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U.S. Department of Health and Human Services

Animal & Veterinary

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MUMS Forum II

Environmental Safety
Dr. Paul Bowser, Moderator

DR. BOWSER:  My name is Paul Bowser.  I am with the College of Veterinary Medicine at Cornell University.  I am an aquatic animal health specialist, so I deal with things that have gills.  If they have lungs, I pass them on to people who have far more knowledge than I.  So I deal with fish, and this area of environmental safety is something that I have been told is near and dear to my heart because when it comes to minor species in the United States, in the production environment for this product folks don’t get a pass. 
  (Adjusting microphone.)
  
How is that?  Anything?  Too much technology.  I am technologically challenged.  I am a hunter/gatherer in a dot com world.
  (Laughter.)
  
Open forum comments.  I guess the big question is, you know, should minor species have to go through an environmental assessment.  How is that for a start?
  (Laughter.)
  
So what are we doing?  Why are the fish people getting picked on and why do all the lung breathers get a pass?  Does anyone want to take that one?
  
DR. RAO:  --- for example, --- is useful in producing --
  
DR. BOWSER:  Identify yourself please.
  
DR. RAO:  I am Dr. Rao from India.  --- is used for producing ---.  --- is being produced right from --- in Indonesia, Malaysia, Philippines, Thailand, and then here in Southern America, Equador, in many countries, and most of it is coming to USA, Canada, France, UK.  For the past 25 years I see they have been using --- in hatcheries and ---.  In the final --- it is in the final stage --- safety is left out, and once it is cleared it gets cleared. 
  
But I would like to ask one basic question.  For the past 25 years in these countries --- through the year --- tilapia, and not a single case of any adverse effect, either on the human population living in those countries or those --- species or the other biotypes in that country has been ---.  --- from Oregon State University did find some residues in the hatcheries.  It is in ---.  I have gone through the paper.  I thought he would be attending this, and I wanted to have a personal discussion with him.  It looks like he is not attending here.  He has not come to attend this workshop. 
  
What I would like to point out here is even with
--- two nanograms of ---, that is testosterone to be very specific, if you go through like a giant expert quantitative work on --- WHO world report it is mentioned there.  So --- does have something in places.  Should we really think about it?  I am --- no.  We are in the final stage for --- for release.  Can’t we take the experience and ---?  Send somebody there and study the situation for about six months and make a decision.  This has been going on for the past at least four or five years.
  (Laughter.)
  
DR. WEBB:  The governor of California drinks the fish water.
  
DR. EIRKSON:  I am Chuck Eirkson.  I am the team leader on the environmental staff at CVM.  The question right there I think, I mean, if you look historically I would ask who has ever looked to see whether there were any impacts from any of those drugs that we are getting in the environment.  Only recently have they actually started looking, and they are finding effects from the steroids, testosterone and other things getting into the environment.  So that addresses one issue that we need to look, and that is one of the things an environmental assessment basically does.  So I think there are plenty of scientific reasons why we need to start looking more and more in some cases at possible environmental impacts, in particularly the aquatic environments. 
  
Historically, I mean, there is a lot more history and really a lot more data looking at use of animal drugs in the terrestrial systems.  We have been looking at terrestrial impacts or environment assessments for terrestrial impacts since the late ‘70s, early ‘80s, and that data went into a lot of the changes that we did in our regulations in 1997 to categorically exclude many, many of the minor use products.  We didn’t have data that would support categorical exclusions for all the aquaculture drugs, but what it still does is it opens up a door that if you get an approval for an aquaculture drug in one species and if the management systems are the same, the way that categorical exclusion is written you can get a categorical exclusion for an aquaculture drug as well.  So the principle still applies in aquaculture drugs.  Once the information has been gathered, once there have been approvals, the same regulations, the same requirements apply for aquaculture as they do for the terrestrial products.  So, I mean, there is really no difference in the way that we handle aquaculture versus terrestrial.  The difference is in what is available right now, what is approved right now, compared to what is going to be approved.
  
