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I N D E X

International Workshop on
Minor Use and Minor Species: A Global Perspective

October 8, 2004

MUMS Research - Species Grouping
 Dr. John Babish

MUMS Research - MRLs and Tolerances
 Dr. Ronald Baynes

Human Food Safety Issues
 Dr. Kornelia Grein

MUMS Forum II
 Human Food Safety

Open Public Comments III

Coordination of Programs
 Workshop Review: Action Items

KEYNOTE:  “---” denotes inaudible in the transcript.
      “*” denotes word was phonetically spelled.

P R O C E E D I N G S
 (8:30 a.m.)
    

DR. WEBB:  Before we get started in this session, just to remind you that your parking is complimentary.  Show your badge, and if your badge doesn’t work you better run back up and get the codes that in the back.  This morning’s final thrust is towards the human side of our work, and our first speaker is Dr. John Babish.  He is formerly a professor of toxicology -- I don’t know why he got fired -- at Cornell University.
  (Laughter.)
  
He was formerly the northeastern regional coordinator of NRSP-7.  I don’t know why he got fired from that either.  However, we did hire him back as the national coordinator a few years ago, so obviously he has been forgiven.  Since 1996 he has been consulting with development and application of bioinfomatic technology for pharmaceutical and food industries, and with that I would welcome John.

MUMS Research - Species Grouping
Dr. John Babish  

DR. BABISH:  Thank you very much, Alistair.  I am going to go through a lexicon of new words this morning probably for most of you.  What I would like to do is to introduce some of the concepts of bioinfomatics that have been developing over the last five years, primarily in the areas of cancer research.  They include cluster analysis, self-organizing maps, and mathematical techniques to illustrate connectivity.  So the first word that I want to reintroduce to the lexicon is species grouping.  If you look at Medline and do a Medline search on species grouping what will come up as synonym is crop grouping.  I would like to suggest historically that I believe comes from the IR-4 program and the plant and agricultural people. 
  
I believe species grouping for what we will be talking about and what we would like to do in MUMS is more appropriate for a couple of reasons.  One, I don’t believe there is any one of us that would like our dog or cat to be referred to as a crop.  Secondly, I think that using the term crop grouping imposes a limit to how you define the problem.  For example, if you are thinking of catfish as a crop, you might think of a catfish fillet as what you are interested in grouping with a chicken wing.  So crop grouping is not exactly a term that allows you to be expansive in your thinking.  You will see that expansive thought is an important part of cluster analysis.
  (Slide.)
  
Now let’s take a look at the problem.  We spent yesterday seeing what the problem was worldwide, and what I was struck by was the fact that there is an enormous similarity in minor drug us around the world, and I was also struck by the lack of movement in addressing the issues we have identified.  We are all pretty much stuck in the same place.  Some of these figures, well, the figures we will see in the next couple of slides, are basically from the NRSP-7 program and it is 23 years of work in minor species.
  
The economics of species grouping is very interesting because as an individual species or these minor uses or minor species, they all represent very small markets.  But if you look at those markets in aggregate, they become very big.  For example, one set of numbers will bring the total of this diverse aggregate to about 1.5 billion in the United States.  The second thing that most analysis of the market impact frequently ignore are the accessory industries that are built around these niche markets, and those will multiply this figure by about three-fold.  Another problem in assaying, trying to get your hands around these figures, is that they are very loose.  You can make these figures go anyway from about 1.5 to 4.5 billion dollars or you can make this figure almost double.  So there is a range of estimates.  I tried to take the lower estimates of each of these, but also want to give you what I have seen as some of the upper estimates.
  (Slide.)
  
So in reality we have a large aggregate market with a large number of associated accessory industries.  As we saw yesterday, this is a low figure for a new animal drug, but it is close to the median on the figure.  It ranges from the
50-million or so down to about eight-million.  We have been told in our review last year that the cost of addition of a new species to the label is about two- to eight-million dollars.  The NRSP-7 cost for a species is about $300,000.  That figure is artificially low, because it doesn’t include the contribution of the states.  There aren’t any state officials here, so I can say that what they are paying is not include.  That figure is at least $500,000. 
  
Currently we have 13 active projects.  Again, a slight underestimate because some of those species drug combinations include several species.  For example, in aquiculture an oxytetracycline fish project may involve four species.  So there are really about 20 active projects, 41 potential projects, again a slight underestimate.  That might include 50 unique species drug combinations.  So if we look at this, the cost becomes relatively high, even using the low figure for drug approval, but what is most important to me and I think is important to the industry is the time that this would take.  NRSP-7 has been in existence for 23 years, and we have 31 approvals.  A lot of those approvals came early on before Steve and his crew were involved, and now it is very difficult and the bar is raised.
  (Laughter.)

Don’t put that in the transcript.
  (Laughter.)
  
Off the record.  No.  As we heard yesterday, worldwide the criteria are becoming more and more strict, so these figures are underestimates.  If we want to address drug approvals in the manner that we have done in the past as single species drug approval, then it is going to take us anywhere from 25 years to somewhere into the 22nd century.  This estimate is based upon what we know now, and doesn’t include the shifting sands of regulation.  It also doesn’t include the changes in disease pattern or the addition and loss of minor species.  So the regulatory problem is big; the time frame is unacceptably large.  In my opinion, the only effective answer is species grouping or clustering.
  (Slide.)
  
Now this information is from the NRSP-7 database where we have represented 10 aquatic species, six avian species, five ruminant species, and three fur-bearing species.  So we want to start somewhere and want to be most cost-effective.  What we will be looking at the possibility of species grouping in these avian and aquatic species.
  (Slide.)
  
Now in the approaches to species grouping, here are some new words that cover some old technology or technology that has been invented by the bioinfomatics people; and they are derived from the words genomic or genome.  Okay.  So we all know what the genome is.  It is our DNA sequences.  The characterization and clustering of metabolites of representative drugs and species of interest.  Now we have seen the literature.  I have been to presentations, and this type of characterization or clustering technique is being applied, and it is one of the most familiar to most of us.  That is where we take a drug, a model drug, and look at the range of metabolites among various species.  Then we try to look at the similarities of those metabolites and cluster or group those species with similar metabolites.  That is now called metabolomics.  Then there is the characterization and clustering of zenobiotic transformation capacity in the species of interest.  We can do that now with genomics, proteomics, and model metabolomics.  The advantage of model metabolomics is that from looking at the range of metabolites or the metabolism of a model substrate you can then begin to ask what if questions and you can characterize the biotransformation system in a general or way that allows you to do what if, and it is not drug specific.
  (Slide.)
  
This is just a quick review of biology.  Here we have the genomics area covers not only the DNA sequencing, but what is most important is not DNA, but transcription of the DNA.  It is not your genome that is important, but your transcriptome.  That is what gives you your individuality.  Your transcriptome is the message, the messenger RNA.  That can be done in a high throughput bases with RTPCR, real time polymerase chain reaction.  That way you can quantify the message.  Proteomics looks at the active protein or primary protein products.  Then these proteins, active proteins, produce metabolites, which are measured through metabolomics.
  (Slide.)
  
Now sounds pretty complicated, and it is real complicated and real expensive when you are doing things like trying to understand various cancers or when you are doing whole genome analysis.  Whole genome analysis will look at 20- to 30,000 genes of expression under various conditions, either normal or diseased states, and in these situations you have a series of impossible questions with no real answers.  However, we want to apply this technology to species grouping, and species grouping is specific for looking at the ability to metabolize drugs, absorb drugs, distribute drugs, or excrete drugs.  The question becomes relatively simple with respect to bioinfomatics.
  (Slide.)
  
Here is a schematic of what we want to look at.  What we want to look at is determining drug action across species, and that can be divided into mechanism of action, absorption, distribution, metabolism, and excretion.  For all of these processes, mechanism of action falls out on a single-drug basis; but for the other processes we can identify those genes, transcripts of those genes, and proteins associated with those transcripts that relate to the possibility of drug metabolism in a particular species and among species.  For our example today we will take metabolism, and within metabolism we will examine the phase one transformation system. 
  (Slide.)
  
The question and the range of the question become even more straightforward when you look at drug bio-transformation by the cytochrome P-450 system.  You can see here in this is a pie chart for human drugs, the extent their metabolism is associated with individual isozymes of
P-450.  You can see here that the CYP3A, sometimes known as the garbage disposal of drug metabolism, accounts for more than half of all the drugs that undergo biotransformation.  Looking at CYP3A expression and protein in the species of interest and grouping on those drugs that are metabolized by CYP3A is a very important part of one of our variables.
  (Slide.)
  
