VMAC Meeting

January 22, 2002


Procedural Comments

†††† by Aleta Sindelar††††††††††††††††††††††††††††††††† 4



†††† by Dr. Stephen Sundlof†††††††††††††††††††††††††††† 7


ADAA 1996:Legislative Overview

†††† by Jarilyn Dupont†††††††††††††††††††††††††††††††† 10


Food Safety

†††† by Dr. Mark Robinson††††††††††††††††††††††††††††† 23

††††††††† Questions and Answers†††††††††††††††††††††††† 37


Setting Tolerances for Drug Residues

†††† by Dr. Lynn Friedlander†††††††††††††††††††††††††† 44

††††††††† Questions and Answers†††††††††††††††††††††††† 57


Codex and International Aspects

†††† by Merton Smith†††††††††††††††††††††††††††††††††† 67

††††††††† Questions and Answers†††††††††††††††††††††††† 83


Seafood:Safety & HACCP

†††† by Dr. Kim Young††††††††††††††††††††††††††††††††† 85

††††††††† Questions and Answers†††††††††††††††††††††††† 99


Compliance with Tolerances for Imported Meats

†††† by Dr. John C. Prucha††††††††††††††††††††††††††† 107

††††††††† Questions and Answers††††††††††††††††††††††† 125


Public Disclosure and Environment Assessment

†††† by Dr. Mark Robinson†††††††††††††††††††††††††††† 140

††††††††† Questions and Answers††††††††††††††††††††††† 144


Open Public Session

†††† by Dr. Jim Heslin, Moderator†††††††††††††††††††† 145


††††††††† Presentation by Dr. Bob Livingston†††††††††† 146

†††††††††††††† Questions and Answers†††††††††††††††††† 155




I N D E X (cont'd)

VMAC Meeting

January 22, 2002


Presentation of Questions

†††† by Dr. Stephen Sundlof, Moderator††††††††††††††† 162


Committee Deliberations

†††† by Dr. Cory Langston, Moderator††††††††††††††††† 165


































Keynote: ‑‑‑ indicates inaudible in transcript.


(8:40 a.m.)

Procedural Comments

by Aleta Sindelar

††††††††† MS. SINDELAR:Mr. Chairman, members of the committee, invited guest speakers, FDA staff, and public participants, I would like to welcome all of you to the Veterinary Medicine Advisory Committee Meeting.

††††††††† I am Aleta Sindelar, the executive secretary for this committee.I will be providing information regarding the public information made available at this meeting.The advanced notice of proposed rulemaking for import tolerances, and read the conflict of interest statement for the public record.

††††††††† First, the Veterinary Medicine Advisory Committee Meeting will be open in entirety to the public.Thus, all information presented at this meeting is open to the public.

††††††††† At the back of the room, you will find a spiral bound book containing the information provided to the VMAC members in anticipation of this meeting.All comments provided for review to the committee prior to this meeting are also made available.

††††††††† A new agenda reflecting the speakers for this meeting has been copied for your review.All Powerpoint slides of speeches presented today, as well as the aforementioned materials, have been transmitted for posting on the CVM website.

††††††††† The comment period for the advanced notice of proposed rulemaking for import tolerances has been extended to March 11, 2002.Additional information for submitting comments can be found on the CVM website, and, in particular, the CVM update dated December 12, 2001.

††††††††† And, finally, the conflict of interest statement for the public record reads as follows:

††††††††† "The following announcement addresses the issue of conflict of interest with regard to this meeting, and is made part of the record to preclude even the appearance of such at this meeting, January 22, 23, and 24, 2002.

††††††††† Federal conflict of interest laws preclude the participation of committee members and consultants in advisory committee meetings if they have a conflict of interest unless a waiver from exclusion is granted by the agency.

††††††††† Based on the submitted agenda for this meeting, and a review of all its financial interests reported by the committee participants, it has been determined that all interests in the firms regulated by Center for Veterinary Medicine, which have been reported by the participants, present no potential for a conflict of interest at this meeting with the following exceptions:

††††††††† In accordance with 18 U.S.C. 208(b)(3), a waiver has been granted to Dr. Robert Holland, Dr. Deborah Kochevar, Dr. Alexander MacDonald, and Dr. John Waddell.

††††††††† Under these terms of the waiver, Drs. Holland, Kochevar, MacDonald, and Waddell will be permitted to fully participate in the discussions and deliberations, which will involve human and veterinary medical issues related to the import tolerance in the context of the Food and Drug Administration's mandate from the Animal Drug Availability Act to establish these tolerances.

††††††††† They will also be permitted to participate fully in discussions and deliberations pertaining to antimicrobial drug effects on pathogen load in food producing animals, as it pertains to the preapproval process of new animal drug applications.

††††††††† In the event that the discussions involve specific products or firms not on the agenda, for which FDA's participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the public record.

††††††††† Screenings were conducted to prevent any appearance, real or apparent, of conflict of interest in today's committee's discussions.Copies of this waiver statement and the waivers addressed in this announcement are available by written request under the Freedom of Information Act.

††††††††† The guest speakers have also been screened for potential for a conflict of interest or appearance thereof.Dr. Scott McEwen would like to disclose that he is negotiating a contract with Vetrepharm, a subsidiary of Bioniche to do a field trial on a matter unrelated to the issues to be discussed at this meeting.

††††††††† Dr. Thomas Shryock would also like to disclose that his full-time employment is with Elanco Animal Health, a division of Eli Lilly & Company, and he holds stock in Eli Lilly & Company.

††††††††† With respect to all other meeting participants, we ask, in the interest of fairness, that they address any current or previous financial involvement with any firm whose products they wish to comment on."Thank you.


by Dr. Stephen Sundlof

††††††††† DR. SUNDLOF:Well, good morning, everyone.I am Steve Sundlof, and I am the director of the Center for Veterinary Medicine.And I would like to take this opportunity to welcome everybody to this Veterinary Medicine Advisory Committee.

††††††††† This committee is very important to the deliberations of the Center for Veterinary Medicine.We rely heavily upon the expert advice of this committee to give us guidance as we try and deal with some of the issues that are, in many ways, the most complicated and difficult.

††††††††† We need this advice in order to be able to make positive progress towards resolving some of the, again, very difficult issues that face the center on a day-to-day basis.So, again, welcome everyone.

††††††††† We originally had proposed to talk about import tolerances back in September, and the terrorist attack of September 11th caused us to reschedule that meeting.We were able to put this advisory committee meeting back-to-back with another one, in which we are going to be dealing with another very important issue to center, which is pathogen load, and how we deal with that particular issue in the evaluation of antimicrobial drugs.

††††††††† So it is good to have the opportunity to have everybody come together.We think we will have a very productive meeting during the next three days.If there is anything that I can do personally to make people stay more comfortable, please let me know.We will try and do everything we can to accommodate everybody's needs.

††††††††† I would like to then introduce the Veterinary Medicine Advisory Committee.I will start with our chairman, Dr. Cory Langston, who represents the Discipline of Pharmacology; Dr. Alicia Anderson, who represents Public Health in Epidemiology ‑‑ thank you for raising your hand so that people will recognize you ‑‑ Dr. Wanda Haschek-Hock, who represents pathology; Dr. Ann Parkhurst, who represents biostatistics; Dr. Debbie Kochevar, who represents companion animal medicine; Dr. Robert Holland, who represents minor use in minor species; Dr. John Waddell, who represents food animal medicine; Dr. Dennis Wages, who represents avian medicine; Dr. Tom Carson, who represents toxicology; Dr. Barbara Glenn, who represents animal science; Dr. Richard Wood, who represents our consumers; and Dr. Alex MacDonald, who represents chemistry.

††††††††† So, thank you all, panel, for coming.Some of you I know had a little difficulty in getting here, but we are glad you all made it.And, with that, I am going to turn it over to Dr. Mark Robinson, who will talk about food safety.

††††††††† Oh, I am sorry.I am a little out of order here.It is Jarilyn Dupont, who is going to talk about the legislative history behind import tolerances.

ADAA 1996:Legislative Overview

by Jarilyn Dupont

††††††††† MS. DUPONT:Good morning.Dr. Sundlof asked the Office of Legislative Affairs ‑‑ excuse me ‑‑ Office of Legislation, actually, to come in and provide sort of a background on the legislative history, with respect to the Animal Drug Availability Act, particularly, the Section 4, which is the important tolerances.

††††††††† So I am going to go through this very, somewhat dryly, in one sense.Because, as most of you know, legislative history has an official history and an unofficial history.What I am going to give you is the official history, because the official history is unfortunately all that matters to bodies as yourself and to the court.

††††††††† Of course, there is an amazing unofficial history, which I am sure Dr. Sundlof would be glad to relate to people during the break, and all of the lobbyists involved, and the individual companies who wanted something.

