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U.S. Department of Health and Human Services

Animal & Veterinary

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Human Food Safety

DR. WEBB:  There is a handout for the last two lectures, for Dr. Clayton’s lecture and for Dr. Carnevale’s lecture.  I am giving them out.  If you didn’t get them, you can collect them on the way out. 
DR. CRAIGMILL:  Welcome back, everybody.  We are in the home stretch as we say.  We are going to go ahead with the human food safety forum.  You may think we are late, but again it has to do with math and calculating out times.  We are actually right on schedule, sort of.  We are going to delve in now into the food safety forum, and one of the things we thought is that because some people wound up with crooks in their necks yesterday from turning around, if the speakers would stand up or come to the front when they want to say something, or we can turn our seats around.  We can do anything.  We had hoped to have this actually almost like people facing and back and forth.  Not regulators on one side and industry on the other, just so that we can see one another when we chat on this.  As we get into this with the human food safety issues, does anyone -- would anyone like to start with an issue or a question, or should I go to my loaded list again?
VOICE:  I have a question.
DR. CRAIGMILL:  Yes, sir.  Please identify yourself and your affiliation.
DR. SUBRAMANYAM:  My name is Mark Subramanyam.  I am with Schering-Plough Animal Health in regulatory affairs.  Dr. Grein --- regarding data, reducing the data requirements and supplementing the MRLs.  Okay.  I would like to know if the CVM has any proposals in that direction for the minor species.
DR. BABISH:  She is in the red coat.  Come on down.
DR. FRIEDLANDER:  I feel like I should get a door prize.
DR. CRAIGMILL:  Door number three, right?
DR. FRIEDLANDER:  CVM for food safety for minor species does do a lot of extrapolation.  The tolerance for a major species will be applied to an appropriate minor species.  So for cattle the tolerance in cattle will be applied to sheep or goats.  We do a lot of extrapolation.  You don’t have to repeat the toxicology studies.  You don’t have to repeat the metabolism studies.  The total residue studies are not repeated.  Essentially what we are looking at is a depletion study to establish a withdrawal time and a justification for why we should be applying the tolerance to the minor species for food safety.
DR. CRAIGMILL:  Could we followup with that and ask if food consumption factors are taken into account for that?
DR. FRIEDLANDER:  The food consumption factors for CVM are the same for all species, so you have already got the food consumption factors established and we go directly to the tolerance.
DR. CRAIGMILL:  Thank you. 
DR. CLAYTON:  Thank you.  Rick Clayton, IFAH-Europe, and I have a question to one of the previous speakers as well if that is okay, to Ronald Baynes.  It is slightly flippant, but I would like to know.  The proposed transparent method, a “PAR”, it is not actually transparent to me what P-A-R means.
I have searched the slides, and I couldn’t find it.  I’ve been trying to guess.  I don’t know how accurate I have been.  The other question is slightly more serious, and that is the correlation between US tolerances and the EU MRLs. The whole basis for the sort of scientific basis for the extrapolation of MRLs in the EU was on a risk analysis approach.  Where after studying all the published MRLs they concluded there was no significant difference between a lot of them; and because of all the safety factors, the fudge factors that are applied, the CVMP took a very straightforward approach by saying anything that had an MRL within a 10-fold difference was in effect equivalent when you consider you apply some of the safety factors.  So I was interested in the graph that Dr. Baynes put up, and a lot of those substances on there are within that sort of range.  I was just wondering whether I court propose to analyze the data in the frequency distribution, putting the different MRLs into appropriate frequency.  For example, groups within a 10-fold difference, et cetera.
DR. BAYNES:  Yes, that is an excellent idea.  However the issue still remains you need to develop a withdrawal time, and this is again the purpose of my discussion.  How do you come up with an extended withdrawal time?  If you are looking at factors of 10 you can see the problem here.  Simply even the example I gave there with a factor two or three, going from 0.1 part per million to 0.3 for oxytetracycline for the tolerance for milk you can significantly influence the withdrawal time.  Yes, that is a nice recommendation.  I think that is a nice way for us to look at it in the future.  I think a nice distribution of where we stand.  We would probably get a better picture, but again it will influence the withdrawal time.
DR. BAYNES:  A PAR over -- was it --- or coffee who came up with a PAR? 
DR. CRAIGMILL:  Do we drink coffee?
DR. BAYNES:  The original acceptable residue again, those of you who play golf, that was the idea.
DR. CRAIGMILL:  Any followup, further questions related to human food safety issues?  Dave Scarfe.
DR. SCARFE:  Yes, good morning.  I am David Scarfe.  I am with the American Veterinary Medical Association.  I would just like to say a great deal of admiration to the conveners of this.  This is an exceptional forum of distinguished people from an international perspective.
We have heard a great deal about some rather sophisticated ideas of trying to get to useful endpoints to utilize drugs primarily for minor species and minor uses, and I think we have got the opportunity with an international distinguished group like this to look at two things that we found to be enormously useful to accommodate the use of drugs where there are no approved drugs, and they are two-fold.  Number one, extra-label use, we have heard this sometimes called off-label use in every single one of the presentations.  The second is some mechanism to avoid or rather accommodate safety aspects, and specifically I would like you to focus on FARAD.  These are two enormous tools which over a number of decades we have tested, played with, some of which we have got into legislation to enable us to actually perform it. 
