carcinogenic, teratogenic, mutagenic, or multi-generational developmental studies. Also adequate pharmacological studies should be included, and normally the studies will involve any of the laboratory animals like mice, rats, guinea pigs, rabbits, et cetera.
  (Slide.)

Now if an antibiotic is going to be used either as a MUMS product or like any other product, we are now trying to be able to be compliant with the modern requirements by international bodies whereby studies should be done to evaluate its potential on the microbial ecology of the human GIT, and this also should involve risk-based evaluation of all antimicrobials used in food animals for their potential in human health. Most of this evaluation should be based on known bacterial pathogens like E. coli, salmonella, campylobacter, enterococcus. So this is really a emerging issue in the last 10 years with antimicrobial agents, and we find that a lot of antibiotics are finding their way out in agriculture, and there is a lot of concern on the public health issues and the people are getting worried, about the costs. Due to cost, increased cost of these products and also the increased cost of research in coming up with new molecules because of possible development of resistence which can come due to either misuse or overuse of the antibiotics.
(Slide.)

In terms of safety, which is really a requirement which is just basically the same. What you do, if it is a new compound, the reviewers will establish an ADI, and that is from ADI, then MRL will then be established. Then the MRL can also be established, and a the authorities should ensure that all compounds for food-producing animals have a withdrawal period before the slaughterhouse. So this process is basically the same as what you do for any other product.
  (Slide.)

Now, you realize that a lot of products for MUMS, some of them will be used let’s say in fish. In my country, for example, we have a few fish ponds, not really fish farms, and certain environmental studies should be done to insure that the products that are going to be used have no effect on the environment. This is becoming increasingly important, because environmental safety is really at issue. For example, even antimicrobials, because if you use a lot of antimicrobial agents we get a lot of transfer of resistence among the various pathogens or even known pathogens, and they can be able to transfer resistance along the food chain. I mean, whereby the transfer can take place. So the data is required which can be able to ascertain that the product does not have any possible side effects in the environment.
(Slide.)

Now, in my concluding remarks, I am trying to equate that. There is the classification minor use and minor species from different countries and developing countries. There is a difference. This can be due to either dietary difference or it can be due to geographical difference, and there needs to be a harmonization whereby we understand when we talk about what we mean by minor species and what we mean by major so that at least there can be ways in which we can share our common understanding. There should also be surveillance for potential for antimicrobial resistence in man and livestock. This should be underway, and there should be regular interactions through seminars. Workshops should be encouraged, and the harmonized regulation for these compounds should be undertaken in a global perspective and within the regions. Competent regulatory authorities should offer training opportunities and sabbaticals for experts from developing countries. Now I must say that technically in my country, or if I take my country as a case study for Africa or most developing countries, per se we have very few drugs that are specifically meant for minor species. I would say that most drugs are used off label, and this is basically because the markets cannot be able to sustain them. Our fish farming is not very advanced. We depend entirely on farming for fresh water. We have Lake Victoria, which is very, very large. It is in Kenya. We have the Indian Ocean, which is very expansive. So we have only very few aquaculture, but nonetheless we are but pawns. I mean the aquaculture, whereby we use these drugs, and there is definitely a need, especially when it comes to MRLs. Because currently we tend to use a lot of products that are intended for either poultry if they are fish, but we have got a few special cases where we can be able to use certain products. Hence, it is quite important that we really come up with policies either as a priority it is very, very challenging in terms of NRSP and the CVM to come up with this program, and this can be a really good way forward in trying to bring and harmonize what happens in various regions.

Again, we don’t have any legislation as far as MUMS is concerned. I saw that even in Europe. As Peter was talking about that. We don’t have any legislation which says that you have to register a particular drug or you have to have approval for a particular drug or in a particular need. So it is our understanding that currently the regulatory authorities are trying to come up with regulations if they approve a drug, the farmers -- say ostrich farmers may require such drugs, for example. They are most likely to use either one for poultry, and what the veterinarians will do is that there will be an extended withdrawal period which can be like a three-times fold or four-times fold just to protect the human consumer. That is currently what we have. But this is nonetheless a very good initiative, and I think this is something that we can learn and be able to compare notes.

We also have, as I was saying, if you consider for example a country like ours whereby we also have the game ranching, where we have some of them are in -- you know, once in a while you may have a sick eland. I mean, that is not a common practice for a veterinarian there. But if the owner of the ranch may be able to, you know, get to access to the animal, he may be able to call for assistance. In the zoo, I would also like to share this experience with Americans, how they treat a lion or a leopard. Are you going to give a dose for the dog or are you going to give a dose for the cat?
  (Laughter.)