††††††††† But, unfortunately, this will be a little bit dryer than that, and won't be as interested.But we will go through it.Part of this is published in the ANPR, which has some information about that.

††††††††† Let me just start with something that is kind of not on the chart here.

††††††††† (Slide)

††††††††† This became law in 1996.But, if you will recall, previous to this, I believe it was 1994, was signed the Animal Medicinal Drug Clarification Act, which sort of started the ball rolling with respect to improving the review process with respect to animal drugs.

††††††††† Subsequent to that session ‑‑ that was the previous Congress before this particular Congress ‑- before that came about then they decided that they wanted to try some more.So quite a few bills were then subsequently filed the next Congress.

††††††††† That was also the time when we were doing what was called FDAMA, the Food Drug Modernization Act, which is the big sort of revision of all of the activities at FDA.So this sort of became part of that, even though it was a separate track and did get signed separately.

††††††††† The ADA was designed, you know, to increase the number of animal drugs on the market.This was sort of generated out of a whole collaboration of the unofficial history with respect to industry, with respect to FDA, the administration, manufacturers of drugs.

††††††††† It was passed with extremely strong bipartisan support.If you look at the debate and stuff, there is not a whole lot of discussion that indicates that there was any sort of controversy with respect to this.

††††††††† (Slide)

††††††††† These are the different sections, evidence of effectiveness, limitation on residues.

††††††††† (Slide)

††††††††† Then we have the import tolerances, which is Section 4; veterinary feed directive, which is Section 5.

††††††††† (Slide)

††††††††† And the feed meal licenses, which, as you know, has become a very big issue now also, with respect to the BSC issues.

††††††††† (Slide)

††††††††† This is a path to passage, and this what I am going to concentrate on, and I will go through each of these individual things.Prior to the bill that actually had Section 4, which was the import tolerances, you had S.773 introduced.

††††††††† That actually was from Senator Kassebaum, which is the first part of FDAMA.That did not have in there anything to do with import tolerances, but it started the ball rolling with respect to the issue of trying to move forward on animal drugs, and sort of reinvent animal drugs.That was introduced in 1995.

††††††††† (Slide)

††††††††† Now, between May of 1995 and October of '95, nothing happened on that particular piece of legislation.Nothing happened officially.What was happening behind the scenes was is there was a lot going on with respect to the reinventing government initiative by the Clinton Administration at the time.There was a lot going on with, you know, lobbyists, whatever.And there were negotiations going back and forth with Congress at this time and the Administration.

††††††††† In October, another bill was introduced which also was sort of ADAA was reformed, and that again did not have anything about import tolerances in it.

††††††††† Let's see.Hold a second there.Well, that was it.Hold on.This is what happens when you hit the wrong button, as you can see.So bear with me one second, and I will get back up to the one I was at.Okay.Okay, here we go.

††††††††† (Slide)

††††††††† As you see, neither one contained an import tolerance provision but there was effort.They really wanted to improve "the drug review process" with respect to animal drugs.

††††††††† (Slide)

††††††††† In December of '95, you then had 1477, which was introduced by Senator Kassebaum again.And this was the result of a lot of negotiations, which was the first FDA reform bill, and it again contained animal drug reform provisions.

††††††††† (Slide)

††††††††† In 1996, we had the REGO initiative, which as the reinventing government, with Clinton Administration, and it was reinventing food regulations.And in the National Performance Review Standards, they included a proposal for FDA to focus its review on the safety of drug residue in an imported food products, and including and other animal drug initiatives.

††††††††† That was sort of the first written explanation of exactly what they wanted.And if people would like to look at that, I think it was published in January 1996, Reinventing Food Regulations, under the Clinton Administration REGO initiatives.

††††††††† And part of it was is that ‑‑ let me read you part of this, what it included.It says, "Currently, FDA establishes legally accepted tolerance levels of veterinary drug residues in food only through its drug approval process.Thus, even for drugs that would not be used domestically, for example, because they are intended to treat diseases or pests that are problems here, and for which the only domestic health concern would be that the residues in food be safe, the sponsor would submit, and the agency would review data demonstrating that the drug is effective and safe for use in animals.This requirement is burdensome, both to agency and industry, and adds nothing to the public health or safety of American consumers."

††††††††† (Slide)

††††††††† Subsequent to the REGO initiative, subsequent to all of these bills, they started having hearings with respect to the FDA reform initiatives, S.1477.Dr. Kessler testified and briefly mentioned the effort to improve the animal drug review process.

††††††††† In March of that year, it passed committee; then in March of '96, you all had another bill, H.R. 3200, which sort of became the vehicle for the Animal Drug Availability Act.That was introduced by Representative Klug.

††††††††† It was one of the three different reform bills that were going on at the time.Title 2 had evidence of effectiveness and limitation on residues, and it was picked up the provisions from the REGO initiative that I just read to you.So that is the first sort of public evidence that they were interested in this issue on the Hill.

††††††††† (Slide)

††††††††† We then had the House Commerce Subcommittee hearings that happened over different period of time, Dr. Kessler testified again.Then, in May of that year, you had the reinventing the regulation of animal drugs REGO initiative, in addition to the food on that was issued in January, then again repeated the effort that they wanted to do with respect to the import tolerances.

††††††††† (Slide)

††††††††† The only Congressional history we get on this, you have a special order on FDA reform bills, and in those they briefly mention the effort to get rid of the cumbersome regulatory process, that type of thing.But there is nothing very specific that speaks to what did we mean by this issue of import tolerances?

††††††††† There is nothing that direct.There is nothing that, you know, steps out and says, this is what we meant, or this is the legislative history.But let me also point out that the language itself of the bill is not exactly unclear.It is fairly specific, and it is plain English, and it does pretty much tell you what it means to tell you.


††††††††† You then have it in June being reported to the Senate.And between June and September, is when a lot of the unofficial sort of lobbying and nego ‑‑ I mean, they are official, but that is where the bulk of the effort gives when the committees in industry and everybody is working together to come up with the final bill with respect to these issues.

††††††††† (Slide)

††††††††† You then have the committee mark-up in September of '96, and it was discharged from the committee on September 19, and it included the import tolerance.It was passed by voice vote in about a week, within a week.

††††††††† (Slide)

††††††††† It was then discharged and marked up.They marked up S.773 in the committee and the Senate.They discharged that.It then was passed in Senate, as you can see, on the same day, so that was a very quick process, not a whole lot of discussion.

††††††††† (Slide)

††††††††† Then within a couple of days, it was presented to the president, and then in October it was signed, it became law.

††††††††† (Slide)

††††††††† The provision, which everyone I am sure is familiar with now, and is repeated in the ANPR is, like I said, very self-explanatory, and it is Section 4.

††††††††† (Slide)

††††††††† Now, the only type of Congressional intent that we can tell you that actually occurred was is that we had only three members and one Senator actually mentioned these in the floor remarks during passage.You know, things like:Finally, the bill authorizes FDA to establish import tolerances.

††††††††† Not exactly explanatory as to what they meant by any of the language in the section, they are just pleased that it is done.

††††††††† (Slide)

††††††††† Same thing with Mr. Manton.It just talks about, oh, this will allow us to establish import tolerances.

††††††††† (Slide)

††††††††† Mr. Deutsch spoke about how it would implement the REGO initiatives, which is probably the best information you can get for background on this, because then the REGO initiatives go into a little more about why they intended this to be done.The bill permits FDA to set import tolerances.

††††††††† The House Commerce Committee issued a report when it did pass the bill and when it went to the floor, and it had two references.

††††††††† (Slide)

††††††††† The most significant reference is probably from the Congressional Budget Office.As you know, the CBO does a cost estimate of these bills when they pass.And in doing their cost estimate, they discuss what it means to have this bill actually implemented, and in this it talks about what they thought it meant.

††††††††† Now, this does not, you know, is not the absolute last word, but it certainly gives you some guidance with respect to what they intended.It talks about how USDA monitors residues, sometimes in consultation with the FDA.

††††††††† Well, that sort of sentence, you know, points out that, well, this is the background.If USDA has been doing this at all, if they have done anything at all, then you would interpret that what they had done before was supposedly somehow going to be subsumed into what you are doing now.

††††††††† They did not do anything.Well, then there is no background there, but that gives you sort of a clue as to the type of things that probably the committee may have been looking at.CBO talks to these committee staff.They say, well, what did you mean by this?You know, what did you do?

††††††††† They talk to the FDA.They say, well, what goes on now?What do we do?And they come out with this type of thing.And so, that gives you a little bit of guidance about exactly what was intended with respect to the bill.

††††††††† Again, it is not the gospel, but it certainly would have credence if you were challenging this in court or something, as to what the legislative intent was.But let me stress again that the court is not inclined to look beyond the statute if the statute itself is clearly written, is in English, and they do not need to look to legislative history.