But these are tools that in the interim before all this global harmonization and the transparency with PARs is put in place or something similar, these are tools that you can use at all levels.  From dealing with the individual farmer, he is going to come to you and say, "Doc, I want a drug to take care of this disease you have just diagnosed.  We don’t know anything about it.  We don’t have a drug that is approved."  All the way up to regulatory and the legal issues, if you want --- that the judge asks you what is your justification for using this particular drug in that particular situation.  Or if you want, do it on international trade, the same justification.  We are looking always at two or three common variables.  If one omits or just assumes that the drugs are manufactured adequately, they are looking at safety and efficacy.  Those are the two primary things, and these two tools have given us the where withal to be able to do this.
Extra-label use, I specifically invite everybody in this room to pick up one of the algorithms that has been developed, and we have got legal authority to implement, and with tremendous help from FDA CVM, and put together an algorithm that ends up to, “can you or should use this drug?”  It is defensible.  It has got a sound basis.  The other key important piece of this is when you use a drug.  You have heard this come up over and over again every single presentation.  Is it safe for humans, primarily human consumption?
We developed, or these gentlemen, several of them, developed FARAD a number of years ago.  I am not going to go through trying to explain all the system, but this has turned out to be an exceedingly powerful system.  It gives one the justification for using a drug and the advice that the veterinarian offers the particular client in preventing the exact things that you are talking about that drug approval is supposed to accomplish.  So I invite you to do two things, and as an international audience.  Ask yourselves can these principles of extra-label or off-label, whatever you prefer to call it, use of drugs for minor medical conditions and for minor species where we don’t have drugs and the data that is produced through what we have now as a global FARAD -- this automatically gives you the invitation to participate -- can that information be used across the board on a global basis?  So I pose a question rather than present any concrete idea, an invitation for you to discuss this.

DR. CRAIGMILL:  Thanks, Dave.  We did not pay him to do that.
DR. WEBB:  I would pay ---.
DR. CRAIGMILL:  So he did.  Alistair, do you have a presentation up on FARAD outside or --
DR. WEBB:  I think it has come down.
DR. CRAIGMILL:  It has come down.  Dr. Jones.
DR. JONES:  This is a new question.  It is not response to AUMA. 
DR. JONES:  Dr. Baynes in his talk was asking a question with regard to the EU setting withdrawal periods for off-label uses.
  VOICE:  Excuse me.  Could we have the speaker ---?
DR. JONES:  Yes.  Peter Jones, EMEA, London.  Sorry.  Dr. Baynes was talking about the setting of withdrawal periods for off-label use.  You mentioned actually you had been trying to contact the EMEA.  We haven’t had any contact with you, but we are very happy to talk you if you want to try making further contact.  The reason I wanted to intervene was just to say that indeed there is no mechanism per se in our legislation for setting withdrawals for off-label use.  It is not there.  As Kornelia was talking in her paper this morning, we are trying very hard now to look at whether we can adapt data requirements for setting MRLs for MUMS, and we will see how that pans out.  But what our legislation does do, it allows off-label use under very strict terms as I explained in my paper yesterday and with this article called the Cascade, which is a sort of default system.  When you use something off-label there is a set of standard withdrawal periods, and that is listed in the legislation.  It is 28 days for meat, 7 days for milk, 7 days for eggs.  The problem with that is if you are talking to somebody who farms meat rabbits for example is that the life span of these things doesn’t match up to the withdrawal period.  I mean, the withdrawal period extends the life span of the fattening period, so it is not a very practical of use of that.  But I just wanted to sort of fill in on that.
Could I just also make a comment on FARAD?  What Kornelia didn’t get a chance to say because she was covering a lot of material was in that time when we were working to establish MRLs for these 7-, 800 substances -- and there was a lot of midnight oil burned trying to do that.  We tried so hard to salvage some of these products, and we really, really did with all our experts who were working in the CVMP safety working group to see if there was data anywhere that we could use.  Of course many people were saying, "Well, use FARAD.  Use FARAD.  You can set a withdrawal period."  Well, the problem was we didn’t have a tox package to set the threshold.  I mean, it is fine if you have got an ADI.  Then you can use FARAD data on residue/metabolism to set a withdrawal period.  That was very frustrating to us.  So it is not that we haven’t tried to make the most of it.  It has, I think on some occasions has been useful.
DR. CRAIGMILL:  Yes.  Actually we understand exactly the problem there and your regulatory constraints which we are not under here.  Just very briefly to address Dr. Scarfe’s question to us.  For those of you that aren’t familiar with FARAD, is there anyone --?  Well, probably.  I will just do it anyway, whether you know it or not.
FARAD is the Food Animal Residue Avoidance Databank.  It has also been funded by the USDA since about the same time as the minor use animal drug program.  In FARAD what you have heard primarily from Dr. Baynes is our outreach and advisory function that we offer to veterinarians and producers, and primarily to veterinarians for extra-label use, but also to mitigate accidental exposures to pesticides and environmental contaminants.  We would like to emphasize the fact we don’t just do drugs.  Let me rephrase that.
We do all chemicals.
VOICE:  Not any better.
DR. CRAIGMILL:  Let me rephrase that one, too.

Strike that from the record please.  We do not discriminate between chemicals on the basis of their use and in terms of their residue profiles.  One of the things that we have done over the last 22 years is to collect all the information that we can find in the literature and in our discussions with EMEA at many times.  They have excellent people doing exactly what we do, trying to find the papers, however with a slightly different focus. 