This is just a breakdown again.  The cytochrome P-450 system is very, very well described in the genetics field.  There are 230 genes identified as cytochrome P-450 genes.  Those genes are divided into families.  The families are indicated by the arabic number, 1, 2, and 3 here, and then the subfamilies of P-450 by the capital letter; then individual isozymes within the subfamily are designated by the letter following the subfamily.  Here we see those that are important, and we have characterized what types of molecules each one of these members of subfamilies can metabolize.  Now that is important as you will see at the very last slide when we get to a process called annotation of these variables.
  (Slide.)
  
Here we have an example of a proteomic and metabolomic study that was conducted by Dr. Bowser at Cornell.  What he has been doing in his species grouping program is to characterize the cytochrome P-450 system by western blotting and model substrate enzyme analysis.  The example that we will go through today will include the tilapia, the summer flounder, the hybrid striped base, and the channel catfish.
  (Slide.)
  
The study that I am going to show you some of the results from included treating 50 fish.  The fish were treated with oxytetracycline for 10 days, and then on the post-treatment days one, six, 10, and 21, body weights, liver weights, and hepatic P-450 1A1 and 3A4 were assessed.  The 3A family is the garbage can of P-450 isozymes, and the 1A2 very selective.  Now oxytetracycline is not metabolized, but the intent of this study was to look at the effect of oxytetracycline administration on the amount of these isozymes that are present as well as their activity.  That in effect would influence the metabolism of other drugs or chemicals by the fish.  These 3A and 1AZ activities were monitored predosing and on day one, six, 10, and 21.
  (Slide.)
  
Here is a bar graph indicating the 95-percent confidence interval of three model substrates.  One of them, CEC, represents the 1A2; BFC and benzyl resorufin, both represent 3A4.  What you see here is that with the hybrid stripped bass following oxytetracycline treatment there are no differences at all in the post-observational period.  You see in the hybrid stripped bass that the administration of oxytetracycline does not change drug metabolism of CP3A or CYP1AZ in the post-observational period.
  (Slide.)
  
In the channel catfish undergoing the same protocol, we do see differences in the 3A4 isozyme.  Those differences are reflected early and then they become positive or they are significant only with the BCF model substrate. 
  (Slide.)
  
Immature tilapia undergoing the same protocol of treatment, now do show a dramatic decrease in activity of 1A2; showing that after an oxytetracycline treatment tilapia would metabolize drugs by 1A2 at a much slower rate.  Many environmental contaminants are metabolized by 1A2, and this may have consequences for the growth of the fishin the presence of these contaminants.
  (Slide.)
  
Now that is an example of metabolomics.  Now what is different is that Paul also looked at proteomics.  He looked at the expression of CYP1A2 again during this post-observational period, and here you can see on a western blot those results.  This is where the hepatic proteins are put into a polyacrylamide gel that separates them on the basis of molecular weight, and then you visualize them with an antibody to a particular protein.  The density of the band is proportional to the amount of protein present, so here you can see how much CYP1AZ is present.  One of the things we look for is how many bands are visualized, and with fewer bands you infer a good association of the antibody to the protein.  This antibody is against a human 1A2, so it is interesting and it is also nice to see that you get clean bands here.  This growth shows the relative density of those blots with particular outlier fish indicated.  The point here is can we can start using materials that are made for human isozymes against other species.  In this case in the hybrid stripped bass it is a very clean blot.
(Slide.)
  
However the 3A4 gives us a relatively nice ban where we would expect the protein but also shows a lot of other bands.  So this antibody is not as specific as the 1A2 antibody was.  The point of this is to say that in measuring the transcriptome, the proteome and metabolome there is a validation process that has to be performed across all the species.  This is done in spades for the human and for mice and rats.  The zebra fish is becoming a popular model in toxicology, so the data on the zebra fish are being developed.
  (Slide.)
  
How do we put this all together?  Well, the ultimate in species grouping can occur when you make a gene expression database from the transcriptome, and a protein expression database.  In this side you have both a 2D gel and a 1D gel.  This one is from my laboratory.  Finally, you need a database from the metabolome.  The metabolome can best be measured by model substrates, and the information on gene expression from messenger RNA.  You can also get information from animal tissue banks, containing  historical histology.  Histological slides can be probed with antibodies or can be probed for message and that information can be put into a database.  Here is where the bioinfomatics people come in.  There are any number of algorithms that will allow you to cluster gene expression the basis of whatever theory you wanted.  That depends, however, on gene annotation, protein annotation, and the knowledge of protein interactions.
  
This process becomes very difficult when you are trying to understand the mechanism of cell transformation, a normal cell transforming into a tumor cell.  The process can also be used to identify gene function.  When you are looking at the expression of 30,000 genes you really don’t know what most of them do.  So cluster analysis is used and gene annotation is applied to establish why genes cluster into particular groups.  For example, we were working on breast cancer development and looked at cell cycling in a breast cancer cell, and clustered genes to find functions of several unknown genes.  This is a typical example of he use of cluster analysis.  It is a very difficult process with a lot of unknowns, and annotation becomes very important.  Here the problem is relatively simple, even if you don’t believe it at this point in the presentation.  The process is simple because annotation is known.  You know the genes you are going to characterize.  They represent a relatively small subset of the 30,000 in the genome.  At the most may as a group come up with 500 genes and transcripts that we are interesting.  Gene annotation for all of those would be related to physiological processes, biotransformation, or exclusion processes.  So this, the gene annotation, which is a very, very difficult part in cancer research, becomes a relatively simple and straightforward step.  A second point on this is that many algorithms are available for clustering gene expression, protein expression and activity.  But there are very few that can cluster all three, and what we have been working on is the clustering of the phospho-proteome.  This -ome consists of phospo-proteins that are expressed in various disease states by the transcriptome.  This clustering becomes difficult, but clustering of any selected proteins metabolite or transcripts is a very straightforward process.
  (Slide.)
  
So in conclusion -- how is that for timing?  Alistair is thankful.  Species grouping, through characterization and clustering biotransformation process or excretion, all of the variables associated with the determinance of drug activity, is a relatively straightforward process and can be more rapid and cost- effective than simply doing metabolite characterization.  Metabolite characterization is important and we have a lot of valuable information right now, but by adding a clustering algorithm we can move forward much more rapidly.  Model substrates and model inhibitors are better than specific drugs for comparing species due to their selectivity in characterizing specif isozymes of cytochrome P-450. 
  
The first impulse for a clinician or even a researcher is to use the drug of choice, but it is much better to use a series of model substrates, and there are well-characterized, highly-fluorescent model substrates that can be used to characterize the proteome in biotransformation in determinance of drug activity.  Antibodies for characterizing the proteome are more problematic.  They would have to be developed.  Similarly primers for the message and RT-PCR methodology would have to be developed on a species-by-species basis.  But the addition of genomic and proteomic characterization could allow for the development of a query database that can be cost-effective and the only solution to a problem that will stretch across into the 22nd century.  I want to be the first one to mention problems extending into the 22nd century in a public forum; and I thank you very much for your attention.
  (Applause.)
  
DR. WEBB:  Thank you, Dr. Babish.  Our next speaker is Dr. Ronald Baynes.   In his bio, he didn’t give away he trained -- I believe it was Georgia.  I apologize, ---.  Anyhow, he currently is an associate professor of pharmacology at the North Carolina State University.  He is also an assistant director of the Eastern Regional Access Center of FARAD, which stands for Food Animal Residue Avoidance Databank, and his main focus of research today is on the drug chemical food safety aspects of strategies extrapolating drug residue withdrawal intervals for extra-label drug use in food animals.  With that, we will --.

MUMS Research - MRLs and Tolerances
Dr. Ronald Baynes
  

DR. BAYNES:  Let me thank the organizers, Art and Alistair and many others who invited me to come and give this controversial, if you like, talk or discussion about MRLs and tolerances.  I hope I can set the playing field for
Dr. Kornelia Greein who can go into more details on how this applies to MUMS.  What I thought, the function of me being here was to go over some of the rules for establishing MRL.    (Adjusting microphone.)
  
I hope at the end of the day I can convince you that there is a standard way you can go about deriving these MRLs, tolerances, here in the United States and internationally which are health-based derived safe levels. 
  (Slide.)
  