††††††††† (Slide)

††††††††† When they do a report with respect to this Congressional bills, you have a section-by-section analysis, and that is done by the committee, and it is the committee's interpretation of what they meant by the bill, and it talked about Section 4.But, again, it did not very much discuss it, other than it did repeat pretty much what was in the REGO initiatives.

††††††††† And, again, it talks about, you know, they intended that it be able to be brought into the United States, or diseases or conditions that do not occur in the U.S., and we should not prevent food from coming in even if they have a residue, if they have drugs in it.So that is the type of thing we have there.

††††††††† It talks about establishing a safe tolerance.It does not define what safe tolerance is.It let's FDA decide that.It talks about they may rely on data.It does not talk about the type of data, but just says where the data can come from.

††††††††† If it is an international standard which we rely and it changes, it gives ‑‑ it sort of implies that FDA is the authority to then reject that standard afterwards if it turns out that it is not appropriate.

††††††††† (Slide)

††††††††† And then last year ANPR was published, which is moving this forward.So that is it.I think that gives us about five minutes, if anyone had any questions.

††††††††† (No response)

††††††††† MS. DUPONT:It was that clear?Okay.Well, good.Thank you.

††††††††† (Pause)

††††††††† DR. LANGSTON:Just a note to the committee members that while Dr. Robinson is setting this up, that while you will have a chance to ask additional questions during the committee discussion period, obviously, if you have anything that needs answering right now or could be answered that would be preferable probably.

††††††††† DR. HASCHEK-HOCK:I do have a question.In the one of your notes, it says that currently, under current law, the Department of Agriculture monitors residue as an imported animal food products.And I was wondering, how is that done?And how extensive is the monitoring?

††††††††† DR. SUNDLOF:Well, I will try and answer that one.Right now, unless we develop methods, or if FSIS develops methods for certain drugs that are not approved here in the United States, for the most part, they do not monitor for those other drugs.

††††††††† Now, they do have agreements with the foreign countries that they are not supposed to be using drugs that are not subject to approval in the United States.So the USDA monitors foreign slaughter plants, and basically ensures that they meet the same standards as the U.S. slaughter plants meet.

††††††††† But we are aware, I think just about everybody is aware, that there are drugs that are being used in other countries that are not being used in the United States, and either we do not have the methods, or we do not have the toxicology data to have the same kind of assurance that we do in the United States for domestically produced products.

††††††††† Now, we do monitor for some chemicals, especially things like chloramphenicol, that is part of the monitoring process.But there are very few drugs that are actually on that.

††††††††† This gives us the opportunity to, if we know that a country is using a drug that is not approved in the United States, to require that they provide us the information that is necessary for us to be able to establish to our satisfaction that any residues in the meat or animal products that come to the United States are safe.

††††††††† DR. WOOD:But just to clarify, when you say we, are you talking FDA or USDA at this point?

††††††††† DR. SUNDLOF:This is FDA.

††††††††† DR. LANGSTON:Any other questions?

††††††††† DR. ROBINSON:Could we have the chandelier and the wall sconces down just a bit?

Food Safety

by Dr. Mark Robinson

††††††††† DR. ROBINSON:My name is Mark Robinson.I am the director of the Division of Human Food Safety in the Office of New Animal Drug Evaluation.And, as you know, we are here to talk about import tolerances.I would like to thank Ms. Roberts for the legislative exposť.

††††††††† As she pointed out, we are here specifically to talk about the establishment or the process of establishing tolerances for those residues of drugs which are used in food animals, but which may not be approved for use in the United States.

††††††††† The primary reason to establish import tolerances is to protect the public health and to facilitate trade.Currently, there is a de facto tolerance of zero for any residue found in imported food animal commodities.

††††††††† And, theoretically, this de facto tolerance would protect the public health.But I think it is arguable as to whether this would actually facilitate trade.

††††††††† More importantly, if there is data available, particularly from other regulatory environments, which would demonstrate that something other than a zero tolerance is warranted, then it seems reasonable that we consider this data in our examination for tolerance other than zero.

††††††††† In my association with the Division of Human Food Safety, I have the pleasure and the privilege of working with some of the best scientific minds in the evaluation of new animal drugs.One of the products of these evaluations is a tolerance.

††††††††† A tolerance is simply a benchmark and an upper limit for the level of residues in a food animal commodity that we consider to be safe.We do not say that a residue above that level is unsafe; we say that we do not have data to characterize it as safe.

††††††††† I am a relative newcomer to the FDA, having been here just short of two years.In my previous lives, I have had a fair amount of activity with the FDA.

††††††††† One thing that I learned quite quickly was that the best way to put off an audience was to begin quoting chapter and verse from the Food Drug and Cosmetic Act or the code of federal regulations.So I am going to show you this next slide with a little bit of apprehension.

††††††††† (Slide)

††††††††† The Animal Drug Availability Act of 1996, modified the Food Drug and Cosmetic Act in Section 512(a)(6) to read, in part:

††††††††† "In establishing such tolerance, meaning the import tolerance, the secretary shall rely on data sufficient to demonstrate that a proposed tolerance is safe based on similar food safety criteria used by the secretary to establish tolerances for applications for new animal drugs filed under subsection (b)(1); (b)(1) is the section of the Act that applies to new animal drug applications in the United States."

††††††††† I think the important things to take from this slide is that the data and the decisional criteria used to establish safety need to be comparable for import tolerances, as to those used for determining drug safety in the U.S.

††††††††† (Slide)

††††††††† The things that are evaluated in our evaluation of new animal drugs in the United States are principally sponsor-generated data that demonstrates the effects of defined concentrations of an active ingredient, formulation component, metabolite, or drug product, in relation to specific public health endpoints.

††††††††† The majority of the history of the Division of Human Food Safety in the evaluation of new animal drugs has been concerned with an evaluation of active ingredients or the metabolites.

††††††††† However, there have been exceptions where in a formulation component such as a solvent, a matrix, or some other excipient, has caused us more concern than the actual active ingredient or its metabolites.Therefore, we have also asked the sponsor to examine those.

††††††††† Most recently, in the area of decreased drug susceptibility to antimicrobial, and the introduction or potential introduction of transgenics into the new animal drug application pipeline, we have begun to consider the entire drug product as well.

††††††††† However, the policy and the guidelines for transgenics for antimicrobial resistance are yet to be established.So it is a little premature to talk about import tolerances in those domains.We will focus principally on the chemical drug residues for the rest of this talk.

††††††††† (Slide)

††††††††† The reason for evaluating this data is captured in Section 512(d)(2), in which it says, "In determining whether such drug is safe for use under the conditions prescribed, recommended or suggested in the proposed labeling thereof, the secretary shall consider, among other relevant factors, the probable consumption of the drug and of any substance formed in or on food because of the use of such drug, also the cumulative effect on man or animal of such drug."

††††††††† Now part (b) alludes to chronic exposure.We also consider potential acute exposure problems, but the emphasis is on chronic exposure.Part (a) alludes to the obvious, which is that after the first pass of this drug in the animal, there will probably be residues left in the edible tissues, and we need to consider what the potential effect might be on the consumer.

††††††††† But it also opens up a door to another area, which is as big or as small as you want to make it, which is any substance formed in or on food because of the use of such drug.

††††††††† The various considerations in the public health and the technology sectors are dragging that part of the Act around such that a definition as to we consider and what we do not is a matter of open debate.

††††††††† (Slide)

††††††††† The point of the evaluation is to identify any potential adverse human health effects that may be caused by the consumption of new animal drug residue in edible tissues from food animals, and when one is identified to try to mitigate any potential adverse human health effect.

††††††††† Now, this is really a binary function.The data presented by the sponsor either will indicate that something may happen or it may not.There is no gradient, either qualitative or quantitative, in this evaluation.

††††††††† We need to make a determination that if an effect is observed, we need to find out if we are concerned about it in relation to other observed effects.If we are that becomes a focal point of our evaluation and tolerance establishment, and we need to find out if there is a way to mitigate that effect.

††††††††† (Slide)

††††††††† The previous slide highlighted the word "residue," so I thought I would throw up again from the code of federal regulations the definition of a residue.It is any compound present in edible tissues of the target animal which results from the use of the sponsored compound including the sponsored compound, its metabolites, and any other substance formed in or on food because of the sponsored compounds use.

††††††††† Now, again, this harks back to 512(d)(2), and opens up that big door of in or on food because of the sponsored compound's use.This definition was derived principally in order to cover the issue of carcinogens, but it has been applied in a wider arena such that we use it basically as the standard definition of residue today.

††††††††† As I said before, because we do not have policy or guidance for other issues like antimicrobial resistance or transgenic animals at this time, it is premature to consider those areas with regards to import tolerance.And so, we will focus on the chemical residues.