What we have been doing is we have been taking all of these papers, which now number approximately 8,000 articles that we have retrieved from the literature that have some type of pharmacokinetic or residue data.  We extract that data, put it in a standardized format, and enter it into a database.  We have approximately 43,000 records right now from which we have generated new data on about 50 percent of the articles.  We will extract data from papers, take data out of tables, take data out of graphs -- which is actually possible.  You can extract mean data from these -- and then enter it into our database, perform pharmacokinetic analysis, and we currently have about 10,500 half lives for different chemicals.  For about 2,000 separate chemicals in a variety of species ranging from emu -- I think we even have a whale record, Marilyn, and a few others.  But we have just about everything in there. 
The purpose of this is to be able to perform interspecies extrapolations on the basis of allometry if it is possible, or simply to look at and perform an analysis of multiple studies looking at pharmacokinetics and residues in a variety of species.  That is my overview.  We currently have partners internationally, and we are seeking more, and I am going to come back to this again a little later just to see whether or not this mechanism is a way in which we can help to harmonize or/and collect data into a central area so that we don’t have to keep searching all around to find information about minor species, but we have a one-stop shopping place as we say.
DR. BABISH:  People might be interested in how much all of this costs.
DR. CRAIGMILL:  A lot.  We calculated that over the last 22 years in FARAD it is somewhere around $3.5- to $5-million.  The AVMA has been a primary promoter.  Dr. Bernadette Dunham is our heroine here, our true head; before she went to work for FDA was a dynamo in the political arena in getting FARAD into legislation and authorized and funded.  She is probably most responsible for that of anyone, and for which we love her dearly -- and worship her.
Now that she works for FDA, we have no respect for her whatsoever, but --

I am just kidding.  Anyway, it has been a major thing to have that happen, and we are still struggling.  FARAD has existed on a year-to-year basis for the last 22 years.  Some people think we are permanent.  We are not.  We can disappear overnight with the stroke of a pen in a committee, and without the continued support of the AVMA and others that could happen.  We think we are very close to actually getting into permanent semi-permanency and longer-term funding.
DR. BABISH:  Any user fees, Art?
DR. CRAIGMILL:  The user fees are zero for US citizens.
DR. BABISH:  And this week only for the UK.
DR. CRAIGMILL:  The first one is free.  That is our drug focus.
No.  We have to because of cost accounting practices within the federal government and the fact that we are funded by the federal government, we have to charge foreign users for accessing this just to -- so that when we are audited and somebody comes in and looks we have to say, "Oh, you know, you spent some time working with this country, Australia."  We will use Australia for an example.  Everybody likes to pick on them.  "What are you doing?  Where is your funding for this?"  This is why we have to get money from that to cover it, and so we do charge a fee for access now to the databases, and particularly because the databases that we have developed are -- have been developed at such extreme cost.  Dr. Webb at the University of Florida and Kandi Crosier and his crew, Carolyn, they do all the compendium work and have been working on a global compendium which I am going to bring up again a little later as another possibility for helping to coordinate work on minor species. 
Right now we are on food safety, and I want to drop a bomb right in here, and that is -- okay.  No, I want to drop -- I want to ask a question -- strike that one -- in relation to and just bring out one of the things that we didn’t talk about yes.  Is there a difference in how countries handle the regulations on injection sites?  Everybody is looking at their shoes again.
And I just wonder if we can open that up again for discussion on how injection sites are handled maybe we should work with a non-controversial topic.  Injection sites, how they are considered with respect to setting MRLs or tolerances?  Eric.
DR. MITEMA:  In my country we currently are not using these, but we also take common sense the fact that we try to incorporate the JECFA recommendations.  Part of the JECFA recommendations considers -- puts common sense over the injection sites in terms of how to set up -- I mean how to fix the withdrawal time.  But it is something that, you know, is being considered.  But currently, we are not really, you know, using that unless, you know -- unless it is a very, very critical case.  But we attempt to go by the JECFA recommendations.
DR. SHABNAM:  Javad Shabnam from Health Canada, Human Safety Division.  When we establish the target tissue then we consider injection site if it is not higher.  We consider 10 times of maximum residue limit in muscle.  It shouldn’t go over 10 times of the maximum residue of muscle. That is our consideration.  If it does, we have to increase the withdrawal period based on that.
DR. CRAIGMILL:  Lynn, I wonder if we could ask how the injection site data are used in setting withdrawal times in the US, if I can pick on you again.  Or do you want to differ to somebody else?  Lynn Friedlander, CVM.
DR. FRIEDLANDER:  No, I won’t put anyone else on the hot seat.  As mentioned by my colleague from Health Canada, we have routinely allowed a residue of 10 times the muscle tolerance at the inject site.  We also -- well, I should say that we consider that the likelihood of you eating an injection site to be a rare occurrence.  Obviously it is a more rare occurrence as we decrease the number of injection sites over the body of an animal.  If the animal is a pin cushion it is a little harder to justify it as a rare event.
We also have the opportunity on a case-by-case basis to look beyond that 10X number with supporting data and with a justification for what kind of acute effects we might expect from that rare, but obviously high-level, residue exposure resulting from an injection site consumption.  This is not a common issue for us.  It tends to be very product-specific.  It can be injection site-specific in terms of whether it is a subcutaneous or an intramuscular injection.  So each of those things are taken into consideration, and the regulated industry can of course come in and make their case for why they would like to explore this option with us.
