• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Animal & Veterinary

  • Print
  • Share
  • E-mail

MUMS - Industry Perspective - EU

Dr. Rick Clayton

DR. CLAYTON:  Well, they have no excuse.  It is 8:00 in the evening for me, so if I am not asleep there is no need for you to be either.
  (Laughter.)

Two things.  First of all, thank you very much to the organizers for the invitation and also thank you very much for giving me such motivation to finish on time.  It is a unique experience for me today.  It is my first time in Washington, and it is the first time I have been physically threatened with violence if I don’t finish on time as well, so --
  (Laughter.)

With that I am going to move straight on and try this gadget.
  (Slide.)

I am not going to do much on the background.  It has been well covered already by many people, particularly on some of Peter Jones’ earlier slides.  Of course on an industry slide, we will want to use slightly different words.  For example, we talk about “harmonization of legislation”, “increased time-cost” for product development, but also continual “regulatory creep” is an issue for industry, and also you will see that industry will use terms like the “global competition” now and the need to access global markets.  I should also explain in the handouts that you have you will find my standard presentation on EU regulatory affairs.  That is because in the speakers guide I was asked to answer a few questions about how products are registered and distributed in the EU.  So you will find that standard presentation in the pack.  I don’t actually think you want to hear about all that, because you should really know most of this stuff.  What you really want to hear from me is industry’s take on all this.  So that is what I am going to present today, and this is what will be on the CD Rom as well later, so I am told.
  (Slide.)

So what I am going to do now is look at some of the major issues for the European industry.  The first one here is that we are struggling to communicate the real value of our products.  Quite often in European legislation up to now veterinary medicine products have really been seen as a hazard, but, as Peter Jones indicated, our legislation has just undergone a major review over the last three years.  The new legislation was published in April, and it comes into effect in 2005.  In the new legislation this word "hazard" in places is now replaced by "risk benefit".  Now this is very, very important for us.  A small thing, but important.   Medicines availability as a whole is a very major issue for the European industry, but MUMS within that is just a small issue, because by definition these products bring no value to our shareholders.  We have bigger concerns, such as keeping our existing products on the market and even being able to develop a new product for major species.  That is a big enough problem for us a well, let alone MUMS, but we do actively participate in all discussions on this because we want to make a good contribution.  We say it is part of our good governance if you like to engage in this issue. 
  (Slide.)

So our major issues are the cost of product development, manufacturing and marketing for all products.  We also have a major issue trying to keep those on the market.  We have a thing called a “5-year renewal” in the EU at the moment.  We also had big discussions that have been going on for many years about the scope and application of new guidelines or revisions to guidelines.  Do we have to keep redeveloping our products to meet changing guidelines?  This has a big impact on what happens at renewal if new standards are applied, and the outcome of all that is that in the EU we are spending in the region of 35 percent on what we call defensive research, and this is twice the amount that you spend here in the US.

Now we did think when the MRL regulation deadline was reached, and the review of the MRLs was complete that this figure would come down, but we found it has not, and that is probably because there is always something new coming along, like eco-toxicity, and now antibiotic resistance.  There are always unique and new studies required.
  (Slide.)

Some other major issues.  Well, we have been talking about minor uses and minor species.  Well, in the EU this is actually more of a three-dimensional problem because we have “minor countries” as well.  For example, does anyone know where Latvia is or how many cows there are in Malta?  So These minor markets are quite a problem, and it is a problem because, as Peter said, of the translations. These translate into a practical problem when you have to start printing labels in all these different languages for the different countries.  So of course you can imagine that when you have to print labels for somewhere like Latvia or Malta, the two examples I mentioned, the cost of labels is actually more than the market value.

Another major issue for us is the fact that the mutual recognition procedure isn’t working as effectively as it could, as the legislature intended.  For MUMS it is not actually a big issue with us.  Bit of a misnomer to call it a major issue in this context, and I am going to move straight on from that. 
  (Slide.)