††††††††† (Slide)

††††††††† The objectives of the human food safety evaluation are to determine the concentration of total residues in the edible tissues of a food animal that when consumed daily by an individual over a lifetime will cause no harm.

††††††††† This, in effect, is what we refer to as "the acceptable daily intake" or ADI, and that is what I will cover.I will actually take this one step further to the derivation of what we refer to as a safe concentration.

††††††††† In the next talk, Dr. Friedlander will carry on to define the concentration of a marker residue in the edible tissues of a food animal that will be indicative that the edible tissue is safe.This is a tolerance.

††††††††† (Slide)

††††††††† Underlying the evaluation are a number of factors that I think are important to keep in mind.The factors that need to be constant are the purity, strength, and identity, including the identity of the active ingredients and the formulation of the drug product.

††††††††† If we are evaluating something other than that which is going to be marketed and used, then we are operating in a vacuum and the evaluation has no sense.Also, in the human food safety evaluation, we assume that good agricultural practices have been applied, in that enough of the drug is going to be used to achieve whatever purpose is intended, but that only enough of the drug is going to be used.

††††††††† This is actually transgential to our evaluation, but it becomes important in establishing the tolerance with respect to the residue chemistry and depletion studies.

††††††††† (Slide)

††††††††† A bit of historical perspective.Originally, in the United States, we did not accept any detectable residues in food animal commodities.This is the no residue or zero residue tolerance.This was technologically limited in the sense that zero changed over time.

††††††††† (Slide)

††††††††† As we learned more, a universal truth was established, and tolerances for all drugs except for carcinogens were established at 0.5 part per million.This again included minimal, if any, hazard assessment.

††††††††† (Slide)

††††††††† And, as we gain knowledge about the effects of residue levels of drugs, the CVM moved to a risk-based assessment, which is effectively stated as the set risk, which is a reasonable certainty of no harm, would be equal to the evaluation of the hazard mitigated by a control of human exposure.

††††††††† (Slide)

††††††††† Put another way, the public health risk is regulated by assessing the potential hazard posed by the drug in controlling the exposure in order to meet the standard of a reasonable certainty of no harm.

††††††††† (Slide)

††††††††† The hazard assessment, which will be the subject of the rest of this talk, is composed of ‑‑ this is for chemical drug residues.It is composed of a number of toxicological studies including a genetic toxicity battery, 90-day feeding studies in rodents and other mammals, multi-generation reproductive studies, developmental studies in rats, and an evaluation of the potential effect of antimicrobial residues on the human gut flora.

††††††††† In certain cases, special studies are called for where a subchronic 90-day study is in completely reviewing, we may ask for a lifetime study, or a carcinogenicity studies may be called for based on the results of the genotype studies.

††††††††† (Slide)

††††††††† All testing is conducted through oral exposure in surrogate species.We do not have the luxury of using human exposure data accept in very limited circumstances due to the ethics involved with testing animal drugs in humans.So we look at surrogate species and expose them orally.

††††††††† (Slide)

††††††††† The objective is to define the concentration of drug substance that produces no effect in the toxicological assay of greatest relevance to human exposure, the no observed effect level or NOEL.

††††††††† Now, as kind of a loaded statement there, the toxicological assay of greatest relevance ‑‑ well, this is a matter of expert opinion.We run a full series of tox tests with no prejudice as to which might be the most relevant.

††††††††† The data often speaks for itself, but we also may need to consider what is the purpose of the drug in the animal and what may its potential worse case effect be in the human?That may drive us also.At this point, we introduce something that can only be explained as expert opinion.

††††††††† (Slide)

††††††††† The NOEL, or the appropriate NOEL is divided by a safety factor to obtain the acceptable daily intake, which is the amount of drug residue per kilogram body weight per day that can be consumed daily over the lifetime of a human without harmful effect.

††††††††† (Slide)

††††††††† Now, where do these safety factors come from?Again, back to the Act, Section 512(d)(2) says in part:

††††††††† "In determining whether such drug is safe, the secretary shall consider, among other relevant factors, safety factors, which in the opinion of experts qualified by scientific training and experience, to evaluate the safety of such drugs are appropriate for the use of animal experimentation data."

††††††††† (Slide)

††††††††† In our evaluation, we generally consider that the variability in human response is 10X.Now, you would have to speak to a cultural anthropologists, or someone else who understands this better than I, in order to understand why we are focused in-base 10 on factors of 10X.

††††††††† But these are tried and true, in the sense that if you can prove a negative, these have worked over the years and have been accepted internationally, not just within the United States.

††††††††† Also, because we work in surrogate tox species, there needs to be some compensation for the potential that a study in a rat will not be totally revealing with respect to what happens in a human, or in a beagle, or in a non-human primate.

††††††††† So, another factor may be introduced for the inner species extrapolation.Further, if we are relying on a subchronic exposure in order to establish what might be the chronic exposure effects, we may or may not add another factor of 10, so that the total possible ‑‑ and there is a mistake here.I apologize.

††††††††† The total possible safety factor that could be applied to the NOEL is anywhere from 1 to 10,000.We have examples of both extremes.But, for the most part, the vast majority of drugs evaluated fall somewhere in between.

††††††††† (Slide)

††††††††† So what does this all add to?As I have tried to show you the NOEL, which is micrograms per kilogram per body weight daily, divided by a safety factor, determined by expert opinion, results in generation of an acceptable daily intake, which is also in micrograms per kilograms body weight per day.

††††††††† The final step before going into the residue chemistry evaluation, is to define a safe concentration.The ADI is related to the total chemical residue exposure.

††††††††† This is multiplied by the average weight of an individual in the United States, which is currently considered to be 60 kilograms, and then divided by a consumption factor in order to determine the safe concentration for the total chemical residues in that edible commodity.

††††††††† These consumption factors are mutually exclusive.They are listed at the bottom.We consider, maybe not quite accurately, but we consider that if a person consumes 300 grams of skeletal muscle that they are not going to consume liver, kidney, or fat during that same day.They will not be exposed to the residues during that same day.

††††††††† The only point at which these are not mutually exclusive is for milk and eggs.If you have a drug which is for use in laying hens, the sponsor has a choice of partitioning the ADI so that some of it is for the egg, some of it is for the hen.

††††††††† Similarly, for a lactating dairy cow, if a sponsor is concerned about milk discharge, they can partition part or all of the ADI to the milk, one-and-a-half liters of milk consumed per day, and the rest would go to the other edible commodities.

††††††††† I know you all are hanging on the edges of your chairs waiting for the rest of the chemistry part.I think you will have to wait until after the break.

††††††††† (Slide)

††††††††† One last point that I would like to make is that the underlying assumptions that I illustrated before are not actually part of the human food safety evaluation as we have it divided up administratively in the CVM.

††††††††† The purity, strength, and identity issues are really in the chemistry and manufacturing control.We do not deal with them.We assume that they are being done and have been done, and history shows that they are done very well.

††††††††† Also, the good agricultural practice considerations are handled by the division, either the Division of Therapeutic Drugs for Food Animals, or the Division of Production Drugs for Food Animals, so that this is an area in which are not directly concerned.

††††††††† But, again, the evaluation that we do relies on these factors being constant, so that the drug that is used is the same one that we have evaluated.Thank you very much.Questions?

††††††††† (Applause)

††††††††† DR. LANGSTON:Any questions for Dr. Robinson?

Questions and Answers

††††††††† DR. KOCHEVAR:How problematic are those assumptions in facilities that the FDA has no knowledge of in other countries in terms of good manufacturing practices, the purity, strength, identity issues?

††††††††† DR. ROBINSON:Problematic, as was alluded to earlier, we deal with imports, principally, USDA deals with imports, but also FDA does on the basis of equivalency.There is equivalency for slaughter house operations.There is also equivalency with respect to the standards used in other regulatory environments.

††††††††† So it is a big problem if there is no regulatory environment in which the drug is being used.If there is a regulatory environment, and the drug that we are talking about is approved for use in that regulatory environment, which is really, if I can shade this, that is the only way that talking about import tolerances really makes sense, and we need to be aware of what are the standards in that environment.

††††††††† But the fact is that most of the environments, the regulatory environments of which I am aware, have similar standards for chemistry and manufacturing control.We would need to probably become more aware of the effect of those standards.

††††††††† DR. WOOD:In your underlying assumptions, one on the list is good agricultural practices.Is there a clearly identified list of good agricultural practices for approvals in the U.S.?And how can that be measured as we review imports from other nations?Is there a code of practice that is universal?And how easily and carefully can that be evaluated, is one of the assumptions, or parts of one of the questions that are before us.

††††††††† DR. ROBINSON:Right, and I think it is in question 1.This is an area that I cannot speak to well.There may be others who can.We have no list that we can hand you.The basic GAP that we live by is that through the evaluation of the new animal drug in one of the animal divisions, either production drugs, or therapeutic drugs, that they will look at the efficacy data.