DR. REEVES:  Phil Reeves from Australia.  I guess the approach in Australia is fairly similar to what Lynn just described for the USA.  Basically the residues at the injection sites are much higher than what they are away from the injection site.  That makes it impractical to be trying to get the injection site residues to comply with the MRL.  So basically what we do is look at short-term dietary intake for injection site residues, again on the basis that consumption of an injection site is probably going to be a rare event.
There are a couple of issues that don’t seem to go away.  Certainly for Australia the biggest issue is International trade; and basically the problem is it is all very well domestically looking at the science of it, and the science of it says that you should probably be doing short-term dietary intake calculations in working out the toxicology because it is not a lifetime of consuming injection sites.  You can easily extend the withdrawal time to take onboard the injection site residue.  The problem then becomes one of International trade, because if those carcasses or tissues are exported, you have got to try and figure out how that importing country is going to test those carcasses. 
For example, what happens if a sample is taken and it exceeds the meat MRL or tolerance and in fact the sample actually came from an injection site where in your country it might have been quite permissible.  I know a few years ago we put up a draft guideline at CCRVDF and we are trying to address that issue.  At the time we suggested you take a second sample from the diaphragm simply because it was very unlikely that the diaphragm was going to be objected.  Of course it all got too difficult, and that particular guideline went by the way. 
The second issue that I have encountered fairly recently is where what you have at the injection site is actually lipophilic drug which partitions into the fat obviously, and I have heard all sorts of arguments about trimming of injection sites at slaughter.  I have seen various recommendations for what maximum volume should be injected at any one site, and again in the draft guideline we put a few years ago for the CCRVDF to consider I think the maximum volume at any one site was meant to be 10 mLs.  Of course, that was not acceptable to certain countries.  They said that is not practical on animal husbandry grounds, and so that didn’t stack up with good reason.
This problem with some of the long-acting lipophilic compounds is an interesting one because, you know, you can have these rules about injecting high on the neck or close to the ear or something like that, and then you got to have trimming at slaughter.  But in reality, you have got to have some sort of visible lesion before you can trim it, and I’ve looked at lots of data and if you don’t see visible lesions in 100 percent of cases then what that means of course is that you are not going to have trimming at the meat processing plant.  So again in terms of exports for trade, that leaves a problem. 
The other part of that of course is what does the MRL apply to?  Does it apply to fat or does it apply to meat? And if you have got one of these long-acting lipophilic compounds whereabouts -- how has the chemical partitioned between meat and fat at the injection site?.  So you could be led up the garden path I think with the sort of comparison that we are doing.  So I think there are a lot of challenges there.  I think the science can be working out, but I am not sure the legislative part could be worked out so easily.
DR. CRAIGMILL:  Thanks.  Kornelia, go ahead.
DR. GREIN:  Kornelia Grein, EMEA.  In the EU the situation is that the MRL established for muscle is also used for the residues for the injection site, and there is a guideline also from the CVMP there which is a number of years old which is currently under review.  There has been an update being done.  The concept had been proposed to be maintained.  The guideline had been under consultation.  Currently the comments received are being looked at, and we will come in shortly with final conclusions for the time being on that matter.
DR. CRAIGMILL:  Thank you.  Are there a lot of situations where the injection site drives the withdrawal time?  Most probably it is the most important factor.
DR. JONES:  Peter Jones.  Thank you.  Yes, I am aware that.  I think it was John Owusu from NRA in Australia wrote the paper from Australia, the one that went back and forth to Codex and there was -- I think that we have all tried really hard.  The idea that you are not looking at lifetime exposure even if you have the misfortune to eat an injection site or consume part of an injection site.  So there was this long debate within our committee and group of experts on using the acute reference dose.  But despite the best intentions, there were those that were still concerned that even if you took on that concept the business that was referred to by our Australian colleague is that the trade issue can’t be overcome.  Even though you might accept what is a very good risk assessment approach and you accept the chances is one in however many million that you are going to ingest that injection site, if somebody samples at the port of entry and the whole consignment gets sent back home, then your political masters are going to say that is not an appropriate way to deal with this issue.  That is what we have struggled with time and time again.  I think this is about the third time we have tried to review this guideline, and it is a troublesome one.
DR. CRAIGMILL:  Thank you.  Phil, if I could ask you to expound a little bit upon how you address the issue of export withdrawal times versus domestic withdrawal times.
DR. REEVES:  As I said in my talk yesterday, somewhere between -- depending on the commodity, but it like 60 to 80 percent of the produce that -- of the production would actually be exported from Australia.  So it is very, very important to us, and as a result of that we have in our legislation before we can approve the drug the trade aspects have to be taken into account, and they must not unduly prejudice trade.  So in fact that is probably by far the most difficult thing to deal with.  Obviously, you know, we deal with public health and environment and all the other issues the same as what we heard yesterday and today. 
We have another problem as well, and I guess together with New Zealand, Australia is one of the last two countries which receives a lot of new drugs for the first time.  Particularly when they apply to sheep and cattle to a lesser degree, but certainly with sheep; and it is because of the huge numbers of sheep that we have and the sort of pests that are there which require treatments.  So because we are often the first cab off the rank, there are no MRLs in place set by either JECFA or other countries.  So we are in a position where we are setting MRLs for the first time, and so then we have got a problem immediately with trade because nobody else has got a standard set.  Which means that the acceptable standard for trading partners is no detectible residues, and so then we basically have two standards in a way. 
