Animal & Veterinary
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.