††††††††† If the sponsor has proposed a concentration of a drug, or a frequency of use of a drug that achieves a purpose that can also be achieved by a lower concentration or less frequent use of the drug, based on their own data, then we will suggest strongly that they go for the lower concentration or less frequent use.That is really the extent of our participation.

††††††††† DR. WOOD:Does that same subjective principle apply for good management ‑‑ manufacturing practices as well?And that is not on your list, but it is a part of the question before us.

††††††††† DR. ROBINSON:No, GMP is very strict, very.There is books full of information on GMP's that need to be adhered to.

††††††††† DR. HASCHEK-HOCK:My question is:I assume that most countries also that do the ADI and the safe concentration, and if they do, do they use the same formula like 60 kilogram person?

††††††††† I could think of maybe some Asian countries where the average weight might be less.And the consumption factor, I would also assume that in some countries it would be a different consumption or a different ratio between those different types of products.

††††††††† DR. ROBINSON:Those are both valid points.The consumption factors would not make sense in other cultures in the average weight of an individual could vary.There are differences in different regulatory environments already.

††††††††† What is important to remember is that we would not take the product of the work in another regulatory environment.We would take the data that is presented to another regulatory environment, the EU Japan, and do our own analysis based on our own standards.

††††††††† So, to the degree that it is arguable that our average weight and consumption factors are relevant, it is kind of an abstract concept.But, to the degree that they are relevant, they are the standards that we would apply in the United States even to an import tolerance.

††††††††† DR. LANGSTON:And relative to that data that they provide to you, do you have any feel for the amount and quality of the data such that you can drive a NOEL?

††††††††† DR. ROBINSON:We have had a number of submissions for drugs which have already been approved for use in other regulatory environments.And the quality of data, honestly, has been as variable as the quality of data that we received for new animal drug applications that are just for drugs used in the United States.

††††††††† We look at it with the same eyes.This is for sponsors who have come in.They have a drug product approved, what's hypothetically in the EU, and they actually want to get new animal drug approval in the United States for use.

††††††††† The consistency of the data is generally good, and is generally revealing enough to establish a NOEL, sometimes not.Sometimes we need to ask for more.

††††††††† DR. KOCHEVAR:I wonder ‑‑ and this may just be a point where I need clarification.When we establish tolerances here for drugs, it has to be on the formulation that is actually used in that animal.Is that standard the same for drugs coming in, or can the data be related to just the active ingredient or the marker residue?

††††††††† DR. ROBINSON:That is really one of the questions to the committee.It is a bit of a circular argument.We establish a tolerance which is for a substance, and that is what is codified in 21 CFR 556.So I won't use any specific substance.

††††††††† Substance X may be an active ingredient in drug product use produced by a variety of companies in a variety of different formulations, but the tolerance is for that substance.But each drug product receives consideration for a tolerance, so the tolerance actually ends up being linked to the drug product.

††††††††† We need to figure out a way, if there is a way, to reverse engineer the relationship that we currently have, so that the detection of a chemical drug residue in an imported commodity could be related with some certainty to the use of a drug product over which we have some knowledge.

††††††††† DR. LANGSTON:The issue of the safety factors has always interested me, and as you alluded to that they all seem to be units of 10.And while I agree you have not had a problem, actually I do not know of human health consequence from a human ingesting a drug residue unless it was grossly high, such as no withdrawal time applied at all, for example.

††††††††† But, back to my point, has anyone ever looked at, for example, using two or three standard deviations of the NOEL instead of 10X?Or, in other words, what is the basis for these units of 10?

††††††††† DR. ROBINSON:I will answer the second part first.I think the basis for the units of 10 is that we have 10 of these things and we think that way.

††††††††† Yes, a lot of people have used a variety of means, and there are people here who can speak to this much better than I can on the risk-based approach to basically eliminating safety factors as a consideration.

††††††††† But, so far, we do not have the proof of the pudding or any standardized method so that we are sticking with the process that we have in place, and which has so far served as well.

††††††††† Yes?

††††††††† DR. WOOD:Just so that I am real clear, currently, as the FDA looks at tolerance levels for residues, then based on your earlier comments, there is no consideration or evaluation when it is an antimicrobial of resistance capabilities or dynamics?

††††††††† DR. ROBINSON:No, I am sorry if I gave you the wrong impression on that.We have been for the last four years considering the effects on changes in bacterial drug susceptibility due to the antimicrobial drug product.It is just that we do not have policy and guidance established for that.

††††††††† We have handled it on a case-by-case basis for the last four years.So it would be putting the cart before the horse to establish a process where describing an import tolerance when we do not have the same mechanism in place for drug approvals in the United States.

††††††††† DR. LANGSTON:Thank you very much.I believe that we will break until 9:45, if you could please assemble back here.Dr. Lynn Friedlander will take you the rest of the way to the derivation of a tolerance.

††††††††† (Whereupon, the meeting was adjourned for a short break.)

††††††††† MS. SINDELAR:Okay.Why don't we start the meeting back again?

††††††††† And let me introduce Dr. Lynn Friedlander, and she is going to speak on setting the tolerances.Thank you very much, Lynn.

Setting Tolerances for Drug Residues

by Dr. Lynn Friedlander

††††††††† DR. FRIEDLANDER:Good morning, everyone.Can you hear me all right?

††††††††† (No response)

††††††††† DR. FRIEDLANDER:I am Lynn Friedlander.I am currently the acting team leader for the Residue Chemistry Team in the Division of Human Food Safety.And our team is responsible for evaluating the scientific data that comes in to support the new animal drug approvals in food animals, specifically, the data that is used to establish tolerances and for our domestic approvals to set meat and milk discard times if they are needed.

††††††††† (Slide)

††††††††† Now, as Dr. Robinson pointed out, we are going to focus on chemical residues in this part of the presentation, as he did in his.There are potentially other benchmarks that could be used.But since we do not have guidance in place, I am going to stick to the chemical residue aspect.

††††††††† I kind of feel like I am getting a class of students back from their winter break or something, and I cannot tell how much you forgot while you were having coffee.So, the first thing I am going to do is I am going to sort of very rapidly rehash the material that Dr. Robinson went over.

††††††††† Ah, mood lighting, thank you.

††††††††† (Slide)

††††††††† This is our definition of residue.It is in the regulations.It is the same one you saw before.It is any compound in the animal tissues of the target animal formed as a result of the use of the sponsored compound.It is the parent drug.It is the metabolite.It is anything else basically.

††††††††† (Slide)

††††††††† We have already talked about the toxicity data that is generated as part of a domestic approval.I am not going to talk about the microbial safety data.As Dr. Robinson mentioned, this is an evolving area.The guidance is not there yet.

††††††††† So I am going to skip right down to the residue data in the food producing species.I am going to talk a little bit about analytical methodology, because that ties into the whole process.And then I did want to remind you that all of our food safety studies are done to conform to good laboratory practices.

††††††††† Dr. Robinson talked about the basic toxicology package.If we need it, we can ask for additional special toxicology studies.The end goal here is to calculate the no effect level, to assign an appropriate safety factor, and then to calculate the allowable daily intake.

††††††††† (Slide)

††††††††† There is the little formula.

††††††††† (Slide)

††††††††† We do a safe concentration, which is basically a way of spreading out the ADI over the kinds of food people eat so that consumption value is what we think people eat for any of the food animals derived commodities.

††††††††† (Slide)

††††††††† And the safe concentration is the amount of residue that can be eaten in any of the edible tissues each day for the entire life of the consumer without exposing them to more than the allowable daily intake.

††††††††† (Slide)

††††††††† Here is our risk equation.You have seen that before.And the goal of the residue group in the tolerance setting procedure really is to mitigate the hazard that has been identified by the toxicology studies.

††††††††† In a domestic approval that is accomplished by assigning tolerances, and, where necessary, withdrawal periods from meat, milk discard periods for milk, and eggs are a little special.They have a zero withdrawal that they have to comply with, or they are not approvable.

††††††††† (Slide)

††††††††† Dr. Robinson talked about the basic studies that go into doing tox.We also have a fairly defined set of studies that are basic to the tolerance setting procedure, the residue chemistry procedure.We look at comparative metabolism in the toxicology species.

††††††††† This is basically our link to everything that was done as part of setting up the ADI in the safe concentrations.So we do a little bit of work with rodents, or whatever the appropriate toxicological species is.

††††††††† We do total residue and metabolism.For the residue chemistry group, total residue means radiolabeled.So we are talking about drugs that have been appropriately labeled for a study, and then this is basically a mass balance kind of thing, and a metabolism study.

††††††††† The analytical method comes into play because it is a little hard to track metabolites if you do not have some sort of method.Total residue, it is easier to do without a method or an analytical method, a chemical method.But the metabolism actually requires that you have an analytical method, and so that is also part of the residue.