What we have for domestic consumption is based on the sorts of considerations that we have been hearing about here to do with human food safety and so forth.  But we have a second standard which is in a sense a higher, a tougher standard, and that is to do with facilitating trade.  So to jump that second hurdle what we have to do is to let the residues deplete further to non-detectible levels.  So it has got nothing to do with public health, with human safety.  It is purely to do with meeting with major trading partners.
So Australia recognizes the important work of Codex in this area; Codex MRLs, can be adopted internationally and it has got the sort of support of the WTO and the SBS agreement on sanitary and phytosanitary (SPB) measures.  But again because we are sort of seeing some of these chemicals so early, there are no Codex MRLs in place, and often it takes something like 10 years to get those standards, those MRLs in place.  So then what we have to do is go out setting up bilateral trading agreements with all the countries where we want to export that particular commodity to.  

Just one example, again partly because of our climate and so forth we have different pests to what you might have in Europe or the US, and in particular the cattle tick is very important.  So in about the early ‘90s we had a product or a new chemical, fluazeron, which is an insect growth regulator come to our country, and we approved it in about ‘94.  But by ‘95 we realized that it was lipophilic, and most of these things that I am talking about are lipophilic and very persistent.  It was going to upset our beef exports, you know, which are worth round about the $4-billion per year, and it was far too big to be jeopardizing.  So what we had to do was take this particular product off the market while the company went and set up bilateral trading agreements, and they did that with my beef trading partners.  That included the US, Canada, Japan, Korea and Taiwan.  Now that took from 1995 to 1998 to occur.  Now that company had that very good product off the market for something like three years while they got all of those conditions in place.
Now if Codex MRLs had been in place of course there is no need for any of that.  It would be nice and clean.  So it is quite difficult, and those are the kinds of issues that countries like Australia and New Zealand face with respect to drugs. 
DR. CRAIGMILL:  Thank you.  I didn’t mean to put you on the spot, but I thought that was a very interesting example.
DR. SCARFE:  David Scarfe again from American Veterinary Medical Association.  Philip has raised I think a very important key topic, and I urge you to look at the name of this workshop, the global perspective, and that has to do with international trade.  We are all dealing with the same problems.  I have heard perhaps for the last 20 years, I have heard in informal discussions over the last two days, from multiple different people one common topic, and I think it needs to be put into a public forum for discussion.  I realize it is very problematic.  I also recognize that it has some precarious overlaps with issues in human drugs, but that very simply if a drug has gone through a process of approval in one country, why can’t I use it?

I realize this opens up some fairly large can of worms, but I emphasize here that our perspective is really looking at species for which we have no drugs and conditions for which we have no drugs.  Yet across the water, across the geopolitical barrier, this entity has developed this supposed sound scientific basis for why these drugs should be used.  So I pose the question, why cannot I get a drug from Canada to use in a condition that I have?  It may be a life-threatening thing.  Put this in the perspective of national security today, biosecurity.  Like if you thought beyond the initial 9-11 and the catastrophes that we have had and are going on today, we know that there is going to be a desperate need if there is an outbreak of certain diseases in any country. 
So I ask the question to the international audience here, because I get asked daily on this.  Why can I not use a drug elsewhere?  If your answer is you give your bureaucratic answer or your administrative answer or whatever answer you want, it could be sound science, then the next question you have to ask is what has to be done to change that situation.  So I opened the can of worms, and go at it.
DR. CRAIGMILL:  Dr. Sundlof is just jumping out of his seat to answer that question.  David said a bureaucratic answer would be okay.

DR. SUNDLOF:  Yes, it is a good question, and on the human side at least in the United States we are going through this process right now of drug importation or re-importation from certain countries and whether or not that should be allowable.  The FDA has taken the position that we can’t support or do not support drug importation from other countries, and the basic reason is -- just kind of from our perspective.  I will speak for the FDA in this case.  The whole premise on which we assure safety and efficacy is by our ability to go in and validate that the drugs were produced under the standards that we hold these companies to.  That means physically being in the facility validating that the drug was indeed produced under the quality standards and that the data that went into the application can be verified and validated.  Without that, we really don’t have a good way of explaining to the public if something happens that the FDA can’t control these problems.
The one thing that we put a lot of effort in is making sure that the public feels very confident in the products that we regulate, and the only way we can do that we feel at this point in time is that we have this trust with verification process by which we can actually go in and validate that the products are produced under our standards.  The one thing, because that is so important to us, the one thing that we never want to be in a position with the public is to say when the public says, "Well, is this particular product safe?" and we say we don’t know.  That is the one thing that I think regulatory agencies, the one value that we hold most dear, is to maintain that confidence of the public.
So that is kind of the backdrop on which I will talk about some of the efforts which have been made.  We have and are working towards what are called mutual recognition agreements with a number of countries, and those have been difficult to establish.  But basically what that means is that we would have these agreements that if a country approved a drug or did an inspection on a plant that produces drugs for the United States for instance, that we would recognize their authority.  That requires these mutual recognition agreements to be worked out such that there are  phase-in periods where we do joint inspections and we make sure that each other’s, that each of the countries that are involved in it, are conforming to the standards of the other country. 