So I don’t know whether. If you are going to use ampicillin for maybe for treatment, whether you are going to use a dose for a cat. Is there a need that you should come up with a product specifically for the wild animals? Yet we know the dog and the cat belong to the same family. Thank you very much.
(Applause.)

DR. CRAIGMILL: Thank you very much. I will just talk loudly for a second while we wire our next speaker. Our next speaker is Dr. Tatsuro Sekiya. He is currently a senior veterinary officer in the Office of Veterinary Drugs at the National Veterinary Assay Laboratory. He is a veterinarian, and he has worked as a technical officer at the Ministry of Agriculture, Forestry, and Fisheries in Japan since 1993, primarily involved with drug residues in food-producing animals. He has also been a data reviewer, and with quality testing of drugs, GMPs, GLPs, et cetera. Dr. Sekiya, please. Welcome.

MUMS - Japanese Perspective
Dr. Tatsuro Sekiya

DR. SEKIYA: Thank you. Thank you, Dr. Craigmill, and good morning, ladies and gentlemen. Today I will try to present here about MUMS in Japan. First I would like to introduce to the background of MUMS situation in Japan. Then I would like to talk about the current status of MUMS approval and finally about the issue for the future.
  (Slide.)

Also in Japan, MUMS has been attracting attention increasingly, and there are some background for the situation. Firstly, I would like to point out diversification of dietary lifestyles and eating habits of Japanese in recent years. Individual dietary preferences and the eating habits have been changing. Therefore, it is necessary for livestock farmers to raise various kinds of animal species for food products to fulfill the consumers needs. Under the circumstance, consciousness towards healthful diets becomes particularly stronger. For example, there are needs for the meat of less fat content for the reason of health.
  (Slide.)

With a higher standard of animal hygiene and veterinary practice in recent years, the kind of animal species --- to be applied have been extended, and this situation may be the factor for increasing interest in MUMS. The growing awareness about animal welfare may also be a factor for the extension of the field of veterinary practice. Furthermore, with regard to companion animals or pets, a great variety of species have begun to be raised. Now it has become to be the subject of veterinary practice from rabbit or hamsters, to ornamental fish or reptiles.
(Slide.)

Well, under the background I mentioned to you in a previous slide the needs for MUMS have been certainly increasing.   However, I should say that pharmaceutical industries are reluctant to develop MUMS and to make efforts to get MUMS approval. The reason for this is that enormous cost and time have to be invested for the development of MUMS and for getting approval. For getting MUMS approval the requirement of verification of quality, efficacy, and safety of the drug by conduction of safety studies and clinical trials in compliance with GLP and GCP have been becoming more and more rigorous, and the current position, the organizations such as mergers and acquisitions are continually made among Japanese animal drug industries, including foreign affiliated companies. With this situation, development of drugs such as MUMS with no great sales volume and profit can be expected after being marketed has become difficult from an economic viewpoint.
  (Slide.)

Next I would like to talk about the situation of MUMS in Japan. First, what is the definition of the wording, minor species and MUMS, in Japan? There are no legislative clear definitions for them. We judge it based on general interpretation Animals other than major species animals can be regarded as minor species animals.
  (Slide.)

Well, then what is the definition of major species animals? Again, there are no legislative clear definitions for them. When we judge it on the basis of raising head count, cattle, swine, chickens, cultured fish, dogs and cats can be categorized in it. Therefore, although there are no clear definitions, animals other than cattle swine, chickens, cultured fish, and dogs and cats can be regarded as minor species animals in Japan.
  (Slide.)

With regards to horses, I think it may be appropriate to categorize into minor species animals from the veterinary medical viewpoint because of the slowdown of the development of new drugs for horses in recent years.
  (Slide.)

Well, obviously minor species animals in Japan. For example, ostrich, emu, deer, geese can be quoted. The
raising head counts of major species animals are thought to be 1,700,000 for dairy cattle, 2,800,000 for beef cattle, 9,000,000 for swine, and more than 10,000,000 for dogs. However, for example, the raising head count of ostrich, about 10,000, and deer are around 5,000. They are very small in number compared to those of the major species animals. As for the other minor animals in Japan, ducks, turkeys, quails, guinea farms, pheasant and wild boars, et cetera, are raised for food production.
  (Slide.)