††††††††† The residue depletion withdrawal study is something we do for domestic approval, but it is not particular relevant to import tolerances because that will have been taken care of in the regulatory environment from which the food product originates.So that won't be something that would really fall into the import tolerance discussion.

††††††††† (Slide)

††††††††† The comparative metabolism study is done in usually rodents, and it is a way to decide whether the toxicology evaluated the right stuff.You feed drug to the toxicological species, but people do not eat rats, people eat cows.

††††††††† So the rat is serving as a surrogate for people, and you want to make sure that the rat has been exposed to the same sorts of things that people will be exposed to when they eat food.

††††††††† Generally speaking, we are looking at profile matching, making sure that the profile is comparable.If you come up with compounds that are not matched, if there are compounds that are found in ‑- that are not found in the toxicological species, that are subsequently found in the food producing animals, then we are probably looking at additional testing to cover that deficiency.

††††††††† (Slide)

††††††††† The total residue and metabolism study is probably the linchpin of what we do for food safety, in terms of the tolerance setting procedure.As I mentioned, this is a radiolabeled drug study.It is usually conducted at one to one-and-a-half times the proposed dose.

††††††††† This ensures that we see a full dose to the animals.We require that the company that sponsors the drug, administers the drug by the root of administration that will appear on the label.

††††††††† Now, this is in direct contrast to the tox studies which are all conducted orally.If a drug is going to be administered by subcutaneous administration, then we see total residue and metabolism study in the food producing animal by the subcutaneous root of administration.

††††††††† We also want to see the same kind of dosing that is going to be on the label.So if it is a three injection dosing regime, we want to see a three injection dosing regime.

††††††††† If it is feeding in the diet for an extended period of time, we are usually looking at a determination by the sponsor that they have attained steady state, and that keeps them from having to do studies for six months, or ten months, or whatever.

††††††††† We also want to see it in the intended species.What this means is that every time a sponsor comes in for a new species indication, they are looking at doing this total residue and metabolism study again.So you do it for cattle; you do it for swine; you do it for chickens.There is not very much material that crosses over for another species.

††††††††† We would like to see it in both male and female animals unless there is some peculiar reason why that would be inappropriate, say, a drug is only approved for one gender.

††††††††† The total residue and metabolism study does two things, two very important things:It determines the marker residue; and it determines the target tissue.The marker residue is the residue that will be used to monitor depletion of total residues in all of the tissues.The target tissue is generally the edible tissue that depletes most slowly.It is not always the case, but generally that is true.

††††††††† And, most often, it is liver or kidney, and that should be no surprise to you.The organs of elimination are usually pretty well-loaded with drug on the way out.Very rarely, we find that the target tissue is muscle or fat.

††††††††† The total residue and metabolism study also provide a metabolism profile in the food producing animals.This is what we are going to go back and compare to the toxicological species.This is where we are going to do our comparative matching, make sure that what was in the rat is also in the cow, or the pig, or the chicken.

††††††††† We use this total residue and metabolism study to establish or marker to total ratio.The marker to total ratio is what is going to allow us to calculate a tolerance.

††††††††† (Slide)

††††††††† Analytical methodology is a little hard to fit into the talk because it sort of comes in very early, but a lot of it is not completed in its final form for regulatory purposes until somewhat later.

††††††††† We are basically looking at two kinds of analytical methodology:  A determinative method, something like HPLC, will measure concentrations of drug residue in the edible tissues; and then we are also looking for a comfirmative method, something like LCMSMS, that will verify the identity of drug residue.

††††††††† This is important when we take cases to court and we need to be able to say that what we found really is what we say it is.Screening methods are important because they are rapid, but the are not required for an approval.

††††††††† General speaking, what we ask is that drug sponsors show us how their new drug is going to perform in existing screens, so we know if something is not going to continue to function the way it has functioned in the pre-approval process.

††††††††† (Slide)

††††††††† This is one of, I think, only a couple of pictures I have got for you, but pictures usually at least wake people up a little bit.What we are basically doing a plotting of total residue and the marker residue.

††††††††† We have identified the marker residue.We have identified the target tissue.We have plotted total residue.This is the radiolabeled component.What we are looking to do is find out how long it takes total drug residue to deplete to the safe concentration.

††††††††† Remember, the safe concentration is the allowable daily intake adjusted for food consumption.What we want to see is when that happens.When does total residue deplete to the safe concentration?

††††††††† Now, in this graph I have got it coming off just a little bit after three days.We also want to know what the concentration of the marker residue is at that same time because this is what is going to allow us to establish the tolerance.

††††††††† The concentration of the marker residue in the target tissue at the time the total residues have depleted to their safe concentration is what we call the tolerance.

††††††††† (Slide)

††††††††† So here it is, all the word, and the pink tolerance.

††††††††† (Slide)

††††††††† You can establish a tolerance for any tissue for which you have the appropriate data.In the past, we have done it for just the target tissue; sometimes we have done it for all of the edible tissues; sometimes we do it for target tissue and muscle.

††††††††† You have to have the data to support your assignment.The good news is that most of the time these data are already available as part of the package.So, in many cases, you are not asking for additional information or additional work.

††††††††† (Slide)

††††††††† Graphically, you see it here, the tolerance and its relationship to the safe concentration and total residues.

††††††††† Now the target tissue tolerance monitors all of the edible tissues of the entire carcass.When the concentration of the marker residue in the target tissue is less than target tissue tolerance, total residues in all of the edible tissues are less than their respective safe concentrations.This is the one true statement we can make.

††††††††† (Slide)

††††††††† If we have set a non-target tissue tolerance in addition, say, we set a tissue tolerance for muscle.We cannot guarantee that the muscle is speaking for the entire edible tissues from that animal.What we can say is that when the muscle tolerance has depleted to the muscle, when the concentration in the muscle has depleted to the muscle tolerance, the muscle is safe.

††††††††† We cannot make any assumptions beyond that.We make it very clear that the muscle tolerance speaks only for muscle and no other edible tissues, unless it is one of those rare cases where in fact the muscle has been determined to be the target tissue.

††††††††† (Slide)

††††††††† Now, the important part about the tolerance is it forms the link between the toxicology, the ADI and the safe concentrations, that are handled by the radiolabeled studies to cold residue studies.And that is important because we do not market radiolabeled drugs.We market final formulation, and we need to have a regulatory analytical method that can track the marked residue from those marketed products.

††††††††† (Slide)

††††††††† Here it is graphically, toxicology results, radiochemistry results tie into a tolerance in the analytical method.On the right-hand side, you see withdrawal time and milk discard time.These would be important for a domestic approval, but they would not be important for an import tolerance.

††††††††† (Slide)

††††††††† What is important is that the withdrawal time and the milk discard time appear on the product label in the United States.They appear in the relevant sections of the CFR.The tolerance is always in 21 CFR 556.

††††††††† (Slide)

††††††††† Now, one of the questions that has been asked of the VMAC Committee is, I believe it is question number 2, and that has to do with linking data from products to tolerances.As Dr. Robinson pointed out, we assign tolerances based on the chemical, but we do so having reviewed a product package.

††††††††† From this little graphic, which is where I am going to finish, you can see that for domestic approvals, we have a formulation that comes in formulation A with an original data safety package.From that, we calculate a tolerance for that, and then anything relevant to it such as withdrawal time.

††††††††† Subsequent approvals in the United States, and these are very often generic approvals, must link to that original tolerance.We do not have multiple tolerances in the CFR for the same chemical.

††††††††† And so, formulations that are approved following what we would call the pioneer must either link to the original data, and this is usually a bioequivalence study; or they must confirm the original data with studies of their own.

††††††††† This is probably the trickiest part of question 2, because in the international arena we may not have a mechanism to confirm this linkage the way we would normally have it in the domestic approvals because we would have seen not only the package for formulation A, but for all of the subsequent derivatives of formulation A.

††††††††† That is about all I have for you.I am glad you were able to stay awake after the coffee and the muffins.If we have time, I will be happy to answer any questions.

Questions and Answers

††††††††† DR. HASCHEK-HOCK:I have a question in regarding to the formulation.Can you give some examples or indicate what percentage of cases there are where the formulation has affected the tolerance?

††††††††† DR. FRIEDLANDER:Most of the time where we see multiple formulations for the same chemical, we are seeing it as generic products.And generic products buy their way into that original safety package.So they can literally buy their way into that package; or they can do, for example, blood level bioequivalent studies.

††††††††† So, in many cases, we do not see the same package for one of these second, third, fourth compounds.What we see is blood level bioequivalent study.And then, in all likelihood, we see a final residue depletion study to either confirm or assign a withdrawal time for that second, third, fourth compound.

††††††††† So it is a little difficult to say whether or not they would match the package completely, because we do not see the same package for them.They have certainly demonstrated equivalence by what we consider a suitable package, in terms of bioequivalence.