Where this has broken down in the past is that mutual recognition agreements are based on equivalence.  That the country in question has a process that is equivalent to that of the United States, and I believe that a lot of countries do have processes that are equivalent to the United States.  But when actually try to nail down what equivalent means, it usually comes out that it has got to be identical to our system.  That is what equivalent is, and as a result of that these discussions oftentimes break down.  But we do maintain a certain mutual recognition agreement with a few countries, and we are moving to try and get more of those mutual recognition agreements in place.
The best answer I think though is for the VICH process.  We have two processes of harmonization right now.  One of them is Codex, and the Codex process looks at products that have already been approved and tries to harmonize the MRLs.  I think most countries even if their MRLs are -- their countries’ MRLs are different from the JECFA or Codex MRLs, most countries I think say meet the Codex MRLs.  We are not really too worried about products that are coming in.  So I don’t think with very few exceptions that any country is stopping products coming in that meet Codex MRLs.  A lot of  countries de facto adopt Codex MRLs, and once Codex establishes an MRL many countries just naturally adopt those as their own.  That has been very helpful. 
The other harmonization efforts are VICH.  That means that if a company is generating data for an approval process, as long as the data requirements are the same for all the different countries, if those are harmonized then those data packages only have to be produced once.  They can be reviewed in the various countries, and everything should be very harmonized from that point.  So I think I see the most promise in the VICH process.  I think as VICH goes on Codex will be actually less important in the area of animal drugs because most of the data that would generate the MRLs will be the data that everybody has seen.  It will all be the same data and there won’t be any need for harmonization, hopefully. 
I think there is some hope for mutual recognition agreements, but I don’t think that is going to be around for quite a bit, a long time, because of the nature of mutual recognition agreements and sovereignty of various countries.  That is a long answer, but bureaucrats are allowed to do that.
DR. CRAIGMILL:  That was a bureaucratic answer.  Does anybody else want --?  Okay.  Elaine Jetté.
DR. JETTÉ:  To add a question to your answer, Dr. Sundlof, is there any way that since VICH you see it as a good forum to promote harmonization, is there any way that we could ask this group to have a special working group for MUMS?
DR. SUNDLOF:  I don’t pretend to speak for VICH, but there are processes.  There is a steering committee, a VICH steering committee, and through that steering committee the new work gets assigned.  So a recommendation could be made the VICH steering committee.  Canada is an observer and would have the wherewithal to suggest that, or another country could suggest that.  In the VICH right now, the member of countries are the European Union, Japan, and the United States, with Canada, Australia, and New Zealand I believe are observers.  Is that right?
DR. SUNDLOF: CAMEVET, yeah.  Yeah.  CAMEVET for those who don’t know is South American, Central American, Latin American countries who have come together and formed a coalition.  So that is certainly something that could be considered.  Right now VICH I think is trying to work through a number of the guidance documents.  We will be having VICH-5 -- no, VICH-3 in Washington next year.  Is that --?
VOICE:  In late May.
DR. SUNDLOF:  In late May, and at that time those proposals would be taken up.
DR. JONES:  Peter Jones, EMEA.  Maybe just picking up on the MUMS issue with VICH.  The EU in fact about three years ago raised that as a possible topic, and it was discussed at the steering committee.  But at the time I think the US was fairly supportive, but our Japanese colleagues felt that there were other priorities that merited attention before MUMS.  I think one of the difficulties also was I think it was foreseen that what was minor in one region -- you know, we are back to the same old problem again.  I was talking to our Japanese colleague last night in fact, and given the excellent presentation we had from Japan yesterday there clearly is a MUMS issue in Japan as well.  Possibly at the steering committee or as Steve mentioned at the conference in Washington we could re-engage with that topic. 
Maybe to the AVMA question, sort of a European answer to that which is quasi-political, quasi-scientific I guess.  I share Steve’s concerns that it would be nice if we could get some more progress done under MRAs.  We could spend a few hours telling you about the difficult negotiations between the US and EU on MRAs.  We have concluded them with other countries.  We haven’t been able to do between the US and EU, and of course even if you have an MRA that gives you equivalence on manufacturing, but beyond that you have still got to approve products.  VICH hasn’t gone so far as on the human side where they have worked very hard to get to a common technical document.  The idea being that if your company wanted to authorize your product in the three regions, possibly these other countries as well, you have one dossier.  You submit it the agencies in those countries, and the thing goes forward.
The point I wanted just to make is that I think there is another major issue as to why some products are authorized in some countries and not in other, and that is societal values.  If I take the situation with BST which you have authorized in US, we don’t have authorized in the EU.

Growth promoting hormones, beta estradiol, the same situation applies.  The problem in trying to reach agreement to  whether those products could be registered in all the areas we are talking about is that the EU society has made it very clear that it does not want to see these products used in veterinary medicines.  There were some disasters with BSE --- which swayed opinion very, very strongly, and I don’t want to go into the politics of that.  But such issues impacted very much on the decision as to whether to authorize BST.  There were certainly some safety data that was presented in the EU that suggested that repeat use of BST in high-yielding dairy cows would result in welfare problems.  Again, that is the way the EU looked at it.  So I think that is not just so easy to say if a product is licensed in one country why can’t we have it in another.  There are those other values that play on the political decision as to when you legislate whether you can allow these products to come in or to be authorized or not authorized.  So I just wanted to add that.
DR. CRAIGMILL:  Thank you. 