In Japan, more than 4,000 animal drugs have been approved. Most of them have been approved for use in major species animals. In contrast, very limited number of drugs have been approved for use in goat, sheep, honey bees, quail, turkeys, et cetera. Also there are relatively old drugs approved for the use in horses. A small number of new drugs for horses are available currently. Only two drugs have been approved for the use of honey bees. There are the animal species such as ostrich and deer to which no drug applications have been approved.
  (Slide.)

Next I would like to introduce you on the situation of minor use in Japan. Like the minor species, there are no legislative clear definitions of minor use. Generally speaking, it may be appropriate to regard the following as minor use drugs. Namely, irrespective of the indicated animal species, such drugs for which there are little or inconstant demands because of a their incidence, or sporadic occurrence, or limited geographical occurrence of the indicated disease may be categorized as minor use drugs. Vaccines which are important for animal hygiene and considered necessary to be prepared for just in case of the occurrence of a disease that does not occur ordinarily may be included in this category.
  (Slide.)

Well, under the background situation I talk about, the shortage in available MUMS will eventually lead to the limitation in therapeutic, preventive, and diagnostic options. As a consequence, this may lead to the problem in animal hygiene and veterinary practice. Furthermore, this may lead to the issue of human health.
  (Slide.)

Well, the situation of the shortage of MUMS will result in the increase of extra-label use of human drugs or drugs approved for other animal species. This leads veterinarians to use drugs for which extra-label use is allowed, but the safety and the efficacy are not confirmed in the animal species that they are going to administer it. Under the situation of the lack of the information on appropriate dosage, the veterinary practice has to be conducted relying on the skills of veterinarians. In addition, when an extra-label use drug is administered to food-producing animals, the judgement of withdrawal period is set depending on the veterinarian’s skill and experience because nothing has been established on a scientific basis. Therefore, it has been pointed out that this situation is not only the issue of animal hygiene and veterinary practice, but also the issue of food safety.
  (Slide.)

Well, as for the regulatory requirement for application for new animal drug approval under the pharmaceutical affairs law. Safety studies, clinical trials, and residue studies should be conducted using the target animals, and the data shown in this slide should be submitted.
  (Slide.)

Well, for application for new drug approval, even though for MUMS, it is required to collect and submit the data obtained in compliance with the relevant regulations and guidelines as shown in the previous slide. For the conduction of the studies to obtain the required data, enormous cost and time have to be invested. However, there are no regulatory systems for animal drugs like the process of orphan drug approval for humans.
  (Slide.)

There are some problems or difficulty in conduction of the required studies for application. For example, the limited number of facilities where GLP studies for horses or cultured fish can be conducted. Like this, there are some factors other than the financial aspects limiting development and approval of MUMS.
  (Slide.)

Well, I would like to introduce you to the effort of Japanese regulatory authority to facilitate the development of MUMS and to increase the availability of approved MUMS under the circumstance of background and the current situation as I mentioned. For instance, as shown in this slide, there is a subsidy system which the third-party research institute in place of pharmaceutical industries may conduct the required studies such as safety studies, clinical trials, and residue studies with a national grant; and the pharmaceutical industries can use the study data obtained by these studies for MUMS application. Like this, some subsidy systems are available to reduce the costs for MUMS development and to stimulate the development will of pharmaceutical industries and to facilitate the MUMS approval.
  (Slide.)

For examples of the MUMS approval assisted by the similar national subsidy system, drugs for honey bees and horses and vaccines for cultured fish can be quoted.
  (Slide.)

Under the current situation, there are no available legislative and institutional frameworks to provide increase in MUMS other than the national subsidy system I mentioned previously. Based on the background and the situations I talked so far, it is considered necessary to promote measures further to facilitate the MUMS development and approval, including international harmonization. I believe that it will be important for veterinary practice and animal hygiene, food safety, and even human health.
  (Slide.)

Well, as a conclusion I would like to summarize my presentation. In Japan, there are no legislative definitions for MUMS while the needs for so-called MUMS are increasing. Therefore, appropriate countermeasures are necessary. Thus, further efforts to increase availability of approved MUMS are encouraged. As one of the measures for it, I believe that the promotion of international harmonization concerning MUMS is quite necessary. Thank you very much for listening.
  (Applause.)