††††††††† DR. HASCHEK-HOCK:That answers part of the question.But other examples, would companies not submit packages where formulations do not show blood level equivalency?

††††††††† DR. FRIEDLANDER:As part of the review process, we are entitled to see, and are supposed to see data packages that both support and do not support whatever a company is offering as a product.

††††††††† So if they have studies that, perhaps, are truncated for some reason, a blizzard wipes out a herd of cows or something, we are supposed to see as much of that study as there was.

††††††††† Similarly, if there are data from Europe, whether or not that data supports the position they have, in terms of their pending U.S. approval or not, we are supposed to see that. Data which are not supportive of whatever you want in the United States are not supposed to be hidden from us.

††††††††† DR. KOCHEVAR:I think also on the second half of her question, has there ever been a case where products have been shown to be bioequivalent, but then showed different data at the end of the road for a tolerance level?Has that ever happened?

††††††††† DR. FRIEDLANDER:When you demonstrate bioequivalence with blood level studies, or clinical endpoint studies, that essentially gives you the tolerance.You do not repeat the studies to support the tolerance.

††††††††† DR. KOCHEVAR:But I thought you said there was one study they did have to do.

††††††††† DR. FRIEDLANDER:They have to do the residue depletion study that sets the withdrawal time.

††††††††† DR. KOCHEVAR:Okay.And so, has that ever been different between bioequivalent products?

††††††††† DR. FRIEDLANDER:I could not say specifically.The calculation of the withdrawal time in many cases gets down to the exact conditions of the study.This is particularly true if the withdrawal time is long, because we will only assign withdrawal times that are whole days.We do not assign three-and-a-half days.We do not think anybody would follow that in practice.

††††††††† When you get to more extended withdrawal times, the statistics associated with setting the withdrawal time can throw out numbers that are slightly different, so we can get numbers that are like ‑‑ maybe the pioneer number is 30 days.

††††††††† Because of the statistics involved in the calculation, you can throw out numbers that are like 29 days, or 31 days.We would consider that essentially the same, and it is just that they did not have the exact same animals, in the exact same feedlot, on the exact same days.That is the number crunching part that is throwing out those numbers.

††††††††† DR. MACDONALD:Alex MacDonald.The residue hazard assessment for the total residue looks at that total residue with two assumptions:(1) that the total residue is available to the second species, i.e., man; and (2) that that total residue retains the bioactivity of the original drug, the biological profile.

††††††††† There is a provision that, in effect, to evaluate that residue in terms of its bioavailability to the second species, the bioavailability to man, as to that portion that is absorbed or not absorbed, and the second part is to evaluate that portion that is absorbed in terms of retained the bioactivity of the original molecule upon which the ADI and the tolerance is set.

††††††††† This is in place.The provision is there.This was not mentioned in any of either Dr. Robinson's presentation or yours.How is this viewed today, in terms of evaluating residue exposure to man?

††††††††† DR. FRIEDLANDER:We generally assume that all of the residue is equally toxic.We generally assume that all of the residue is equally bioavailable.If a sponsor wishes to conduct the additional testing to demonstration otherwise, that is certain their option.

††††††††† What we are looking at is for drugs that are not readily available by the oral route, essentially, a demonstration by the sponsoring firm that this is the case, that it was an overly conservative assumption on our part that everything was available and toxic.If they can provide the data that shows us otherwise, then we will certainly consider that in our evaluation and our assignment of the tolerance.

††††††††† I would anticipate that if these data were available for a compound that was being considered for an import tolerance, we would also evaluate those data at that time.

††††††††† DR. MACDONALD:It is interesting that the bioavailability of residues is an integral part now, in fact, a required part for a contemporary application for an MRL in Europe.

††††††††† DR. HASCHEK-HOCK:I need to go back to my original question.And maybe, obviously, a company does not need to present a formulation which does not reach blood level equivalency because the would perhaps just go back and reformulate.

††††††††† But is there any information available that formulation really does affect the toxicity of the compound?

††††††††† DR. FRIEDLANDER:We see a number of formulations in the course of product development.Often these are presented to us as ‑‑ we do not know what the formulation is.But it is going to be so much active ingredient, and plus or minus this inactive, and plus or minus this inactive, and we will see a range.

††††††††† Often those data are subsequently fine-tuned.And, in many cases, all we see will be the single, the winner formulation, if you will.I think part of the reason for that is that the drug development process is very expensive, and most companies do not want to follow formulations that are not going to be successful.And, of course, success is defined in a number of different ways.

††††††††† DR. LANGSTON:I might comment on that.Typically, I would presume that if it is not available, meets those criteria, it would have equal efficacy and toxicity.The only exception to that, relative to a formulation that I am aware of would be if there is a difference in isomers that were not detected by the assay, where you have one active isomer and different ratios.

††††††††† DR. WOOD:One of the questions that we are to address has to do with the environmental impact of tolerance levels.Is that factored into any of the impact ‑‑ into any of the tolerance setting procedures?

††††††††† DR. FRIEDLANDER:I think Dr. Robinson is going to talk about environmental.

††††††††† Environmental is handled by a different group from the food safety group, so I cannot really address it in any extent.It is certainly part of the approval process that we evaluate the environmental.

††††††††† DR. LANGSTON:Just for clarification for the committee, would it be correct to say that one of the issues we have to look at is oftentimes, we are not getting the target tissue in an import like the liver or kidney assay.

††††††††† A big question for us will be if muscle is coming in, what if that we cannot detect at that level in the muscle?Is that a fair paraphrasing?

††††††††† DR. FRIEDLANDER:Very often levels in the muscle are quite low.Before we could consider an import tolerance ‑‑ and I think this is very important.We are going to essentially review an entire application as part of an import tolerance, the entire food safety application.We won't be looking at target animal safety, obviously.

††††††††† If there is not enough information in that package to let us evaluate the produce the way we would want to evaluate it for domestic approval, it is not going to be ‑‑ an import tolerance is not going to happen.

††††††††† We will probably be sending letters back and forth that say, "This is what we need that is more, that wasn't in your package."This is an ongoing, even in a domestic approval, this is an ongoing dialogue with firms as to whether or not we have seen everything we need to see if they could present something differently, or more raw data, you know, presented in a different way to make it more understandable for us.

††††††††† I think the most important component is that for import tolerances muscle is going to be a significant tissue of import and we need to have something that allows us to address what is in muscle.

††††††††† Now, it may be that the level that is in muscle is so low that it is not a concern.You do need to match up all of your numbers with your method performance, and that is a significant component in any approval domestically.The method has to perform at the level of food safety concern.

††††††††† DR. KOCHEVAR: There was a portion of the notebook that we received that regarded the issue of differences between sanitary and phytosanitary measures in different countries, and how there is this ‑‑ there is a need to consider the level of development of a certain country in order to reasonably expect them to meet a standard.

††††††††† At your level of the regulatory process, is that at all part of your consideration, or is that something that is evaluated totally separately, in terms of ‑‑

††††††††† DR. FRIEDLANDER:Of course, right now we are only doing domestic approval.So it is not really part of the equation directly.It certainly is part of the equation in terms of source of bulk drug.I do not know if that falls under the phyto and SPS agreement or not.

††††††††† But, certainly, for a bulk drug coming in, as part of domestic approvals, the bulk drug that is subsequently formulated into drug in this country, that certainly is an equivalence issue.

††††††††† DR. LANGSTON:I took that as being taken from Codex rather than the FDA.Was I correct about that in the handout?

††††††††† (No response)

††††††††† DR. LANGSTON:Hearing no objection, I think it is.

††††††††† DR. KOCHEVAR:So, the answer is you do not.I mean that is not that we evaluate a product, and that that is a separate and not related issue in terms of how you arrive at a final tolerance withdrawal, and all of that stuff.

††††††††† DR. FRIEDLANDER:Correct, but I would couch that in the fact that we are now working in the domestic arena for our approval so.

††††††††† All right.Then it is my pleasure to turn the podium over to Merton Smith.

Codex and International Aspects

by Merton Smith

††††††††† MR. SMITH:Thank you, Lynn.I am happy to be here this morning.This will be somewhat of a change of pace from the previous speakers.The non-toxicologists in the audience may think it is a welcome change of pace.

††††††††† Because the Codex Alimentarius has adopted a number of tolerances for animal drugs in foods, we thought that it would be useful to address this group and describe the responsibilities of FDA with regard to considering and utilizing international standards, and standards of other trading partners.

††††††††† These responsibilities are described in various places in international agreements that the U.S. has signed, in U.S. laws, in U.S. regulations, and in U.S. guidances and policies.

††††††††† Codex Alimentarius is an international organization that sets food standards under the auspices of the World Health Organization, and the Food and Agriculture Organization, both U.N. agencies, for those of you that might not have been aware of that.