DR. OELLER:  Meg Oeller, CVM and NRSP-7.  I just wanted to also say to David that I, in my position, deal with this all the time with people saying if sheep are a minor species in the United States and they are a major species in Australia, why can’t we just have all the drugs that are approved in Australia automatically approved here.  I certainly sympathize with their position, but there are other things beyond the manufacturing and all the things that have already been discussed.  There are things like the fact that there are different breeds of animals in different countries, that there are different parasites, different resistance patterns, and all kinds of other things that have to be taken into consideration that make it not such a clean transfer. 
I would love to hear us continue to discuss things that are transferrable, and one other point I was going to make that has been made is before is this issue of regulatory creep.  Which is that a lot of things that were approved a long time ago were not done under GLP conditions, and even if a company has a dossier that they want to give to another country if it was done a long time ago it may not meet current standards.  So that also comes into it. 
Another big issue is what the market is going to be and whether the drug company itself is interested in sponsoring the approval.  Sometimes they don’t want to because their studies are old, or just because they don’t think that the market is there.  So those are all things that make it not as clean as we might like to see.
DR. CRAIGMILL:  I would like to introduce just a question again to our speakers and to the audience that has to do with the definition of minor use.  We got a pretty clear definition of minor species.  For minor use, the definition is not quite so clear.  Meg is looking at her shoes.  Actually she is trying to crawl into one.  The question relates to a couple of slides where people had minor uses in major species listed, and I will bring up a specific case that we wanted to discuss which is in the US.  It is a case of whether or not we could classify the use of drugs in veal calves as a minor use.  Is there any place in the world where veal calves would be classified as a minor use based on consumption factors, drug use, anything like that?  Does anyone --?
  (No response.)
Should a species or could a species be classified as a minor use based on consumption factors?  In other words, very low consumption of the meat or the product.  For animals again specifically is my question.  Does anyone want to address that?
DR. BABISH:  I think the word is profit, which usually gets people talking.
DR. CRAIGMILL:  I guess nobody wants that.  Okay.
DR. BABISH:  Good try.
DR. CRAIGMILL:  Were there species?  I thought I saw in one talk that there was a minor use that was defined as a minor use on the basis of low consumption.  Did I miss that somewhere?  Dr. Jones, was it in dairy sheep or something?
DR. JONES:  Certainly on the veal calves issue.  Peter Jones, EMEA.  On the veal calves issues, I mean, veal consumption in Europe is huge, so that the distinction would just never be made.  We struggled with this enormously in the deliberations in drafting that position paper that I talked about yesterday, and we have come to the unsatisfactory conclusion that it is minor use on a case-by-case basis, which is a non-answer really.  You know, we were looking.  I know looking at ---, heart worm, canine heart worm, which is prevalent in some areas of Mediterranean countries where the mosquito is present.  That thing is moving up now as we get more and more global warming, call it what you will.  The dog is a major species of course, but the licensing of a product for canine heart worm could justifiably five years ago been considered to be a minor use in the EU.  Now probably that has changed. 
So I think to try and wrap a definition around minor use has been impossible for us, and I think we will just need to consider them on a case-by-case basis.  If a company says, "Look, here we have a product that could be used in a major species.  We need support," be it regulatory support with changes to data requirements, funding, fee waivers, fee reductions.  Then the legislation in Europe allows for us to consider those today, and we would ask for them to put an application in, put that petition in for fee reduction, fee waivers on the regulatory basis.  But as far as anything else, no, we haven’t made any progress I am afraid.
DR. LYNN:  Randy Lynn, IDEXX Pharmaceuticals.  I have heard this answer on minor use in a major species as that it will be decided on a case-by-case basis.  I guess I was just wondering if some of the regulatory people in the room could maybe give us just kind of random thoughts as far as what factors would be considered in that case-by-case basis.
DR. HALEY:  This is Carol Haley, Pfizer Animal Health.  I would like to support that, because -- that question, and I know it is a hard thing for people to answer from CVM and I am not sure whether they are under guidance policies here and how much they can say.  But the thing about industry when it is looking at whether they are going to go for an approval like this is we have to know these things in advance.  We can’t kind of just start saying, oh, we are going to go try to get a minor use drug approved based on what we think FDA might do.  It is really we really need to have something to take to our management to say, you know, this is what they think.  "This is what we think they are going to say when we take this case to them."  So it is one of those cases again where we really have to have that guidance before we can go ahead.
DR. CRAIGMILL:  Hand it to Meg please, Carol.  Thank you.
DR. OELLER:  Meg Oeller, FDA and NRSP-7 again.  Yes, we are doing it case-by-case.  We have just had the law passed which says that we are going to do this.  It used to not matter until the case of the ADUFA fees came in, because the requirements -- I mean, it is pretty clear what requirements we have to meet for any given product, and we have a product development meeting and we can identify what has to be done.  But now we have to actually put a handle on something and say that it is a minor use in order for that product to be eligible for waivers from the user fees, which are substantial, especially if it is for a small company.  So it is a big issue. 
It is something that we have wrestled with when we were drafting our proposals that became the MUMS legislation, trying to put in a hard and fast definition like the human orphan drugs were able to pick an actual number.  They said 200,000 cases, but they know how many cases they have.  We don’t.  We don’t have a central data source that says that you are only going to see so much babesiosis in cattle in this country.  We just don’t know that.  So putting in an actual number or a percentage of the population or any of the other things we considered would put an unreasonable burden on the sponsor to justify it because there is no place they can go and get us that information.  So as much as we like to be hard on industry, we don’t like to give them impossible tasks. 
