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U.S. Department of Health and Human Services

Animal & Veterinary

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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.
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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.