DR. WEBB:  Who wants it over here?
  
DR. PITTS:  Thank you.  My name is John Pitts.  I am from Washington State.  After going through all the Sound wars at Puget Sound, I can tell you it doesn’t matter whether we do find positive environment information because I think we live in a country that currently isn’t hungry enough.  I think they have priorities over the coastlines and the shorelines that would make us instead of looking at these things objectively find other reasons for that wall, and that is unfortunate.  The question, the original question was, is that we don’t have this as a priority, and until we do, it is not going to happen.

DR. BOWSER:  Other comments?
  
DR. JONES:  Thank you.  Maybe Dr. Eirkson if he is still in the room won’t thank me for this, but --
  VOICE:  ---.
  
DR. JONES:  I was just wondering maybe if you could elaborate for us as to your involvement in the VICH and guidelines on environmental safety.  Where that guideline, which is now through phase two, deals with minor species as I recall that if you have an environmental assessment, phase one and/or phase two, for major species then it stops and you don’t have to take that further for minor species.  I don’t know if you could elaborate, because it is some time since I looked at that in any detail.
  
DR. EIRKSON:  I will back up a little bit more even from that and basically address the MUMS legislation that just passed and why that didn’t have an impact on the environmental area.  When it passed MUMS, that affected the federal Food and Drug Cosmetic Act, and that doesn’t -- the federal Food and Drug Cosmetic Act is not what we worked under for environmental.  Environmental review at FDA, as well as any other federal agency, actually works under the National Environmental Policy Act, and nothing has changed within the National Environmental Policy Act and how that is applied to the FDA.  So under FDA and under NEPA basically we have three things we can do with any minor use -- with any drug actually, any decision you make on an INAD-an investigation of a new animal drug application or a new animal drug application. 
  
That is we can categorically exclude it if we have enough information to show us that as a class of chemicals or a class of drugs it is unlikely that is ever going to have an impact in the environment.  Or we can require an environmental assessment, which allows us to look at the possible environmental impacts of an action and then either prepare a “finding of o Significant Impact” and say the data that we have collected show that it wouldn’t have an impact in the environment; or that the EA, the environmental assessment, may show it may require an environmental impact statement, making it a little bit bigger document.  The EA can subsequently resolve the impact, or we can do the aEIS and do a record of decision.  We can still approve the drug.  It is just a matter of what we have to do to get to that point.  Most of the minor use drugs, as I said, are categorically excluded.  The 1997 regulations did categorically exclude most of those things.  Those drugs that weren’t categorically excluded then would require environmental assessment before we could approve the drug. 
  
VICH, as Peter was talking about, came along and actually gave us a couple of steps to do that we could follow whenever we do an environmental assessment.  The phase one environmental assessment or phase one part of a VICH was I think finished in probably about 1999 or ‘97.  I am not exactly sure when precisely, but that is finalized.  What that does basically is gives our agency, the FDA in the US -- also the EU and Japan as well as New Zealand, Australia, and Canada I think now is on board with it -- it gives them the ability to look a drug based upon exposure alone.  There are criteria in aquatic and terrestrial environments.  It is 100 part per billion in soils for aquatic drugs.  It is one part per billion in water.  If you have a chemical introduced at below those levels then usually you can be done.  I say usually because in a lot of cases if you have information to show that a chemical is active below one part per billion you may still need to go on further than that, but the phase one does give you a variety of criteria that allows you to finish an environmental assessment up very quickly.
  
I guess one of the examples of that may be the bee application for tylosin.  I mean, it was a four-page environmental assessment.  It was mostly an academic type of an exercise which just showed that the concentration in the environment was very, very low, and there was no other data to show that there was a concern for that product.  So we got that in, and we worked very closely with Meg on that and actually got the document finished within probably a couple of weeks.  So it wasn’t as if it was a big burden.  I haven’t seen very many aquaculture drugs that would actually fit in there, but there may have been one or two.  The methyl testosterone unfortunately even below the one part per billion, there is plenty of data to show that it is pretty active below that level.  So you are not going to get out from underneath that with that criteria.
  