DR. CRAIGMILL: Thank you very much, Dr. Sekiya. Some of you may have noticed that we seem to be 10 minutes ahead of schedule. Actually this -- and I don’t want any CVM reviewers to listen to this -- this was actually a mathematical mistake, and that really we were supposed to end at noon. We are not 10 minutes ahead. There was this -- believe me. Trust me. I’m from academia.
  (Laughter.)

DR. CRAIGMILL: I’ve heard that one before. Thanks very much. We are actually exactly on schedule, and we will begin lunch at noon and again start promptly at 1:15. Now it is my pleasure to introduce Professor Jorge Errecalde. He is visiting today from the University of La Plata in Argentina where he is a professor of pharmacology, another pharmacologist; we are always happy to see them. He is a fellow of the AAVPT, the American Association of Veterinary Pharmacology and Therapeutics. He is also an honorary member of the European College of Veterinary Pharmacology and Toxicology. He serves on the JVPT editorial board as several other people in this room do as well. He is a veterinarian, again with a doctorate, and he wears two hats. So today we are not sure which one he has got on, but he also serves as the president of INCAM SA, a company which does contract research, I presume for drug approvals. So, Professor Errecalde, thank you for coming.

MUMS - South American Perspective
Dr. Jorge Errecalde

DR. ERRECALDE: First of all, I want to express my gratitude to the organizers of course, because if not I wouldn’t be here; and, secondly, I want to express my gratitude to them because this is -- I have to be hones, this is a new subject to me. In a meeting conducted in Brazil a couple of months ago, less than two months ago, they offered me to participate in this workshop. So I have face enough to come. I came.
  (Laughter.)

The other thing you see is that this title is not the same than the title you have there in the paper, because I think in South America it is difficult to speak about perspectives. I will speak about a sample of facts. It is a sample. Another thing, an interesting thing, is that I have been some 30 years teaching pharmacology, 20 years teaching and trying to train people on the rational use of drugs in veterinary medicine. So I disagree with almost everything I will present now.
  (Laughter.)

So I must be very clear. I must be very clear.
  (Slide.)

I said this subject was new for me. I started trying to understand what is a major species, because a major species I supposed before was large animals, but now I understand very well what you mean, and definitely this is a problem here. That is definitely major species for the Southern Hemisphere, at least this one. I think Eric gave you a lot of examples important, too.
  (Slide.)

So then I started to understand how to classify these, and of course I found that minor species are MUMS because of a lot of things, and a classification should take into account all these factors. However, probably the pubic would understand better a zoological classification.
  (Slide.)

I attempted a zoological classification of various species. Follows a very simple zoological classification.
  (Slide.)

So I speak about I found inferior animals. I call it inferior animals. These are --- animals of some importance in Latin America, and aquatic animals like ornamental and productive of fish and prawns.
(Slide.)

Amphibians and reptiles, where you have a variety here, even snakes and even rodents. You have pet snakes.
  (Slide.)

About birds, you have a variety here.
  (Slide.)

I think you can classify finding a lot of physiological similarities here. Rodents, there are some rodents that are pets here, some rodents that are productive especially in the last part of this transparency.
  (Slide.)

And small ruminants, South American camelids and deers. You find the goat here. I have not included sheep here, considered a major species. These camelids, I will speak about them later, and deer.
  (Slide.)

Wild and zoo animals represent an extremely complex subject as you will see through this range of photographs here, and it is very complicated to speak about that. In general wildlife and zoo veterinarians, know a lot about these animals, although it is one of the subjects in pharmacology that are so dynamic that you have to be catching up continuously. Especially with pharmacokinetic, pharmacodynamic matters. But anyway, these veterinarians are the ones who manage better the wild and zoo therapeutic story.
  (Slide.)

I selected a few species of importance, economical importance. So honeybees is one of them, and there are three diseases, foulbrood, varroasis, and nosemosis. In the two kind of foulbrood, American and European, we can eventually use antibiotics in the case of American; in light infections in the case of European, oxytetracycline, neomycin. What the producers normally use is one gram of oxytetracycline in 100 grams sugar three times weekly per hive.

In varroasis there are different treatments. Pyrethroids in impregnated wood strips, how much pyrethroid is in one strip nobody knows. Coumaphos, amitraz, this is the first time that I know that amitraz could be smoked. They put it in a smoker and they spread some fumes with amitraz possibly there. Formic acid, ten-percent strips or applicators; rotenone and timol are used, too. For nosemosis, fumagylin in patty or syrup.
  (Slide.)