One of the first things I want to reiterate is that doing residues can be a risk to pubic health.  I want to talk about AMDUCA.  If it wasn’t for AMDUCA the Food Animal Residue Avoidance Databank would not exist.  I would like to talk about the pharmacological concepts that we use in deriving extended withdrawal time intervals.  This is the function of FARAD, I also want to ask the question why do we need to establish these safe levels. How do various agencies in the US -- predominantly the US is my focus -- and internationally establish these levels.  Then I want to --   (Laughter.)
  
DR. WEBB:  Start again.
  
DR. BAYNES:  Then I want to propose a transparent method, and transparent is a buzz word that we really like to use a lot nowadays, especially in the arena of harmonization of standards across the board and tolerances and MRLs.  We have come up with a term called a PAR thanks to Dr. Craigmill and Dr. Tomas Martin of Illinois now, and Dr. Jim Revere and myself.  We are saying basically a PAR is similar to a tolerance or an MRL, but it is transparent.
  
Let me first of all before I get to the slides say that what is driving these two things.  Based on AMDUCA, we are required to come up with an extra-label, and extended extra-label withdrawal time.  In order to do this, we need to have tolerance.  If there is no tolerance or there is no MRL, we need to come up with one.  This is where the PAR fits in here.  Okay?  Once we have that line, that horizontal line, then we can pretty much go to the kinetic data and begin to come up with an estimation of an extended withdrawal time for extra-label drug use.  This of course applies to MUMS.    (Slide.)
  
Can people really get sick from drug residues?  Yes.  A classic example is what happened in Spain and France over 10, 12 years ago where people were exposed to livers which were tainted with clenbuterol.  We also have here in the United States six of 38 animals tested at a state fair in 1995 with clenbuterol, and the FDA is well aware of this.  We have individuals who are compounding and smuggling several of these illegal products, or these prohibited products.
  (Slide.)
  
What are these drugs?  Many times they can be over-the-counter or prescription drugs, but I put this up here to emphasize the fact that over-the-counter antibiotic drugs can lead to antibiotic residues.  These are probably the majority of drugs sold in the United States.  So many times if you use these drugs not according to the label, you can result in antibiotic residues. 
  (Slide.)
  
The next category of drugs I want to talk about are the prohibited drugs, and this list is growing since AMDUCA  came into being in 1994.  I heard someone talk about chloramphenicol yesterday being used.  Chloramphenicol is nasty substance.  It causes aplastic anemia.  Therefore it has been pulled for use in animals.  This list I have here is for the dairy.  I normally supply  this list to dairy practitioners, but this can be applied to other species.  Clenbuterol is there; colloidal silver; DES; DMSO; dipyrone, no longer in many veterinary practices; enrofloxacin for obvious reasons has some very strict, strict label uses.   A strict label uses includes the fact that, it cannot be used dairy; and in the last three or four years nitrofurazone; and of course nitroimidazoles because of the mutogenic concerns with these class of drugs.
  (Slide.)
  
Another group of chemicals, moving away from drugs now, are the pesticides.  We tend to ignore these, and this is where our PAR approach can be applied across many species irrespective of whether a drug or a pesticide.  Treat it as a chemical.  In another words, you are not tied down, you know, with extrapolations jut to drugs.  So we can have accidental exposure, terrorist exposure, you name it.  Some of these nasty substances, whether it is dioxin in Europe back in 1999.  In this case, we were able to come up with a recommendation to the folks in Brussels for dioxin exposure.  So these are the kinds of chemicals that we need to pay attention, just not drugs alone.
  (Slide.)
  
AMDUCA, the Animal Medical Drug Use Clarification Act, 1994 came into existence after a lot of hard work.  This slide says that extra-label use of drugs has been legalized and FDA CVM in the United States has published regulations for extra-label drug use.  FARAD is a major source of extra-label drug use information.  This legislation as far as I am aware is not in existence in Canada and other countries, but other countries for the last couple of years have developed a FARAD kind of program, especially in Canada.  They are also recognizing the need to generate a database from which we can make extrapolations, and this is through the mechanism of Canadian G-FARAD.
    (Slide.)
  
What are these guidelines on AMDUCA?  What are these guidelines?  These are very strict guidelines.  You must have a valid veterinarian-client-patient relationship.  Use currently marketed drug for the disease, or recommended does is ineffective.  For example, a veterinarian cannot say, "I want to use phenylbutasone because it is cheap instead of  banamine.  Banamine has been out there on the markets approved for cattle.   This product is obviously more expensive than phenylbutasone ---, but the law does not allow or rather the law says you need to use the currently marketed  product.  Some of you may be aware of a concern and the controversy around fenylbutezone.  We won’t go through that.  We don’t have time for that this morning. 
  
You must have records and other measures to identify the treated animals.  You must have some indication.  Then you must significantly extend the withdrawal period.  Significantly extend the withdrawal period so there are no illegal residues.  This information is not on the bottle.  It doesn’t say 2X dose two days, 3X dose four days.  It is not there on the bottle.  So where do you go from there?  This is why FARAD is in existence, to provide this information. 
  (Slide.)
  
This is one of three kinetic slides, so bear with me.  We can use a drug, give it by some route (eg), by IV administration.  You get an absorption phase going from left to right.  Then you get an elimination phase.  What we do in FARAD is that we use the residue elimination phase, to come up with some explanation of the half life.  We extrapolate that back to the tolerance or the MRL.  I will talk a little bit later why you can’t use the MRL if it is in the United States.  We use a tolerance or a PAR, which is similar to a tolerance, and where those lines cross, that is our withdrawal time.  That is of course is an over simplification.
  (Slide.)
  
What if you give a larger dose?  If you give a dose and it results in a concentration of 10 parts per million --.  Then you double the dose, and we are assuming linear kinetics.  The dose, the concentration in the tissue is obviously doubled to 20 parts per million.  You can see again provided the elimination is linear, the rate constants should be the same and the half life should be the same as seen by the slope.  What if you have a change in clearance and a change in drug distribution?  Protein binding, disease processes can change distribution resulting in differences in protein binding.  Physiological changes in the animal can result in clearance, changes in clearance.  So as a result of that the slope will change.  You get the less steep slope.  So the half life will change, and therefore because of that slope moving to the right you will get an intercept now to the right, which crosses the tolerance level.  So obviously in a diseased animal or the change in physiology, you expect to get an extended withdrawal time period.  Somebody alluded to that I believe yesterday, about concerns of diseased animals; withdrawal times are going to change.
  (Slide.)
  
What we are trying to do here at FARAD is to model these effects.  We are not to the physiological and disease state yet.  What we are trying to do many times is model the simplest scenarios.  That is looking at dose effect.  So all that preamble gets to really what should be my first slide, how is the tolerance derived for this example of oxytetracycline.  Where would you place the tolerance line?  That is the question I ask.  Where do you place the tolerance line for milk data for goats and for cattle?  For cattle, yes, we know.  In the United States that tolerance line should be 0.3.  In the United Kingdom and Europe it is 0.1. 
  (Slide.)

Let’s step backward and look at the process that FDA CVM uses.  We first of all have to recognize that when a study is conducted we are normally going to use data from a series of animals, sometimes 25 animals, five animals for each time point.  We are going to come up with a average, which is the central line through there, and around that we have of course the confidence interval.  So we are going to be looking for the slowest peaking animal, with a conference interval around it.  Now where that line crosses the tolerance or the MRL, that is going to be the withdrawal time. 
  
The examples I have up here are for tolerance one or MRL one, tolerance two or MRL two, is to show you by shifting those lines around, shifting those safe levels around, you can significantly affect the withdrawal time.  Okay?  The withdrawal time will be increased or decreased depending upon the level.  So this slide is showing you a number of things that are important at the regulatory level. 
  (Slide.)
  
This is our strategy.  For the last couple of years we have been asking questions ---, at CVM, at JECFA.  How do you guys do this?  Give us an example.  Please make it transparent so we can get on with the job of doing extra-label withdrawal time based on AMDUCA.  It has been hard.  It has been very difficult.  So what we did was come up with our own system.  This is the PAR.  This system is going to be a mirror image of what is going on in the United States.  The aim is to make it transparent so we can do the extrapolations. 
  
The reason why we want to do this is if you don’t have a US tolerance or a safe concentration, we need to go back to the toxicology data.  It should be available to all of us because it is a drug submission package, and look at the NOEL and ADI or look at the safety factors.  All those are important in coming in with the acceptable daily intake (ADI).  Well, we can spend another hour talking about NOELs, the problems with NOELs.  Why don’t we use benchmark dose?  Why aren’t PBPK methods being used in deriving a better reference dose?
  (Slide.)
  