So we are still working on it.  We left the legislation deliberately a little vague in the definition.  It is not as vague as our old regulation, because there were groups that wanted the numbers to be made certain that they would not be too large.  In the regulations it said a limited geographic area could be a minor use, and we had arguments saying that, well, the eastern shore of Maryland and Virginia are a limited geographic area, but there are a billion chickens over there.  So we have added the phrase "and in a small number of animals."  Unfortunately while we are going through the regulation-writing process we are going to have to wrestle with this question again and try to come up with something that will be a little clearer in the regulations, or worst case in guidance that we will give to industry.   But in the meantime we are trying to do all this on the fly, and applications that come in I would just recommend to industry that they ask first if they can get some particular use considered a minor use, get the letter back, and then ask for their waiver.
DR. CRAIGMILL:  Just as a followup of that, could I ask for suggestions for factors that ought to be considered in this equation that we could pass on as we develop those if people have ideas.  We know profit, John.  Okay.
  --- there is a limited geographical area, a small number of animals.  Are food consumption factors a valid reason?  Should that be something that should be considered in this from a safety standpoint, maybe?
DR. OELLER:  Maybe.
DR. WEBB:  The comment "Maybe" was from Meg Oeller.
DR. BRACKETT:  Jim Brackett from Canada, veterinarian.  One thing we haven’t talked about along these lines is -- well, two things really.  One is animal welfare consideration and the other is best management practices and production.  One of the effects of not having drugs available in specific countries is that there may well be situations where a veterinarian knows that there is a drug available in another jurisdiction that could improve the welfare of the animals within his or her care and there are management practices that could improve production for the benefit of society, the environment or whatever, but it can’t be done in this country because the drugs are not available. So that may be another consideration.
DR. CRAIGMILL:  Those are two good ideas.
DR. HALEY:  I won’t ask Meg a question this time.  Carol Haley again.  I think the point that -- John is it -- just brought up is sort of a point that has been rattling around in my head for quite some time.  As a member of the pharmaceutical industry now I am very much aware of how demonized the pharmaceutical industry has become in recent years, and I think it not particularly just to the pharmaceutical industry.  But I think it is important as people who work in minor species, minor use, go forward into 2002 as John was saying.  
It is not the shifting sands of regulatory, but there are the shifting sands of legal and the shifting sands of state governments, and all sort of things and all sort of people.  Courts, state governments, are becoming involved in the regulation of drugs, and at the moment the majority of that influence is on human drugs, but certainly we can expect this to get into animal drugs.  I think as Andy alluded to yesterday when he was talking about the final days of getting the legislation passed there was a lot of interest by Congresspersons that we -- for example, pay a lot of attention to antimicrobial resistance.  Which is probably a good thing in concept, but I think what it brings -- what is clear about that is that there is a lot of interest by parties other than FDA, and parties other than the scientific community and the trade community in what we do with minor use, minor species. 
So it is very important for use in the minor species, minor use, and whatever we do that we make clear to other stakeholders in this that, number one, we are being careful about safety and, number two, that we are carrying on responsibly, and that things we do in this area are not going to adversely impact the rest of the world.  You know, the world outside of the minor species community.  So I just say that just to keep in mind in terms of communication and however we do any of this thing.  I think the definition of minor use is one of those very tricky areas where people can get concerned that by defining something as minor use we are just trying to get around paying attention to safety.
DR. BOWSER:  Paul Bowser, Cornell University College of Vet Medicine.  I would like to kind of jump in here.  I have been trying to figure out a place to actually insert this in the area of animal welfare, and one thing that those of us in the university research environment and I know in other areas have to deal with are meeting regulations for use of animals in research.  I know Alistair is very familiar with this area, too, and that we are in the current environment under increasing scrutiny to justify the use of animals, justify the numbers of animals that we use, and also increasingly justify the use of experiments that require the termination of the animal at the end of that experiment. 
I was involved with the American Fishery Society over the past several years, them and a group of other groups that work with fish, were developing a set of guidelines for use of fish in laboratory and field studies.  During that process I became of aware of one rather major university in the United States where the IACUC, the animal care and use committee, will not allow a researcher on that campus to conduct an experiment that will require the termination of the animal at the end of the study.  This decision was made under the purview of the particular IACUC, so whatever the makeup of that IACUC is, that is your playing field.  We all know that there is an increased visibility of animal welfare.  There is a increased visibility of animal rights type folks out there, and we have to police ourselves even more carefully.  Throughout the whole process that we are dealing with here: target animal safety studies, human food safety studies, efficacy studies, require some rather creative ways of thinking.  Maybe we are going to be coming to the regulators that make the ultimate decisions with some creative ways to deal with providing quality research data that will meet the standards that you folks need to make your regulatory decisions. 
But it is become a very different playing field out there with the use of animals in research, and I might even go on to say that regulations in the United States and in other countries are certainly dealing with very similar situations.  Regulations in the United States specify vertebrate animals, but again it is up to the purview of an individual IACUC for an institution.  If they want to, they can extend it to invertebrate animals.  So this is something to really think about.  With proper care and use of animals, it is the right ethical thing to do, it is the right moral thing to do, and something that you really have to think about.