What industry is really looking for in Europe is what we call a “coherent MUMS policy”, which is something we feel that you have managed to develop on this side of the pond.  That is something we are still looking to in Europe.  So for example, in Europe there are many little initiatives that are going on, and Peter mentioned the Commission Communication of December, 2002, which really described the problem and made it official, if you like, in Europe.  Following the review in the new legislation there are many new little provisions to try to help encourage innovation and product development for MUMS.  The CVMP has been very busy doing lots of useful things, like extrapolation of MRLs, and in July this year the CVMP adopted, as Peter described, MUMS policy paper.  Then at the national level, because I mentioned national activities as well, there have been some very useful workshops, a little bit like this.  First of all one organized by the Spanish and then more recently a second one by the French in Paris.  Now each one of these initiatives addresse individual aspects of the problem, but we still don’t have -- we don’t have, for example, we don’t have a Stephen Sundlof, someone right at the top driving this.  We don’t have someone in the commission who is prepared to be the MUMS Czar, and we don’t have lots of well-motivated people for example in the universities who are prepared to pick up and run an NRSP-7 type program.  This is a slightly controversial point where I am questioning whether there really is a link between the head and the hands with some of the activities in the EU. 
  (Slide.)

Is this my next slide?  Yes.  This is my “regulatory ship.”
  (Laughter.)

You will recognize it as the Titanic of course, and I like to use this sort of imagery.  This is something I have in my mind.  I see the captain up there shouting "iceberg ahead," and he has pulled his Klaxon that made an interesting sound.  But down here in the engine room, the guys are still shoveling on the coal like anything.  Their mandate is to keep that boiler pressure up to here at least.  They have heard that sound.  They know something is wrong, but nobody is actually telling them to stop shoveling on the coal.  Now that isn’t totally the picture; it doesn’t translate totally into what is happening on the regulatory scene.  That is a little bit unfair, but I am sure you understand where I am going with this.  So I am not going to pick on the CVMP, because they are doing such fantastic work and Peter is in the audience.   

I am going to take one example from a centralized procedure and a couple from the mutual recognition procedure.  So for example, CVMP is in charge of writing guidelines.  These are done in the working party, down here [engine room].  They will write the guidelines.  We will get a draft.  We will go to the working group and say, "Do you realize this is really going to seriously effect medicines’ availability?"  And the answer you get is, "Not our problem.  We were given a mandate to write a good guideline to address this issue.  That’s what we’ve done."  Which is strange because the CVMP are actually very interested in medicine’s availability and are working very hard on trying to resolve it.  But what they don’t seem to have is the correct mandate to then tell their working parties to do things in a different way.  Now that is not totally fair, because in fact things are changing now and we are starting to see this change in attitude come through. 
  (Slide.)

I then have two examples here from the mutual recognition procedure, which illustrates again the dislocation between what the heads of agencies may be saying and what happens in practice.  They will come to conferences like this and they will agree with all these things we must do, but in fact it never translates into any change on the ground.  So in a mutual recognition procedure here from our survey in 2002 we came across the example where there was clearly a problem with developing efficacy data because it was a minor species.  But the assessors just did not take that into account.  They, again, haven’t got the right mandate.  They still have the “check-box” mentality, and I don’t mean that as a criticism, because I am not sure they have any other option; and they do need to have, you know, regulatory decision consistency, but they are still stuck in that situation.
  (Slide.)

The other example I had was a vaccine license in Germany.  I have totally forgotten what the vaccine was for, but it was for a range of species.  When it went to mutual recognition of the member states then of course we become involved, and although as an individual country Germany can take pragmatic decisions and decide that these minor species can stay on the label because of the risk; benefit, although the data may not have been perfect.  You know, you look at the risk benefit and you can take a practical decision.  When that goes to be passed through 15 other member states then of course that doesn’t work.  So these minor species were then lost from the label after the mutual recognition procedure.
  (Slide.)

Okay.  As I said, I do believe attitudes are changing and we are making good progress.  The new legislation has better focus on risk benefit, new EMEA guidelines are beginning to question their scope, should they be applied just to new products, or should they also be applied to old products.  Our position is they should never be applied to old products unless there is a good safety concern, a real safety concern.  So for example, it is very sensible that all products should be TSE compliant with the guideline on TSE.  But just because a monograph is updated, it shouldn’t necessarily be applied to any old products.
  (Slide.)