The phase two section of VICH is something we just cleared about last month basically.  It still has to go to the steering committee.  But that outlines the information that needs to be collected for determining the physical chemical properties of a chemical as well as the information that is needed to determine its fate in the environment, even possible effects.  It sets up criteria for more or less doing a qualitative/quantitative screening risk assessment for a chemical; and if you do that and you come out from underneath that, that pretty much ends the game, too.  That is a little bit more extensive than what might be required under phase one, but there are a variety of steps that are pretty well defined now for what is needed for doing an environmental assessment. 
  
The other thing I will mention, too, is for the most part we would accept, and we do accept and have accepted, peer-reviewed literature for demonstrating endpoints.  You know, the criteria that are set out in our VICH phase two, we would accept peer-reviewed literature.  Now, we would want to see several, I would say three different independent peer-reviewed literature, you know, endpoints that would come within a reasonable order of magnitude of the endpoint of one another to support that, but we would accept that as well.  So hopefully that helps a little bit more.
  
DR. BOWSER:  How do some of the other areas of the world handle this issue?  Anybody want to comment on that?
  (No response.)
  
DR. BOWSER:  Anybody want to speak for Europe?
  
DR. GREIN:  Kornelia Grein, EMEA.  Certainly in Europe we apply also the VICH guidelines, VICH.  Phase one has been agreed already a couple of years ago and we have implemented it according to the VICH agreement, and we have in place at the moment a phase two guideline which is also being revised and in the future we will apply, too the VICH guidelines.  So basically the step-one approach is very similar as described by theCVM.
  
DR. BOWSER:  Do you accept peer-reviewed literature as part of your process?
  
DR. GREIN:  I must say I would not be in a position to say this so clearly, because most of the products that we authorize is due to the EU member states, not at the EMEA.  So I could not say if this would be agreed upon, but I would assume it would be acceptable if it was peer-reviewed literature, but I cannot confirm this.
  
DR. JONES:  Could I just add?  It is interesting how new legislation always brings new hurdle with talk with those of us from the EU about this new legislation, and indeed in the second briefing of the new directive the legal instrument actually underpins the licensing of medicines in the EU.  In the second reading in Parliament there was an introduction requiring not what wasn’t there initially, but there had to be an environmental risk assessment.  That is basic, but there has to be stand alone risk assessment of environmental safety for each additional product, and they want it as a separate part of the dossier.  So this is how much profile this thing is getting in Europe right now. 
  
DR. BOWSER:  Other areas?  In the back, Alistair.
  
DR. BRACKETT:  My name is Jim Brackett, aquaculture veterinarian in Canada.  Our experience so far in the environmental impact part of the drug approval system is quite new.  Our experience so far, though, is that it is other agencies that are applying double, triple, quadruple jeopardy on the process, and that even after drug approval other federal agencies are using unstated policies and open-ended rules.  There are not even flags in the corner of the playing field, let alone level goalposts, and that is particularly for aquaculture drugs.  So the inhibition for getting those drugs actually used and the uncertainty for pharmaceutical companies entering into the drug approval process is coming from other agencies as well as the drug approval process.  So that has to be dealt with to have any of this work in any kind of a practical way.
  
DR. BOWSER:  How do various groups handle issues of antibiotic resistance?  That seems to be a real hot button issue.  The ice cream has arrived.
  (Laughter.)
  
I was in church one time and a cell phone went   off and the priest had a field day because someone had “a  calling”.
  (Laughter.)
  
Again, from your hunter/gatherer and dot com world.  Thank you.  Antibiotic resistance, getting back to the subject at hand.  Does anybody want to comment on that?
  (No response.)
  