Safety factors are another big issue.  All the safety factors, (all the tens and the thousands) are used to drive ADI.  So we are primarily using the same data package to come up with these parts.  Some folks say, "Well, why don’t you use the MRLs?"  One of the public comments yesterday was about that.  Why don’t we just use MRLs so that  minor species, equals major species.  No, that is not going to work here in the United States or in Europe.  In some cases foreign MRLs always equals to US tolerances.  The drug we are now working on, sulfamethazine has a MRL of 0.1 PPM, and for the last five years it wasn’t explained to me why all tissues have a tolerance of 0.1 parts per million.  Anyway, generally they are not always equal.  So one can not always extrapolate MRLs for all purposes.  Foreign methods differ from US methods because of partitioning of the ADI.  Once you derive that ADI how that is partitioned varies from country to country.  Gut flora are considered.  The NOELs are differently as I said.  The MRL determinations are not always strictly health based because of some of the changes sometimes occur at the end of the process.  Even though NOELs may be the same, they are not always strictly health based.  There is always some fudge factor thrown in there at the end, and I can also say that for the tolerances as well.  I don’t want to pick on the MRLs alone.
  (Slide.)
  
I just grabbed a few drugs, threw them together.  I should get a straight line right?  Should be a nice straight line if we are going to harmonize MRLs and tolerances.  These are JECFA MRLs on the left, US tolerance on the right.  I believe this is for the liver.  The liver is the marker target tissue, and we are looking at albendazole, ceftiofur, there is only one that is sort of compliant, neomycin.  You see tetracycline there to the far right.  We --- see problems here with tetracycline with the tolerance being six times that of JECFA’s MRL.  So you see the problems why we can’t use MRLs here for our estimation. 
  (Slide.)
  
So what we are saying is the PAR is similar to the US FDA definition of a safe concentration.  We were looking at total residues.  Again, a safe concentration is equal to the ADI times the body weight divided by the food consumption values.  Again, another variable, and a variable which has a wide distribution within itself because food consumption varies across the populations, even within a population.  An ADI now is the NOEL divided by the safe factor.  The NOEL is the greatest amount of drug found, or toxicant or chemical, found to cause no observable adverse effect in the test animal.
  (Slide.)
  
The NOEL is now divided by these safety factors.  As I said, these safety factors can be 100, can be 200, 300, 2,000, 1,000.  These are some of the reasons why we have these numbers here.  The 100 comes from 10 times 10, where the 10 comes, the 10 is for interspecies, and other 10 for interspecies variability.  Then that 10 is also looking at pharmacokinetic differences, so we have these safe factors, which are fudge factors if you like, which are thrown in there to pretty much provide an estimate until we can have some idea of what that uncertainty is.  Where that uncertainty occures, we will use 10.  Okay?  It is a very conservative value in coming up with that NOEL.
  (Slide.)
  
Food consumption values, as I said, is another variable in this estimation of MRL and tolerances.  We assume based on these total basket dietary studies that have been done over the years that we consume 300 grams of muscle, 100 grams of liver, and so on.  We can assume we consume 1.5 liters of milk per day for 70 years.  Okay?  These are the estimations.  These are some of the estimations we use.  We assume --- more milk and more muscle than other organ tissues, and we really do not eat a full portion of meat product, and this of course pertains to MUMS.  Individuals do not always eat a full portion of meat product from another species.  A big assumption there as well.
  (Slide.)
  
So where are we now?  Do we go with the ADI?  This then gets to a situation where I am showing you where all these variables can impact that ADI, the NOELs, the safe factors and uncertainties associated with it.  We are going to take that ADI, and we need to move on now to derive that safe level, that tolerance, that PAR, that MRL, whatever you want to call it.  How do we get there?
  (Slide.)
  
The next step, partition this ADI.  How we partition this is a matter of deep controversy again.  We can spend a week workshop talking about that.  Okay?  We won’t.  What I found in our research is that FDA, the US FDA, CVM, will follow a procedure which sort of mirrors procedure A where they have taken 50 percent of that ADI.  Right, for the target tissue, muscle, and then reserved 50 percent for milk.  Sometimes they reserve 90 percent for milk.  It varies.  Again, you see the variability of procedure A. 
  
Procedure B.  Just like the previous speaker, I was trying to understand what is going on at the regulatory level so we can better estimate a safe level for primary purposes.  The primary purpose, to get an extended withdrawal time for extra-label drug uses.  This again applies to MUMS.
  
Once we decide how we are going to partition it, we divide the ADI by food consumption value, and I think all countries agree with this.  Okay, 0.3 kilograms of muscle and so forth.  We then come up with a safe concentration for total residues.  That is what the safe concentration refers to.  Then we obtain residue depletion data and begin looking to see if there is metabolism, and if there is metabolism then that metabolite is the marker residue.  Otherwise a paired compound is what we want to monitor. 
  (Slide.)
  
This profile here is just a simplification of what  goes on here.  Once we have the total residues, we can pretty much derive a safe concentration or a PAR, okay, for that tissue.  If the marker residue as I said is a metabolite, we can come up with a tolerance of what we call a provisional acceptable tissue -- sorry, provisional acceptable tolerance or PAT.  We like kind of acronyms at FARAD.  But it works for us because we can estimate again a safe withdrawal time provided we have this horizontal line.  You want a safe line for which to estimate a withdrawal time.
  (Slide.)
  
So I said there are three procedures that I have been able to derive or been able to glean from my observations from all the data that has been approved around the world, and the PARs A -- just summarizing.  PARs A, PARs B, PARs C, pretty much is how we are going to go about coming up with a safe level.  You can use either one or the other, depending on the situation.  To my example, I only have one example. 
  (Slide.)
  
Some of you may have heard this talk before.  I given three, four examples, and by the way this was published several years ago in Regulatory Pharmacology Toxicology.  I don’t have time to go through this entire slide, but what I want you to focus on is that of PARs A look at the values for PARs A which we were able to come up with.  They are similar to the US tolerances, current US tolerances in the United States.  The asterisk pertains to the old US tolerances.  We saw the mirror of JECFA’s MRLs, and you can see the total maximum daily intake at the bottom, TMDI, and you can see it pretty much exceeds the ADI to some extent, significantly if you use the US tolerance.  A matter of contention, an issue, we can debate that ad nauseam, but I won’t.
  (Slide.)
  
The answer to the original question is the US tolerance for tetracycline is 0.3 parts per million under current regulations of the CFR, and this is similar to the PARA procedure, but the EU MRL is 0.1 part per million.  So if the US uses a foreign approved MRL or withdrawal time, this means -- I have to tell the dairy producers here, “I’m sorry you have to throw away more milk.”  Primarily because you have to extend the withdrawal time.  So this is a scenario here.  These are some of the problems when you are trying to extrapolate across MRLs or using MRLs in the United States.
  (Slide.)
  
A summary of basically what I have just said is that there is little or no -- correlation, but really no correlation between US tolerances and foreign MRLs.  In the case of oxytetracycline and the tetracycline family there can be as much as 20 times -- (this is for liver), the EU MRL.  This can result in total maximum daily intakes for us humans based on the assumptions I said, 1.5 liters of milk consumed per day for 70 years and so on -- can result in a TMDI here --- ADI, acceptable daily intake which is based on the tox data.  PARs and PATs, which are the safe concentrations of tolerances, are comparable to US tolerances for tetracycline.  Safe concentrations were found here for ivermectin somewhat.
  
Dexamethasone is a classical one I like to talk about because dexamethasone is approved for use in the United States with no tolerance.  There is no tolerance set.  But under AMDUCA, why would you give dexamethasone to a dairy cow at a higher dose than approved?  If so, you have to come up with some kind of tolerance.  This is where FARAD fits in.  This is what we have been doing.  Okay?  Azaperone is another good example. 

Partitioning methods, by agencies are inconsistent and difficult to follow.  With tetracycline you notice a 40 percent allocation to tissues, 60 percent to milk, not the 50/50 as I said before.
  (Slide.)
  
These enforceable residue levels can be established on health-based principles, not politics -- or how you feel today.  PARs and PATs insures that the TMDI is less, can be less, total maximum daily intake or less than ADI.  These values may be used in the advent of accidental exposure to contaminants or any terrorist chemical attack on food supplies if you like, or as is primarily the function of FARAD in extra-label drug use.  Okay?  The estimated safe withdrawal interval.  These methods are transparent and hopefully would encourage harmonization.  Thank you.
  (Applause.)
  