So I am now going to have three slides on the sorts of initiatives we like to propose.  They are split into short, medium-term, and long-term.  I am going to move quickly.  I am still on green, but the minutes are rolling by.  On the short-term initiatives, well, I have really labored this point today, so I don’t think I need to say anything more.  We see no reason why a product should be removed from the market at renewal unless there is actually a safety concern.  There is no reason to update it to new standards just because the goalposts have changed.  It doesn’t mean to say that the product is not safe.  We are very keen that national initiatives should be pursued in the EU, because things work slightly differently over there, and we have very individual national agencies.  Some of these take this very, very seriously.  As I mentioned, Spain and France have organized workshops, and we really want that to continue because we think they can make good progress and will help to bring others along. 
  (Slide.)

Oh, beg your pardon.  Mutual recognition I am not going to touch on.  This I think is a very important point.  There has just been a roadmap published by the European Commission for EU/US Regulatory Cooperation and Transparency, and it is this type of initiative that is going to be the key to the exchange of information so we don’t try to reinvent the wheel.  Data could be made available and useful anywhere in the world where it is needed.  The last point is to pursue the Federation of European Veterinarians(FVE), their “top-10 list.”  There is actually 13 on that list.  I have it with me today if anybody wants to talk with me about it, and I am sure they will send it to you.  But this, we asked them to just produce a top-10 list to get away from this tendency they had to send the EMEA a list of about 150 needed products.  So that we could just focus on what the really good ones were and see whether we could do anything with them and take them further.
(Slide.)

So, as I said, MUMS is not a real priority for industry.  I am going to have enough trouble explaining why I am here for three days for example talking about MUMS when I get back home.  One of the things that I wanted to do is take this FVE list and for those 13 products try and find sponsors, very much like Meg does for the NRSP-7 program, because there is no point in doing anything unless you have a sponsor.  So I have been wanting to phone around and identify who the active ingredient manufacturer is and see whether they are interested, and try and work the examples through.  You know, maybe from that 10 we will find three that are of any potential, and work through them using the CVMP free scientific advice that they have going at the moment on this 12-month pilot project, to identify what studies would be needed and then come back to the CVMP with the actual cost of those studies.  What I wanted to do was engage in some sort of reiterative process with the CVMP.  

But now I am going to point out one of the key differences between Europe and the U.S.  In the EU we have free scientific advice at the moment, a bit like you do here.  The difference is it is very formalized.  So I was told that if we wanted to come back and rediscuss these things this wasn’t actually possible.  I think that is a big difference.
(Slide.)

Medium- to short-term initiatives.  We do have an opportunity coming up to have a look at the data requirements, because as I said, the legislation has been reviewed, but attached to that legislation is an annex where the data requirements are listed; and now the new legislation is in place, the next thing is they are going to look at that annex.  So that is an opportunity to ask some questions about the data requirements there.

For minor species we are very keen to make sure that things are kept totally proportionate to the risk.  In fact, well, we would like that for all products of course.  For example, no ecotox should be necessary for minor species as a general rule.  A more balanced risk benefit assessment, I have mentioned that.  Now this next point relates to the regulatory ship where we would like the European Commission to give a very clear mandate to the CVMP, who can then give a very clear mandate to their working groups, for example when they are developing the guidelines, to make sure things are kept proportionate and account is made for minor use and minor species.

What we really need in the short term is someone to champion this in the EU and at a top level.  We also really need a MUMS coalition.  Now there is a sort of informal coalition operating in the EU, and back in 2001 industry proposed this, but we didn’t make this suggestion public because we were quite nervous of being seen to promise too much and then not being able to deliver at the end of the day.  So we wanted to keep on the back row on this.  But there is an informal coalition between industry, the vets, the farmers, and the association of veterinary consultants, and probably if there is any one driver it is from a guy in the association of veterinary consultants.  But we certainly do not, and are a very long way off from the unique setup that you have here in the United States on this.
  (Slide.)

So for the long-term, we think it is time to really start getting a little bit more radical, a little bit like has already happened here, and we think it is time to rethink the way veterinary medicinal products are registered.  Why?  Well, because we are here today!  And even I spend so much time at conferences talking about this problem it is obvious that we have probably reached the limit of where we can go with the current setup and legal framework.  The data requirements are really just too high and perhaps disproportionate to the risks that the products present.  