What is specifically -- maybe for CVM folks.  What is specifically required or is there such a thing -- maybe I shouldn’t say specifically I won’t say that.  What do we expect in the way of documentation to demonstrate that there is not going to be an antibiotic resistance issue if we were to look at a new antibiotic in any minor species?
  (No response.)
  
Nobody wants to answer.  Want to try, Steve?
  
DR. SUNDLOF:  No.
  (Laughter.)
  
DR. BOWSER:  No.  You don’t want to touch that one with a 10-foot pole.
  
DR. OELLER:  The short answer is you have to --
  
DR. BOWSER:  I am throwing knuckle balls out here.
  
DR. OELLER:  Yes.  Thanks a lot, Paul.
  
DR. BOWSER:  Old pitching days.
  
DR. OELLER:  This is Meg Oeller from FDA, and the short answer is you have to follow guidance 152 and 52, which is -- is it gut flora?  But they are both recent guidance documents, and they pretty much spell out what you have to do.  It is going to be product dependent just like an EA, but you don’t have to do it unless it is an antibiotic.
  (Laughter.)
  
DR. BOWSER:  Is that maybe why we have only had two antibiotics in fish since 1983 I think?
  
DR. OELLER:  No.  There is a lot more reasons than that.  This is just the latest one.
  
DR. CRAIGMILL:  Meg, if that has already been done for a major species, then what is the requirement for the minor species?
  
DR. OELLER:  Depending on what drug it is and what has been required, you may have studies that were done.  It may be just a paper argument.  It is just going to depend.  Depending on which minor species it is and what your management style is, there are options.  In earlier versions a lot of minor species things were just waived, but that is not true now.  We have to actually go through the exercise and prove why it is not a problem.  For something like the tylosin in honey bees which is an antibiotic, but it is not  used in humans,  it wasn’t a huge problem in terms of antimicrobial resistance.  It was a pretty short argument, and we got it off pretty easy.  Most of the time for minor species we are not looking at new entities, especially not for antibiotics.  These are almost always supplements.  So in most cases we are going to find, unless it is a really old drug that hasn’t been supplemented in a long time, that this has been addressed for the major species.  If it is an old drug and this is never addressed, then we really have to demonstrate that we are not looking at a huge new introduction.  But just following through that guidance is an exercise we do have to do, both of those guidance documents.

DR. GREENLEES:  Kevin Greenlees, also CVM.  It is probably worth pointing out that guidance 152 is a guide for how to do a risk assessment, and it also specifically identifies that you can use published literature to help support that risk assessment.
  
DR. BOWSER:  Thank you.  Other areas of the world, want to comment on this one?  What is expected of you folks?  Yes, please.
  
DR. ERRECALDE:  Thank you very much.  Is this open?
  
DR. BOWSER:  Should be.  Yes, you are on.
  
DR. ERRECALDE:  Thank you very much.  Well, I will speak.  It was not my intention at all, but --
  (Laughter.)
  
DR. BOWSER:  You got the mic.
  
DR. ERRECALDE:  I have this in my hand, so I will try.  There is something interesting.  Evolution of resistance is independent of the use of antibiotics.  Resistance is evolving.  What we can do only, what we can do is to delay the appearance of resistance, and the management of the situation is only possible through the rational use of antibiotics.  The rational use of antibiotics is a bit of knowledge of pharmacokinetics, a bit of knowledge of microbiology, and a bit of knowledge of physiology, and of course the teaching of all this to the people that will be in close work with the animals.  I think that is more of the idea.  Is that okay?
  
DR. BOWSER:  That is okay. 
  