DR. WEBB:  Our final speaker of this morning’s session is Dr. Kornelia Grein.  She says she is a qualified chemist and a pharmacist, so I guess druggists are in again.  She holds a PhD in chemistry from the Free University of Berlin, and she worked for a period of time as a pharmacist.  She then joined the dark side like all these other people did and she went to the German environmental agencies and was scientific administrator in risk assessment.  She was --- to the European commission in adoption and implementation of the EU legislation on existing chemicals.  She then went to EMEA as head of sector for Safety of Veterinary Medicines, and she is also a coordinator for regulatory authorities with the VICH.

Human Food Safety Issues
Dr. Kornelia Grein
  

DR. GREIN:  Good morning, ladies and gentlemen, Mr. Chairman.  Firstly I wish to congratulate the organizers for this workshop for this event.  I think it is an excellent forum for exchanging the approaches, the ideas and the problems, how to overcome the difficulties in having drugs available to treat minor species and minor uses in major species, which is definitely a problem throughout the world as we have seen yesterday.  Then I want to thank all of the organizers for having invited me to speak here on the issue of human food safety. 
  (Slide.)
  
The points I want to address, what are the safety issues, and we have to go back.  I want to report what are the approaches that is being taken in the EU on this, and then I want to address specific issues then --- requirements for minor species, minor uses, and extrapolation of maximum residue limits.
  (Slide.)
  
The issue under consideration is how the consumer of food originating from animals which has been treated with drugs can be protected from harmful residues in food if the animals concerned are minor species or if the treatment concerned a minor use of major species.  This protection is achieved the same as this major species and major uses, through the establishment of maximum residue of tolerances and application of withdrawal periods.  The question is then what are the data requirements and the scientific approach on how to assess the data.  Should it be identical as for the major species and major uses, or whether there can be any adaptation to this approach for the MUMS products?  Certainly I think this is an issue where nobody would question this: the overlying principle for any such considerations must be that the consumer health must not be put in jeopardy.
  (Slide.)
  
On the next slides I want to present to you the situation in the EU, the approach that we take in the EU, and on the first slide I come back to the definition of minor use and minor species, as you have seen yesterday already also in the presentation from Peter Jones.  One point is clear:  In the EU we do not have a definition of minor species and minor uses in the legislation.  We have only a definition in CVMP guidelines.  The CVMP, I believe everybody is familiar with the term, it is the Committee for Veterinary Medicine Products, and since we have a new legislation Committee for Medicinal Products for Veterinary Use.  It is the scientific committee which is part of the EMEA, and it meets once per month for three days and it is responsible for the scientific evaluation of the centralized marketing authorizations, the maximum residue limits in the EU and scientific advice.  It also establishes the guidelines that do support the legislation, and the CVMP has the support of working parties for this task.  The experts that are members of the CVMP come from all the EU member states. 
  
So, the definition given by the CVMP in the guidelines establishes what is a major species, and it is cattle, sheep, pigs, chicken, and salmonidae.  All the other remaining species become minor then.  The CVMP, when this list of minor species was established, and it was a couple of years ago, looked to consumption data in the EU, consumption figures for food.  Cattle and pig meat presents 94 percent of the meat consumption in the EU.  Sheep meat is actually much, much smaller, two to four percent.  However, regionally sheep meat is a major food commodity --- and we cannot use the average across the whole of Europe.  We have to ensure that there are regions that need to be protected in the same way.  That is why sheep meat in the EU is a major species.  Fish consumption is 25 percent compared to meat.  Minor species then are other ruminants, particularly goats and deer.  When we look to other avian species those that are minor are duck, goose, game birds and so on.
  (Slide.)
  
I just want to show you the guidelines.  I don’t want to go into detail now, but merely list them for reference.  There are two guidelines actually which address the point.  The first one is this Note for guidance on the establishment of maximum residue limits for minor animal species.  From the number you see, this goes back to the year 1997, so it is a couple of years ago already that the CVMP looked at that aspect in respect to maximum residue limits.  Actually, this wasn’t even the first guideline.  Two years before there was already a preceding guideline on that matter, as it was always considered important to have MRLs,  even at the time, for minor species, in order to have adequate licensed products on available and also considering the off-label use because to the control of residues it is important that MRLs are available.
  
The other guideline, we looked to the same issue a couple of years later.  As you can see again from the number, this guideline was proposed in the year 2000.  It is called Note for guidance on risk analysis approach for residues of veterinary medicinal products in food or animal origin.   It reviewed again the assessment approach for setting MRLs and extrapolating them to other species and the details of that guideline are presented later.
  (Slide.)
  
The approach in the EU to establish MRLs is scientifically very much similar as to the JECFA or for setting tolerances as outlined by Dr. Baynes just before in the previous speech.  We have a battery of toxicity tests.  The NOEL has been established.  The lowest NOEL is being used by applying an uncertainty or safety factor to establish an ADI.  We have a residue data package, pharmacokinetics data, residue depletion data, and we use a standard food basket and on this basis the MRL is being derived, but [the NOEL should not -- or] the daily intake should not exceed then the ADI.  Regarding the target tissues we are looking at muscle, fat, or fat on the skin for pigs and poultry, liver, and kidney, and where appropriate also eggs and honey. 
  
The first MRLs that were established in the EU go back to the early ‘90s.  We were following the JECFA approach established for all food producing species.  These were penicillins, sulfonamides and tetracyclines.  Later on following again JECFA, there was a distinction between the species being made.  So then also species-specific data were requested on the residues and analytical methods for the species we are looking at.  So we have then later on separate MRLs for cattle, sheep, goats, poultry.  It would be a separation between chicken, turkey, and so on. 
  
Later on, when all the MRL assessments had been completed in the EU for all substances -– I have to say a little bit about procedure later on this whole approach was being reviewed again in this guideline I mentioned already before. 
  (Slide.)
  
The situation in the EU with regard to the MRL procedure, and this may be different to other countries, is that we have a separate procedure to establish MRLs.  MRLs are a precondition for a marketing authorization for any veterinary medicinal product for food-producing animals.  There is a separate legislation, and since this legislation exists, it dates back to the year 1990 and came into effect in ‘92, it has always been a kind of centralized procedure.  There is only one MRL in the EU for a substance though, we have the different member states in the EU.  It was never in the EU legislation that the individual member stats could establish separate MRLs.  It makes sense.  We have to ensure the same level of safety for all consumers throughout the European community and the trade issue.  We cannot have free trade of food originating from animals within the EU with different MRLs, this simply does not work.  So we had always this precondition, even if then in the next step marketing authorizations for the drugs would be issued by individual member states.  They would establish the withdrawal periods fro the products ensuring compliance with the MRLs.
  
The legislation then lays down the data requirements in an annex to the legislation and this is a  list of the different endpoints, and it is a list you know from the normal data package for safety.  That is why we require, to set MRLs, pharmacological studies, the set of toxicity studies, then a residue file comprising depletion studies and an analytical method.  Nowadays this toxicity data package would be according to the VICH requirements which have recently been agreed, but everything has yet to be fully implemented because the two last guidelines were only adopted this year, and for one other guideline the developmental toxicity guideline we need actually a change in the legislation, but this is underway.  That is the situation for major species.
  (Slide.)
  
In the guideline on minor species from the year ‘97, the CVMP looked at the time if one could have a certain reduction of data requirements if MRLS were requested for minor species only.  The approach that had been agreed at the time was that for example no pharmacokinetic study would be required for this purpose then, but as a kind of surrogate studies to establish the oral bioavailability in place of pharmacokinetics would be accepted.  In respect to repeat dose toxicity, at the time, the approach was: two species 28 days tests or one species 90 days test would be accepted in place of two 90-day tests for major species.  For reproductive toxicity, teratogenicity, also certain reduction with them:  One generation reprotox study instead of two generations.  For immunotoxicity, which actually hardly ever was relevant for the MRLs dossier that would not be required, but tests on other relevant effects.  Mutagenicity, there was no deviation at all and also for the residue file, that should be the same as for major species.
  
As Dr. Jones mentioned yesterday, CVMP is at the moment looking to review entirely --- for any of the data requirements for -- in the --- dossier, also --- any possibility to adapt the data requirements for minor use and minor species.  In this context also the CVMP, the safety working party looks again to the requirements for the MRLs.  What I will show you here is just, are really considerations, ideas, thoughts of the working party.
  (Adjusting the microphone.)
  