The snails, this is another interesting thing. Snails are a nice thing to eat because they grow naturally. When they started to culture it, it started to spoil the story, and there are some infections, Pseudomonas, and sprinkled tetracyclines are recommended. Of course Pseudomonas is not susceptible to tetracycline. There are nematode infections, protozoa infections; and what are the treatments? I found that they use two treatments; calcium carbonate sprinkled to harden shells, and they sprinkle oxytetracycline salts, at least some of them. They sprinkle oxytetracycline.
  (Slide.)

Prawns, this is a very interesting chapter because the intensive farming of prawns. You can imagine thousands of individuals in little volume, metabolizing everything there with a tremendous bacterial resistance down. I found that there is a lot of antibiotic use there. Against protozoa, acriflavin and copper sulphate are used. Against ectoparasites, ivermectin and organophosphates. But there is a big problem here. That is the persistence of antimicrobials in sediment. This an excellent culture medium, and all of you are aware of the risk of dissemination of resistence within this and other media. This is a real opportunity for bacteria, real opportunity.
  (Slide.)

Infectious diseases of salmon, you have here a fat salmon full of food and oxytetracycline.
  (Laughter.)

And maybe worse. I have a few diseases here, septicemia probably the worst. There are three possibilities of using oxytetracycline; in injection, in food, or bath for several days. Enrofloxacin, I found that is very used in minor species. Enrofloxacin by injection in unique dose, but it is used in food animals also. I found in a Spanish Web page to probably disorient producers that chloramphenicol could be used in food or in injection. For furunculosis, amoxicillin, this dose in food for 10 days, and erythromycin. It can be used in food for 20 days.
  (Slide.)

Then you will find here that I added a couple of slides to the presentation you have in the book because that was a draft one. Now I will show you this 100 products of fish in Chile. Chile is a leader in fish production in Latin America. They produce it in the fjords, the coast. You see that likely 100 products, I haven’t -- it is not necessary to calculate percentage here. I am not good at mathematics.
  (Laughter.)

But you see that this is 64 percent of antibiotics, only 10 percent of vaccines, and the rest are the other drugs. So there is an enormous prominence of antibiotics in the pharmacopeia.
  (Slide.)

Now you will see the distribution of the antibiotics, and as I told you it is very difficult to calculate percentage. It is never 100 percent. There is a great prevalence of quinolones; 64 percent are quinolones, 20 percent oxytetracycline, 10 percent macrolides, and the rest probably some others with low percentages.
  (Slide.)

Amphibians and reptiles, cayman, we have a few farms in South America, in Argentina in particular. A couple of important diseases are mycoplasmosis where you have pneumonia, swollen joints. Stress is important. Tetracycline injection is used. For chlamydia, in the acute case death, in the ocular case tetracyclines. For salmonella, hygienic measures plus wide-spectrum antibiotics is what technicians recommend. Non-specific septicemia, antibacterials in the early stage; and for coccidiosis, sulfonamides.
  (Slide.)

In turtles and snakes, there is a prominence of gram-negative bacteria, and, as you probably know, there is a relation between metabolic rate and temperature in these kinds of animals. Therefore in correct therapeutic plans we should consider temperature, and especially for withdrawal periods. There are a few antibiotics used in these animals. Carbenicillin I think is too, high dose, about every 48 hours at 25 degrees. Doxycycline, 50 mg/kg every 72 hours at 20 degrees; amikacin, 5 mg/kg, every 48 hours at 30 degrees; enrofloxacin, 10 mg/kg every 24 to 48 hours at 30 degrees. Metronidazole for anaerobes at 20 mg/kg every 48 hours; they didn’t say anything about temperature.
  (Slide.)

About birds, I consulted a couple of experts, one very well known in Argentina, and where we discussed these parasitic disease where levamisol used to be dosed orally for three days. That has been only about pigeons and canaries.   In the case of capilariasis, ivermectin; known does injected is difficult to understand how you can inject a canary. Sometimes they say that they put -- I don’t know the gauge, but in a thick gauge they put a drop of ivermectin and the punch the wing. So that is a lethal dose of ivermectin. That is the real dose. That is what the practitioners do. About tenia, praziquantel orally or subcutaneously, one does (10 mg/bird). For Trichomonas, ronidazole or metronidazol, orally seven days treatment. For coccidia you have oral sulfamethazine, and for lice, cipermethrin in spray.
  (Slide.)