DR. MITEMA:  Thank you.  Antimicrobial resistance is a really muddy issue, and I know currently we are coming up with the guidelines, especially to perform risk analysis whereby new antimicrobial agents will have to undergo some evolution.  So I would think that in the future I will see some guidelines coming up in all cases, especially pertaining to that.  Again, you also have to take a common sense to the fact that right now you have got a lot of bacteria in the environment, some of it resistant bacteria, and we know for example that certain antibiotics are either excreted  unchanged either in the feces or in the urine, and if for example the penicillins, one penicillin group compound is being used in the minor species.  What is its potential effect on the E. coli which could be the same strain the human being in the minor species. 
  
I know a lot of different groups of people have done a lot of work.  They do a lot of surveillance programs whereby currently they even try to look at the resistance profile of the various antimicrobial agents on various let’s say pathogens.  Various different bacteria in the environment for example in soil, in water, or et cetera, et cetera.  I think the whole idea about this is that what would happen if a particular antibiotic was being excreted unchanged, because if it is being excreted unchanged it would definitely mean that the bacteria may have access to it and may change its
resistance potential in terms of aquatics also.
  
DR. JETTÉ:  Elaine Jetté, Canada.  We don’t have any specific exemption for MUMS drugs as far as antibiotic resistance.  In the VDD website we have a draft guidance for drug sponsors to help them submit data, and we have a special framework for antimicrobial drugs.  Perhaps my colleague from the human safety division wants to add some information.
  
DR. SHABNAM:  --- (away from mic.)  I am Javad Shabnam from VDD Health Canada.  I am not really a specialist in that field, but we have a team and we have a guideline on our website, and they work on it.  I can’t comment more than that.
  
DR. MACMILLAN:  This is Randy MacMillan.  One of the hats I wear is with the National Aquaculture Association, the US Trade Association, and I think it is really important regardless of the technical issues to recognize that it is actually in aquaculture’s best interest that the environmental, the food safety, the target animal safety -- but in particular the food safety -- the environmental issues associated with antibiotics of drugs in general are clearly identified or reviewed by FDA CVM, because that for our market, that is a signature of national approval that this drug is safe.  When it comes to selling our fish, for example, to US consumers, that signature of safety, that sign of safety is real important to them. 
  
When it comes to the environmental side of the drugs, we are under assault so to speak from a large number of environmentalists, the environmental community in general, forcing us, continuing to put pressure on us, to demonstrate that our environmental footprint is non-existent or very minimal.  The review process that FDA/CVM has is rigorous, and even with MUMS, the provisions of MUMS, it is still going to be rigorous.  But assuming we do get more drugs available from the MUMS provisions, we will be able to state that our federal government has approved the use of those compounds.  They have agreed that the sponsors have adequately demonstrated that it is safe to consume the animals that have been exposed to these drugs, and that the environment is not adversely or significantly harmed as a consequence of a fish farmer’s use of those compounds.  So the NAA, the National Aquaculture Association, really supports FDA’s effort to insure the food safety and environmental safety of those compounds.  Thanks.
  
DR. BOWSER:  Good point.  I think the issue of good environmental stewardship on the part of all these agricultural entities is extremely important.  Because we are dealing with the public, and they are going to make decisions that may be, or may not be based on science, but it can make or break an industry.  So good comment.
  
DR. BEAULIEU:  I just want to validate what Randy just said.  I was party to the late-stage negotiations on the MUMS bill, and I can state categorically that if there had been any impression on the part of the people we were talking to that we intended to apply a lower standard under the MUMS bill for either environmental circumstances or particularly, antimicrobial resistance, MUMS would never have passed.  Absolutely would not have passed.
  
DR. REEVES:  Phil Reeves from Australia.  The situation is exactly the same in major species as minor species with all applications for antibiotic products.  Basically what happens is the Department of Health have set up an expert advisory group on antibiotic resistance.  They assess all these applications, and they tend to be categorized as well into those which are used in human medicine, those which are related to antibiotics used in human medicine, those that are used for growth promoting purposes, and those were there is absolutely no relationship between the proposed drug and the human counterpart.  As with everywhere else in the world I guess, prudent use is just emphasized, and they are now setting up post-marketing surveillance programs so that they should be able to come back in years to come and just monitor the profiles for any increases in resistance.
  