Okay.  So these are no final conclusions.  These are just considerations at the moment, but at this event here I thought it might be useful to share the results with you.  The outcome can in a couple of months be different, but it might be useful to see what has been discussed.  So, with respect to repeat dose toxicity, experts have said a 28-day study doesn’t make sense.  One needs a longer term study, and there was the question: Is one study, a 90-day study, sufficient?  Would one need not two different species?  Regarding reproductive toxicity, teratogenicity, they also said a one-generation reprotox study is not of much of value.  If one carries out a study, it should be a two-generation study.  Then it was discussed,  can one really justify having no study at all available.  For teratogenicity, embryotoxicity, the VICH approach, which is a tiered approach, was considered as a good approach by the experts.  Anyway, the new VICH data set would be required.  In respect to carcinogenicity, it would support not to require to test, if a criteria set would apply like, for example, if there is no analogy in chemical structure with a well-known carcinogen negative mutagenicity tests and no carcinogenicity signs have been seen during toxicity testing.  In respect to a routine analytic method, it was considered necessary to have it largely similarly validated as for major species because it is required for the residue surveillance.
  (Slide.)
  
Regarding marketing authorizations, for the toxicity data would be the same consideration as for the MRLs.  In a way, it is the same sponsor, they have anyway the data set available and, so the ADI has been established.  There is no need for having another consideration.  We would also look to: Are there any possibilities now in respect to withdrawal periods, and this would be now more for cases where we have already a maximum authorization for example for a major species –- could one extrapolate withdrawal periods?  Also the question was asked what is it with analytical methods.  Is always a fully-validated method necessary if one has already a product available for a major species?  So these are questions that are now under discussion; and we expect that these guidelines may be finalized by the beginning of next year and they will be then issued for consultation in the next year, and we will be interested to see the comments on this.
  (Slide.)
  
Now I want to come to the issue of extrapolation of MRLs.  I said before, the CVMP reviewed the whole approach, how specific MRLs have to be at the time.  The assessment for all old MRLs has been carried out.  To explain what has happened is that when this legislation on MRLs came into place in ‘92, it was said at the time that for any new product that comes on the market MRLs must be established before.  However, of course many products were on the market, and for those it was a transition period originally until the year ‘97, which was extended then until the year ‘99, where all -- for all pharmacologically-active substances contained in veterinary medicine products for food-producing animals must have been assessed and MRL been established.  Otherwise, the products would have to disappear on the market.  So the EMEA assessed at the time over 700 substances for which we had to receive dossiers first.  For around 100 substances, we could at the end not establish an MRL because the data were insufficient.  Sometimes, for a majority, the applications were withdrawn after we had sent to the companies a so-called list of questions, or incomplete letters as it is also being called, or sometimes the responses were still insufficient, and we had not sufficient data.  For more than 100 substances which MRL values were established, around 500 substances where considered that no MRL is necessary, and we put them in a list which sometimes contains clarifications for which species, the supply of which route of administration this would apply.  This is one of the lists, the annexes.  There are certain substances, number of 11, that are completely forbidden in the EU, but also any substance that is not on this kind of positive lists are equally forbidden to be used in veterinary drugs for human food consumption.
  
So we had a wealth of data at that time then available from all the substances, and we looked again how to the approach in the future in respect to extrapolations.  So we arrived then at this list that MRLs could be extrapolated from major ruminants to all ruminants if possible, from major ruminant milk, that means cattle meat, to sheep milk, goat milk, major monogastric mammals, that means from pigs for example, then to horses, rabbits, chicken, to poultry and from salmonidae to all other, fin fish.  Also in addition there could be if identical or similar MRLs were derived in cattle or sheep, pigs and chicken, MRLs can be extrapolated to all food-producing species.
  (Slide.)
  
We would need for the extrapolation to minor species a confirmation of the marker reside.  So a certain amount of residue data, but certainly no radio labeled study, and approval of the applicability of the analytical methods.
  (Slide.)
  
The guideline was implemented then, and we had at the time very much the call of the veterinarians, the industry, to make automatic extrapolation, looking -- opening all the dossiers again, looking for data available.  We did this only for those substances where we could do an extrapolation to all food-producing species.  We checked in particular the analytical methods; are they are applicable?  This list of substances came out of this.  There were three substances more, but they had really insufficient analytical methods to allow for this approach. 
  (Slide.)
  
For the remaining possible extrapolations, the CVMP would of course apply this approach for any new application that would be in the process, but we wanted -- had the plan that we would wait for applications from companies with dossiers, paying the fee, and would undertake then only the work if there is really a sponsor out there who wants to bring the product on the market.  Anyway, not unexpectedly, because we know also there is not much interest on the reasons we heard yesterday from companies to develop additional claims for minor species, we did not have many applications.  Certainly we still wanted to have products on the market, so the CVMP considered that, you know, of course MRL is only an MRL, not a marketing authorization, but it could extend and incentive for industry.  So we went ahead and tried to look at other possibilities, looking where there are really essential substances.  Areas, species, where we know there is a lack of products, and we would make then a list and try to extrapolate MRLs to these species where they are needed without an application, without any fee. 
  (Slide.)
  
The first kind of trial where we applied this approach was in respect to sheep and goats, particular milk-producing animals where the veterinarians in Southern Europe particularly said there are no products available, and in particular for ectoparasiticides.  There was obviously a real lack of any product that is authorized, so we established a list of substances for which MRLs could in principle be extrapolated.  We wanted to have only the old non patens products, not favor any company, a single company who could benefit on this, and of course we looked if the analytical methods would be available.  We submitted then a list for consultation, and this is then after consultation the list of substances for which these recommendations for extrapolations could be made.  I believe they have been transferred into legislation in the meantime.
  (Slide.)
  
For the future we want certainly to look for any Annex II substances at some time.  There could be the one or the other extension possible.  If needed, we would look to this without fee if a company wants to apply for an extension of Annex entries substances without MRLs I have to say.

Certainly any application from a company or a sponsor who wants to make an extension would be considered, but also we may look to other extensions for essential substances.  Maybe chicken or rabbits, I think that is possible if we have the data in-house that could support this.
  (Slide.)
  
To sum up, reduction of data requirements it seems for MRLs and marketing authorizations that are exclusively used for minor species, are only possible to a limited extent.  We want to ensure consumer safety.  If MRLs or marketing authorizations are there for major species, there seems some extrapolation possible, certainly with the MRLs, but also possibly in some cases with regard to withdrawal periods and analytical methods.  Thank you.
  (Applause.)
  
DR. WEBB:  Well, we are just about to go on a break.  We would ask you to be back at five minutes past 10:00. 
  
Just one thing, I have been asked by several people about the absence of a representative from China.  This was all arranged, and the individual got promoted and was immediately given other jobs and had to drop coming to this meeting.  The alternate person, it was too late for them to get a visa from China to come.  So that is the reason.  However, to show that -- they didn’t do this to show this, but just a note to you, they are interested in continuing this dialog.  They actually have joined FARAD, so there is going to be continuing international contact with them. Public comments, please, if you have any, register at the front desk.  Thank you, and back at five past 10:00.
  (Whereupon, a break was taken.)

MUMS Forum II
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. CRAIGMILL:  CVM?
  (Laughter.)
  
DR. CRAIGMILL:  Lynn.
  
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?
  (Laughter.)
 
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.
  (Laughter.)
  
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. CLAYTON:  The a PAR?
   
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.
  (Laughter.)
  
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. CRAIGMILL:  Okay.
  
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.
  (Laughter.)
  
We do all chemicals.
  (Laughter.)
  
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.
  (Laughter.)
  
Now that she works for FDA, we have no respect for her whatsoever, but --
  (Laughter.)

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.
  (Laughter.)
  
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.
  (Laughter.)
  
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.
  (Laughter.)

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?
  
VOICE: CAMEVET also.
  
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.
  (Laughter.)
  
DR. CRAIGMILL:  I guess nobody wants that.  Okay.
  (Laughter.)
  
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.
  (Laughter.)
  
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.
  (Laughter.)
  --- 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.
  (Laughter.)
  
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.

Open Public Comments III
  

DR. CRAIGMILL:  At this time we are actually scheduled to have another 15 minutes devoted to open public comments.  Is there anyone who wishes to give any new comments to be made into the record?  If not, we will go directly into the wrap-up/benediction phase of the meeting, but if we have anybody who wishes to again make an open public comment we are required to ask that at this time
  (No response.)