This is another interesting transparency because we have here virus and bacteria of pigeons and canaries. For paramixovirus there is a vaccine. For adenovirus and herpes virus some practitioners use homeopathy. I don’t know what the result of homeopathy in viruses, but they say that it works. For paratifosis there is a trivalent vaccine that is working properly. For Strepto and Staphylococcus in canary foot that is a common infection; chlortetracycline, 1.5 grams in 5 liters orally seven to 14 days. For mycotic proventriculitis, ketoconazol orally.
  (Slide.)

Now with rheas, there are a few farms of rheas now, and it is growing in Argentina. This is a growing business in South America. There are few ratite pathologists. Enteritis, they say that antibiogram, is necessary and the treatment based in probiotics, and antimicrobials. For rhino-tracheitis, for dust plus mycoplasma plus stress oxytetracycline. I gastric verminosis, they use levamisole, fenbendazole, classical avermectins. For ectoparasites, pyrethroids, amitraz, and avermectins.
  (Slide.)

For rodents, we have rabbits in this group. That is a good example because there are several farms now after the last devaluation in Argentina. It became productive again to breed rabbits. There are skin problems here. Mange is one; injectable ivermectin, 400 micron per kilo is what they are using. For ringworm, iodines. For internal parasites, injectable ivermectin. In the respiratory system we have rhinitis, so enrofloxacin or oxytetracycline being the selected drugs in general. In the reproductive system, enrofloxacin, oxytetracycline, maybe others, but you will note that in general enrofloxacin and oxytetracycline are very much used. In the digestive system, enterotoxemias. The technicians say, "Okay, we need antibiogram," and the same with colibacilosis. In coccidiosis, robenidin in food is preventive, and therapeutically sulfonamides.
  (Slide.)

With the chinchilla, this is a table that is distributed among producers. Here are the drugs here and the different categories. Ivermectin is used the same dose in categories, except when they treat the whole animals at one centimeter in five liters of water. They use the commercial formulation one percent, but they put it in five liters. Oxitocin only postpartum oxytetracycline, they use it in death when pneumonia symptoms appear. Formaldehyde once a month, they spray everything and ventilate. Enrofloxacin when death animals without diagnosis or depressed animals without diagnosis appear. This is the indication. Zeranol is an interesting thing. They use half of a pellet implanted zeranol has some effect in the hair of the chinchilla and helps maturation. But of course these animals become sterile after application. The animal has to be killed two months after implanted with zeranol.
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With the South American camelids, here you are. The vicuna, the alpaca, guanaco, and the llama, and it is interesting but it is a theory of evolution. Shortly ago I found that the alpaca is the evolution of the domesticated vicuna, and that the llama is the evolution of the domesticated guanaco. It is pretty interesting. Of course you can see a lot of difference here, but there are several different kinds of alpaca. This is a very nice one ---. This not a very nice vicuna.
  (Laughter.)

But that is a theory. This is an interesting chapter because South American fauna is very rich in small mammals, but not very rich in large mammals, and these are the largest herbivorous mammals we have in South America, and then have been domesticated for a long time. People have been living with these camelids since a long time. The Incas exploited these kind of animals and they used to gather all the animals in a big region --- to obtain fiber and meat or whatever. The second year, a different region, a third region to come back to the first region in the fourth year. It was rather rational. When the Spanish came of course it was a --- exploitation. When the Spanish came, the exploitation turned into absolutely irrational, and they started to kill animals to obtain anything, and that was very negative for these animals. This evolved now to very small familial exploitation. A family or a group of people have little herds in the mountains, and they sell the fiber annually. This fiber sells for good quality, especially the vicuna and alpaca. Well, there is a proof of that. The Inca chief using vicuna clothes, whereas the normal citizen uses guanaco clothes. These are animals with not big food requirements. They live in the mountains. They are very rough. The problems in winter with the snow when there is no food, and sometimes the government officers go on the hill and prescribe antibiotics and vitamins, but the real problem is food.
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The National Service of Animal Health of Argentina requires a few things, not a few, to register a new drug for minor species. It requires a monography covering all aspects required by the MERCOSUR regulations. This is you will remember is Argentina, Uruguay, Paraguay and Brazil. Chile is working very properly in registration, too. Bibliography data covering aspects of safety and efficacy, and experimental evidence on efficacy, withdrawal time, stability, and innocuity are required too.
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So to conclude here, I have a very original conclusion here. This is an extremel