So can we rethink that and radically reduce the cost of product development?  I say radically because we do need more head room.  We don’t know what is around the corner and, you know, antibiotic resistance has just arrived as a major data requirement.  What is next?  

It is interesting that this has even been discussed on the human side.  So in the UK there is this guy, Professor Rawlins from the National Institute of Clinical Excellence.  So, you know, a guy who is part of the establishment.  He himself is questioning some of the data requirements, and suggesting they should be looked at.  I am on orange.  I have got to move on.
  (Slide.)

Now this really is my main take-home message today from industry.  In the long term, everything I said on the previous slide we think can be built on by taking pharmaco-vigilance very seriously.  What we want to do is really support a harmonized and fully implemented pharmaco-vigilance system across the EU.  To demonstrate we are committed to this, we produced a good pharmaco-vigilance practice guide for the industry earlier this year.  But if we are going to invest better resources in that very important aspect of drug control, there has to be tradeoff, because the veterinary industry is not awash with money as you know.  If we are going to place more reliance on post-marketing surveillance, we need to place less reliance on the pre-authorization data requirements.  So we need to reduce the date we produce up front and focus more then on in-use surveillance good surveillance.  Industry can not afford to do both.  We think this a very sensible approach because of course you then end up with a much better targeted system, because all this data up front is really based on data assumptions and theory.  Whereas what actually happens in the field may be different.
  (Slide.)

This is a quote from a guy called Bill Jolly who happened to be the New Zealand agricultural or veterinary cache in Brussels at the time of the VICH-2 conference.  While you read that I am going to have a little drink of water.  So there is really my main messages, but the future, as we say, is a much better pharmaco-vigilance system, and in the EU we really need someone to pickup and drive this MUMS coalition, because I can’t even if I’d like to.

Now I have a couple of minutes left, and what I thought it would be useful to do is do a little comparison between what you have here and what we have at the moment in the EU.  But the first thing is I am going to do a comparison of a definition of major species. 
  (Slide.)

Now I already had this information for the US and the EU, and you will see straightaway that there is a standard block of major species here, and then I picked out the differences in bold here.  So in the US you also have horses and turkeys.  Thank God for Thanksgiving Day, and in the EU we have sheep meat and Salmonidae.  Now the next bit is the result of an overactive mind at 5:00 this morning.  Of course I am still on EU time.  I discovered that if you look in your packs that in fact Latin America and Canada, although this is only a proposal from Canada at the moment, is exactly the same as the US.  Japan, again no firm legislation, but this is what is generally accepted.  It is actually the same block here, but not sheep, and farmed cultured fish.  Switzerland again the same block.  Sheep as well, the same as the EU, and horses.  Then Kenya, again the same major food-producing species, but also sheep and goats, which is their essential difference. 
  (Slide.)

I now have a series of slides in my last minute.  I might go straight to the last one in that case.  Doing a sort of comparison now between what happens in the EU and the USA.  So you have an extra-label use.  We have the cascade, which Peter Jones described.  You have a thing called flexible labeling, which we don’t.  You have guidelines on how to satisfy MUMS.  These are under development in the EU.  We hope to see some first ones maybe the end of the year or early next year.  Data extrapolation, yes, but only for MRL data in the EU at the moment. 
  (Slide.)

Now I what I want to get onto is EU, market exclusivity.  That is quite important.  This looks horrendously complicated, and it is.
  (Laughter.)

I suggest you save that for a question and ask me what that means.
  (Slide.)

This is what I wanted to focus on.  On, my time.  I am on red.  Let me say as a concluding sentence, Chairman, this is what I pointed out earlier.  If you look at the guidelines on minor use and minor species in 1999 in the USA, you will see it says seek scientific advice early, and you can get protocol approval, and the whole thing seems to give more emphasis on what I have called “partnership” and continual dialogue.  We don’t have that sort of setup yet in the EU.  Thank you very much.  
  (Applause.)

DR. GRIFFITH:  Thank you, Rich.  It impresses me how afraid all these speakers are of Alistair.  It is just amazing. 
  (Laughter.)

They have all commented on how vicious he is going to be.  Our next speaker is Dr. Richard Carnevale.  Dr. Carnevale is the Vice President for Regulatory, Scientific and International Affairs at the Animal Health Institute, and with that I think we will just proceed.