Coordination of Programs
Workshop Review: Action Items

Seeing none, what I would like to do now in the next half hour is to actually address the question I would like to pose to everyone here because we have a large group of people who are devoted and interested in this topic, is what practical things can we individually and collectively do to coordinate work towards MUMS approvals internationally.  Are there ideas?  I would like to have this in a brainstorming session.  How can we actually progress without trying to form a VICH committee?  What in the meantime can we do to actually help make progress in this field?  Elaine Jetté, and we are going to be taking extensive notes on this.
  
DR. JETTÉ:  Since the VICH is not meeting until next year and since VICH is already structured, Canada is an observer and I don’t know where -- what is the term of reference of this working group.  I am sorry for not knowing more about it, but perhaps like most of the countries represented here are either observer or members, and perhaps we could set up a working group to prepare for that meeting and do -- be better prepared to lobby the official VICH group to work more aggressively on MUMS.
  
DR. CRAIGMILL:  Do I have a second?  That is a good idea.  We had one suggestion from a gentlemen yesterday suggesting that when there is a major species approval in one country for an approval, then that species could be considered as a minor species in another country.
  
DR. DODEMAIDE:  Robert Dodemaide, Eco Animal Health, Princeton, New Jersey.  What I said yesterday was that I used the example of sheep and turkeys.  Sheep are major species in Australia, New Zealand and the UK or the EU, and turkeys are major species in the United States and they are minor species in other jurisdictions.  What I said yesterday was that if, for example, a complete package is provided to the authorities in the UK for the use of a given drug in sheep and that application goes through a rigorous review and the product finally gets a marketing authorization, I think the sponsor at that time should then be able to present those exact same data to another jurisdiction where it is a minor use, such as the US, and Steve and his boys and girls would review the package according to their rigorous standards and make a determination of what the US tolerances and the withdrawal period should be. 
  
But I think because it is a minor use it should be approved really without further requests for further data.  I think the package from the UK should be pretty well accepted as is unless there are really valid scientific reasons.  I mean, the parasite for example might be quite different in the US to the UK, so perhaps a small confirmatory field study may be required to provide some US data for the studies, but otherwise I think because it is a minor use I think a package such as that would be far more beneficial and provide far more information than just going through the MUMS procedure locally where the data package would be far less complete and would not have already been through this rigorous approval process where it is a major use.  Thank you.
  
DR. CRAIGMILL:  Thank you.  Dr. Jones.
  
DR. JONES:  Thanks.  Peter Jones again, EMEA.  There will be plenty of opportunity to say thank you and to congratulate these guys for the excellent jobs they have done, but one of the things that has really impressed me being here this week is the collaboration that has taken place between the various parties.  Regulators, veterinarians, extension scientists, academics, and I just wonder whether we can’t get that to infect other regions of the world.  I think what I was saying yesterday in my talk was that we have a frustration back home, but those people at the sharp end, the veterinarians and producers, don’t seem to be doing enough.  I want to put on the record my appreciation for what the industry has done in the EU.  Rick gave a very good talk about what they have been doing in IFAH*, and as he said, maybe his management is saying, "Well, why would we want to take this thing up as a campaign and do something with it?"  To their credit, the industry group in Europe has been really very supportive, has been driving this thing forward, but it has been disappointing I think that the vets have not done more and the producers have done little enough.
  
The FVE, the Federation of Vets in Europe, has been becoming more active.  They have had some major restructuring in that organization, but I just wonder through some forum like the World Veterinary Association, WVA, I don’t have much to do with that since some considerable time now.  But whether we could take what you have done in the US and sort of the collaboration that has taken place between veterinarians and animal scientists at all levels and somehow get that -- you know, the infectious spirit of enthusiasm that you guys have clearly got here and sort of help us in other areas to have that happen so that there is a portion of drive coming from elsewhere.  Because when that sort of thing takes off with a head of stem as it clearly has over here, then I think that in other areas, politicians, those that draft the legislation, will maybe listen some more.  So that was on suggestion.
  
If while I might have the floor I might just address something else very briefly.  Rick in his closing remarks yesterday talked about access to regulators, and I know that he was making the point that on a particular idea that he had that he hadn’t felt able to discuss that with the CVMP --- EMEA in sufficient depth.  I just wanted -- and he knows that I might say this because we talked about last evening.  I just didn’t want anybody going away with the fact that at the EMEA the doors are always shut and we are not open to people coming in and folks coming in.  Transparency is our byword really.  We really encourage people to come and talk and talk to us, and we try to facilitate that. 
  
We have meetings between the CVMP and the interested parties two or three times a year when any representatives can come in at fixed times when the committee is in session or after they close their session but then a post-meeting.  An agenda is fixed.  Two or three items can be on there, and we have a real good dialog and a good debate.  We have focus groups.  We have info days twice a year.  We have got one coming up in December, and indeed we have got a document going back to the committee next week which is really all about transparency and opportunities for how interested parties can come and talk to the committee, can come and talk to EMEA, to the working party experts when they are drafting guidelines.  So I want people to know that we are a very open organization in case anybody got the idea to the contrary.  Thanks for letting me say it.
  
DR. CRAIGMILL:  Thank you.
  
DR. SCARFE:  David Scarfe again.  To use Peter’s segue way, thank you, it is more a concept or an idea, but certainly I was going to wait until near the end of this discussion because one has to ask the next steps.  I truly believe, number one, next step is beginning to share information in an open forum, and that can obviously come in terms of publications, and I know there will be at least a CD that comes from this.  But the other is actually getting the heads together to start discussing.  Usually those come in the shape of workshops and symposia and such like, and I am certain this group probably will end up to conclude that we need the next steps.
  
Peter specifically mentioned the veterinary profession and the producers, and he also mentioned the World Veterinary Association.  I don’t know the feasibility.  I would have to investigate if there was any interest in this, and we would need interest clearly expressed, but 2005 World Veterinary Congress is being hosted by the United States and specifically by AVMA in Minneapolis next year.  This is intended as a global perspective as is every annual World Veterinary meeting or every World Veterinary Association meeting, usually hosted by different countries.  
 
I don’t know what the opportunities are, but we certainly could look into a forum such as that, whether there are special sessions that address minor species.  I do know that we will focus on a lot of drug issues.  We generally refer to them as therapeutic agents because it is a catch-all, but we also specifically look at certain minor species.  Things like sheep and goats, small ruminants, the aquatic animal sessions are fairly extensive.  Whether something else can be built on as an ancillary or addendum to the whole World Veterinary Congress approach I don’t know.  I will perhaps leave this all open to discussion.

I would point out very clearly that even though these meetings, even AVMA’s annual convention, typically consider, you know, favoring the veterinary profession.  These meetings are open to all, and in fact in some cases we actually go out of our way to invite industries in because the veterinary profession does not live in isolation.  We do interact intimately with all levels, from governments at the international level, all the way down to the producer and producer organizations.  I just open some of this up for potential discussion. 
  
DR. CRAIGMILL:  Sounds like a great opportunity, Dave, if that is possible to set up something there.
  
DR. JETTÉ:  I am just talking as a freelancer.  I have experience in the World Veterinary Congress.  I know that for example OIE organizes sessions, so I don’t see why such a session could not be organized under the VICH umbrella or Codex umbrella. 
  
DR. CRAIGMILL:  We will take that as a second for the motion.  I would like to ask a question as to whether or not people think that the establishment and posting of a global compendium of drugs that are available for minor species might be a useful thing.
  
DR. HALEY:  I have a question about that.
  
DR. CRAIGMILL:  Yes.
  
DR. HALEY:  Carol Haley again.  A question, who would put that together and how would you get the information to go into it?
  
DR. WEBB:  FARAD has started doing that.  We are accumulating labels from overseas countries and putting them into a standard database, but it is extremely hard to do without active cooperation from the countries.  So we will be soliciting help of people.  I think it is well worthwhile because you can see the commonality, the differences, and the gaps, and it helps guide researchers and regulators into filling those differences and gaps.
  
DR. CRAIGMILL:  In fact, those were the two followup questions.  The first was would this be a nice idea, and then the second, who is going to do it and where is it going to reside and who would be running it I also think that there -- it is not just the country regulatory agencies or registration agencies.  The pharmaceutical manufacturers also have to assist heavily in us getting these data.
  