DR. BOWSER:  Anyone else?
  
DR. DUNHAM:  Bernadette Dunham.  I am with CVM, but in case you don’t know, this is the International Workshop on Minor Use and Minor Species, and everybody has been talking about the value of interacting and collaborating; and we all did give an awful lot of credit to what we call over here the MUMS coalition, and people are saying we need to develop coalitions.  But you might want to while you are here, and certainly tonight and tomorrow, do speak with Dr. Randy MacMillan, because he was chairperson of the United State’s MUMS coalition.  I just want you to know that.  Thanks, Randy.
  (Applause.)
  
DR. BOWSER:  Other comments from the floor?  Yes.
  
DR. EIRKSON:  I am Chuck Eirkson again with the environmental, and in addition to working with the VICH and some of the other ones, we just went through a process with the Joint Subcommittee on Aquaculture working with the Environmental Protection Agency and their requirements and regulations for aquaculture drugs.  One of the things that I wanted to point out is that I don’t know if there will ever be a complete relinquishing of state versus federal requirements in terms of what you do with aquaculture drugs or anything else.  Because historically I think even at a federal level, at least in the states and from what I have seen in Canada and some other places -- and in the UK as well I think -- you approve a drug on a national level, but then the actual use of it is geared towards the site that it is being used, and that is dealing with water quality issues at that site. 
  
If a particular site, it is my understanding -- and I am not an expert in the area, but if the particularly area has some degradation to it already, if the water quality is low, then they apply a little different standard to that site in terms of the effluents that can be introduced into that site.  If an area is pristine, then they apply a different standard.  So if you have a drug, an aquaculture drug, that will go into a site that is pristine, then the amount that may be allowed in that particular area -- and it needs to be site specific -- would be lower than it might be in another area. 
  
So what we try to do at a national level basically is just be sure, hopefully, that at the standards we are applying it is unlikely that an impact will occur.  But it is always going to be a prerogative of the state, the people at the states who issue permits to discharge directly into those states, it is always going to be their prerogative to, you know, change that, modify it, or in some cases they may restrict it completely.  I don’t really see that as being something that is going to be completely changed. 
  
What you can do and what we try to do with EPA, is work cooperatively with them.  Let them know how we go about making our decision, make the data that we have available to us for our decision, make that data available to them in the field so that they can it, and also keep the lines of communication open between the federal level and the state level in order to use the drug at that level.
  
DR. BOWSER:  Other comments from the floor? 
  (No response.)
  
DR. BOWSER:  What do you think, are we done, Art?
  
DR. CRAIGMILL:  We are almost done.  We have --
  
DR. BOWSER:  Well, let me, before I pass it off to you, thank you all for staying here to this late hour.  I didn’t tell Art when he asked me to chair this session, but the last time I got up before an audience in Washington, DC was with the Catfish Farmers of America down at the Washington Hilton.  I got up, got introduced, started talking, and we had a fire alarm.  Everybody left and nobody came back, so thank you for staying.

(Laughter.)
  
DR. CRAIGMILL:  Thank you, Paul.  There are two things.  First of all, Alistair wants me to be sure to remind everyone that beginning at 5:30 at the gazebo there will be a reception hosted by the Friends of NRSP-7.  Which means you don’t have to buy drinks; you get them free.
  
DR. WEBB:  But you can’t drink much.
  (Laughter.)
  
DR. CRAIGMILL:  You will be given a ticket or ---.
  (Laughter.)
  
DR. WEBB:  Can I just have your attention? 

Dr. Scarfe at the back from AVMA got these brochures freighted in this morning, and it is a nice laminated version of the extra-label drug use algorithm that came out of AMDUCA.  It is available at the front desk.