DR. HALEY:  This is Carol Haley again.  This gets back to my point that I made earlier about all the other influences going on or all the other people who have an interest, stakeholders who have an interest in what pharmaceutical companies do.  I would guess that if a pharmaceutical company were to give you a list of their products that were approved in other countries to put on a compendium that people in US might use to decide whether to use a drug extra-labelly, that the pharmaceutical companies would not do that because they would be concerned about being not in compliance with what promotion of off-label use was.
  
DR. WEBB:  Having spoken of FARAD, one thing we haven’t said in case any of you have a feeling FARAD is not funding by FDA.  It is funded by USDA, which is the farmers’ friend and not --- up the back, so I am paying due credit.
  
DR. CRAIGMILL:  Yes.  That is an interesting question about whether or not to provide information about the availability of drugs in another country.  If you were to post those information on your website I believe that would probably be construed in that fashion.  If, however, someone like NRSP-7 were to take that information, launder it very nicely, and to represent it in a standardized format -- which is actually the basis behind our compendium.  Alistair, which countries have we started with on this?
  
DR. WEBB:  We have Australia and the UK because they speak a language I can understand.
  (Laughter.)
  
DR. CRAIGMILL:  But in two weeks we are having a Chinese delegation come, and we will be providing them with the software in order to have them start developing a compendium of their veterinary products.  Which is kind of exciting because they will probably take the format which we have developed and using what are called lookup tables in these databases, they can look at it and read it in Chinese and we can look at it and read the exact same information in English when it comes to withdrawal times, doses, species, et cetera.  Kornelia Grein.
  
DR. GREIN:  Kornelia Grein, EMEA.  I just want to inform about the situation in the EU, again I cannot give you a commitment to provide you these data for all EU member states because it is 25 countries and not all of the products are available.  In some countries there are public list of the products, in others there are not.  But there is a project at the EMEA in the new legislation, under which we will have one list of all products in the EU, but this is a huge task.  This will take time.  Then once this will be available, and I can of course then take for the EU those for the minor species.  But it is not something that will be available in the next year or two-years time.  I am sure about that.
  
DR. CRAIGMILL:  In that regard, can I ask a quick question?  Will those uses which are considered minor or minor species be indicated as such, or will there be no differentiation?
  
DR. JETTÉ:  I think I cannot.  I am not in a position to explain exactly what type of details will be given, but I would assume that we would have the species indication and when it is approved in the different member states.  At the moment if there would be an issue, we would be looking at for example Peter mentioned in his presentation yesterday that we were looking on a kind of list of essential products together with this coalition and industry that are really missing essential products.  We need really to go to all EU member states and ask what we have for these types of thing, for this indication, for this substance, other products, etc.  It has to be done in a tedious way at the moment because no EU-wide database is available right now.
  
DR. CRAIGMILL:  We are aware of compendia or lists of products that are approved in the EU, Australia.  Switzerland has a very nice compendium on their website that is even translated into our language for the most part.
  
DR. SCARFE:  David Scarfe again, AVMA.  Just to take that lead and perhaps another invitation, I believe at least some sort of compendium of what drugs are approved in different countries is an exceptionally useful tool.  But the pivotal part of that is the data that --- decision is vital.  I cannot emphasize that enough, and I would suggest that we in fact have some call it government-neutral mechanism to actually collect and to some degree utilize that data.  That is again, and I am not trying to sell their program, Global FARAD.  That data is vitally important for them to do assessments to provide information, and for their benefit I again emphasize free information, at least in most cases, that they cannot function without these data.  They need the data. 
  
I think we all respect the problems in federal agencies, irrespective of where their jurisdiction is, listing series of drugs that are approved outside of one geopolitical entity.  But if this has any merit, that may be a superb repository for this data, which is useful, can be reported in an independent fashion, can be identified clearly whether under certain jurisdictions it is legal to use or not legal.  But to many of us I think the important part is the data that comes from that can immediately be used.  So you have the key individuals here if there is any interest.  I would suggest very strongly making those contacts and seeing if you could support and at least build something along that line.
  
DR. CLAYTON:  I just wanted to expand a little bit on what Kornelia said and the availability of databases.  As she mentioned, there will be an EU product database which will start off listing the centralized procedure products and then for the nationally registered products, and that is a long-term program.  But a lot of this information is available already on the European Commission website.  You have an index of centrally-authorized products, and that is in English; and for products that have been registered through the mutual recognition procedure the heads of all European veterinarian agencies have a common website, and there is a product index.  I cannot guarantee -- well, I know it is not complete, but it does have a very large number of the mutually-recognized products on there.  The gap that is missing is all the products from the past that are registered nationally and haven’t been taken through the mutual recognition procedure.
  
DR. JETTÉ:  Speaking as a freelancer again because I don’t have the authority to suggest that as a Canadian representative.  Like Peter said, that regulatory authorities cannot do it all on their own and I agree with him.  I think the key is collaboration.  I think also another key is to look at the MUMS issue in little pieces rather than as a big piece and a very complex problem.  So what I would suggest is that I know most of us do not have the authority to make a decision today, but if we would go back as regulatory people and talk to those who can make a decision and propose to them that each country could act as champion of a species well, if we agree with the idea, that it could take one species and act as the clearinghouse for that species and as the facilitator for that species.  I am using the example of Australia with sheep.  Many countries could act on aquaculture because there is a big industry there, and although it is a minor species there is a lot of expertise going around.  So this clearing house would gather information, facilitate contacts, be responsible for coordination so that at the end of the day there would be something precise, and something concise, and something that we could work on, you know.  Because right now we have got all kinds of concepts and we have got all kinds of ideas, but how do we channel them into a digestible package?
  
DR. CRAIGMILL:  Thanks.  That is a great idea.  Well, as people approach hypoglycemia, Meg, did you want to speak?
  
DR. OELLER:  Okay.  This isn’t a new idea.  This is Meg Oeller from FDA CVM.  I just wanted to say, following up on what Peter Jones was saying about what his group does with outreach to industry and since no one laughed at my joke where I said we like to be hard on industry I better be clear that we are very much interested in working with industry, always have been, that companies can, bring in applications that they have submitted in other countries.   We already have everything in place to try to take whatever we can use out of those packages.  Sometimes when we are dealing with old applications it is not a lot, but with Andy Beaulieu and I now working in the new Office of Minor Use and Minor Species we are really hoping that people will come in and work with us and we can use all of our old mechanisms and our new ones to try and help get more drug availability for MUMS species and thanks to everyone who came and made this such a great workshop.
  
DR. CRAIGMILL:  Thank you, Meg.  Well, I think we have just about reached the end, and I think we should call upon the person who paid for most of this or who arranged for the payment to give us a quick summation.  Steve, would you like to say a few final words?
  
DR. SUNDLOF:  Sure. 
  (Laughter.)
  
DR. CRAIGMILL:  Put a mic and his hand and he will just go.
  
DR. SUNDLOF:  Well, I just want to say thank you as well, and echo Meg’s words and Peter’s words that this whole thing works because there are a lot of people that feel passionate about this issue and have come together, and when you have that kind of momentum good things happen.  Good things have been happening in this area of minor use, minor species.  Not nearly as quickly as we would all like it to happen, but it is.  I think it is a momentum that will continue on and gain in strength as we go on.  Having this as an international issue certainly I think will help that process out a lot.  I hope we have more of these.  This has been very enlightening to me and we also are going to be looking at some of the suggestions that we just heard here today and looking for ways that we can take advantage of these new ideas to advance the minor species and minor use issues that we are dealing with.  So just in closing again we at CVM were very proud to be one of the sponsors of this symposium and thank you all for making it such a wonderful success.
  (Applause.)
  
DR. CRAIGMILL:  And I think unless Alistair has anything else to add to this since --
  
DR. WEBB:  Well, I would particularly like to thank the people who helped us.  Joanne Kla, Kandi Crosier, Carolyn Whitford, Sandy Ogletree, Carol Rupert* and others who helped keep things going on and kept everything going fun; and the two people who logistically got everyone here and paid the bills, paid the airline fares and everything else, Meg Oeller and Aleta Sindelar.  We thank them very much.
  (Applause.)
  
DR. CRAIGMILL:  So thank you all very much.  A special thanks to all of our invited speakers who traveled so far to come and share their expertise.
  
DR. WEBB:  And have a good trip back.
  
DR. CRAIGMILL:  And have a safe trip home.
  (Whereupon, the meeting adjourned at 12:04 p.m.)

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