††††††††† (Slide)

††††††††† First, I would like to look at some of the major trends, societal trends, business trends, regulatory trends that have caused FDA to become more involved in what I am going to call just generally international harmonization.That is not in its broader context international harmonization.

††††††††† I mean by that, not only harmonizing requirements, but also looking to see if differing requirements are equivalent, assessing the equivalence, and just looking outside of our domestic activities and not working in a void, but looking outside to other countries and other organizations.That is what I mean by international harmonization.

††††††††† (Slide)

††††††††† First of all, if there is one thing I want everybody to get out of this, if you will look at this slide, I think it is the most dramatic and most important depiction of why FDA has moved into the area of international harmonization.

††††††††† You can see that the number of imports coming into the United States has increased exponentially, particularly, since 1995.This slide was taken from a presentation given by one of our deputy commissioners a couple of years ago at the FDLI meeting.

††††††††† You can see at the bottom that, at that time, our full-time equivalents, or the number of people working at FDA had changed very little; whereas, the number of imports, as I said, has increased exponentially.

††††††††† I went back and looked at data just the most recent data from the year 2001, and it continues to rise.It is up to 8 million imports in 2001.To be fair though, the FTEs, we have gained some FTEs, but obviously not enough to handle this kind of increase in imports.

††††††††† So FDA's involvement in international harmonization is also dictated by the fact that we have to be more efficient with the resources that we have in looking at the safety of imports.

††††††††† (Slide)

††††††††† Going back to the other factors, trends that have influenced our involvement in international harmonization, the demand for quick consumer access to new products.Obviously, the internet and the media has made consumers very aware of products that are available in other countries.

††††††††† This has put sort of a pressure on FDA to consider what is going on in other countries and other international organizations.The European movement toward a unified market, this began in the late 1980's.There was a program in the European Union called the Single Internal Market by 1992.

††††††††† At that time, the Commerce Department involved FDA in looking at directives that were being proposed by the EU, and looking at the technical aspects of those directives to give advice to the Commerce Department, as to whether or not they made sense, and whether or not they were in accordance with what the U.S. did.

††††††††† Bilateral and multilateral trade negotiations, and I will talk about this more in a few minutes.But, obviously, NAFTA, which took effect in 1994, and the WTO, the Uruguay round legislation are negotiations that resulted in the formation of the World Trade Organization, which took effect in January of 1995, are two of the most important of these kinds of trade negotiations that had an effect in bringing FDA into international harmonization activities.

††††††††† New legislative mandates.This is primarily FDAMA in some of the requirements, and I will go over that in a few minutes too.

††††††††† (Slide)

††††††††† Recommendations for increased international harmonization.These recommendations have come from a number of sources.I won't go through all of these, but just to give you an idea of both external groups and internal FDA studies have really dictated that FDA become more involved in international harmonization activities.

††††††††† The Food and Drug Law Institute in 1988, said something about integrating FDA's policies with U.S. business policies.So that is quite a statement.The advisory committee on FDA in 1991, the so-called Edwards Committee recommended that FDA must strengthen its efforts to harmonize regulatory standards, particularly, with major trading partners.

††††††††† The administrative conference of the United States a body that makes recommendations to regulatory agencies about how they do administrative law.They made similar recommendations about becoming involved and more cognizant of international standards and standards of other countries when we develop our own standards.

††††††††† The White House Council on Competitiveness obviously thought that this involvement by FDA would increase the U.S. competitiveness, business competitiveness.There was a World Health Organization resolution in 1992 that supported harmonization of drug regulations.

††††††††† The FDA Task Force on International Harmonization came out with a report in 1992.I have it here.We took over a year to interview ‑‑ basically interview what we thought were the most important stakeholders in this issue.

††††††††† There were about 75 organizations that we went to to get opinions about how FDA should be involved in international harmonization.These were, as I said, inside FDA, as well as outside.Some of the recommendations that came out of this report are that:

††††††††† !FDA should enhance its participation in activities that promote the international harmonization of standards; FDA should work to enhance international cooperation in the areas of enforcement and compliance;

††††††††† !FDA should evaluate its current product approval programs for the purpose of developing innovative approaches to achieve international harmonization;

††††††††† !FDA should strengthen its dialogue with outside groups concerning its international harmonization activities; and

††††††††† !FDA should enhance the effectiveness of its technical cooperation with foreign governments and international organizations.

††††††††† The report also emphasized that FDA needed to determine how many resources should go into this.And so, over the years we have become more involved in all of these activities, and we have dedicated more resources to doing this.

††††††††† There is a couple of policies that FDA has published in the area of international standards and international memorandum of understanding; the National Performance Review:Reinventing Food Regulations in 1996.

††††††††† There is also an OMB circular that encourages agencies to use international standards that promote the desired degree of health and safety protection. There are regulations, Commerce Department regulations, that describe the responsibilities of federal agencies, in that they should use relevant guides and standards for conformity assessment practices.These are like doing inspections of manufacturers.

††††††††† (Slide)

††††††††† In the area of international agreements, as I mentioned, NAFTA and the WTO or Uruguay round agreements are the major ones.There are other trade agreements of course.Environmental agreements, science and regulatory cooperation agreements.

††††††††† In fact, FDA over the years has had over ‑‑ currently, we have over 50 agreements with foreign regulatory counterparts.All of these support FDA's international harmonization activities in one way or another.Some of them are more prescriptive, but most of them are very general and talked about cooperating with regulatory counterparts.

††††††††† (Slide)

††††††††† These are the provisions within the NAFTA, the sanitary and phytosanitary measures of NAFTA.They are very similar to what are in the SPS agreement as part of the Uruguay round.So let me just go, for the sake of time, go to the WTO provisions for SPS.

††††††††† (Slide)

††††††††† The first one here is a clear recognition.It is important that this trade agreement recognizes that countries obviously have a right to adopt and enforce measures necessary to protect health.

††††††††† Secondly, countries should ensure that measures are applied only to the extent necessary to protect health, and measures must be non-discriminatory.We cannot subject one country's imports to different measures than another country unless there is a scientific or legitimate reason for doing that.Measures shall be based on scientific principles and not be maintained without sufficient scientific evidence.

††††††††† (Slide)

††††††††† The importing country must accept measures as equivalent if the exporting country objectively demonstrates to the importing country that measures achieve the importing country's appropriate level of protection.

††††††††† So this is a provision that encourages the determination of equivalence between countries that have differing regulatory requirements.Equivalence means that although the requirements are different, overall they have the same level of health protection.

††††††††† So this is an important concept that Dr. Robinson alluded to earlier.Measures shall be based on international standards except where they provide a higher level of protection, and then they must be scientifically justified.

††††††††† This is a very important principle of the SPS agreement.SPS agreement mentions the Codex Alimentarius as a recognized international organization.There is one article, or one point that I did not put on this slide, and that is in Article 7, that member countries need to be transparent, especially where they have regulatory requirements that are more stringent than international standards.

††††††††† In that case, they have that notify all of the WTO member countries.This is like 140 countries have to be notified that these standards are being changed in whatever country, and there is a process that sort of ‑‑ there is a central notification point in each country.

††††††††† In the United States for SPS measures, it is in the Department of Agriculture.They coordinate all of these notifications with other agencies throughout the U.S. government, and agencies can then comment back to the notifying ‑‑ the country that is notified of pending regulatory changes.

††††††††† (Slide)

††††††††† Turning to the area of FDA legislation, before 1997, that is before the FDAMA was enacted, as I mentioned, that FDA has entered into over 50 agreements.The oldest agreement to my knowledge is in 1948.I think it was a shellfish agreement with Canada.

††††††††† So, obviously, FDA thought that they had authority to enter international harmonization activities.The authority that we based these agreements on until 1997, or we still base the agreements on these authorities are listed here.I am not going to go through all of them.

††††††††† (Slide)

††††††††† But let me turn to the FDAMA, the FDA Modernization Act of 1997.The critical language in FDAMA that relates to what we are talking about this morning is that FDA must participate with other countries to reduce the burden of regulation, harmonize regulatory requirements, and achieve reciprocal arrangements as determined to be appropriate by FDA in consultation with experts in science, medicine, and public health, and in cooperation with consumers, users, manufacturers, importers, packers, distributors, and retailers of regulated products.

††††††††† So the verb here, "must participate," is fairly strong, but it is qualified by "as determined to be appropriate by FDA."And also, there is the transparency requirement that we consult with all of the stakeholders that are involved in setting up standards to reduce the regulatory burden on industry and harmonize regulatory requirements.

††††††††† (Slide)

††††††††† Also, FDAMA requires that FDA must support USTR in meetings with other governments to discuss ways to reduce the burden of regulation and harmonize regulatory requirements for medical devices.So this just covers medical devices and it is very specific.

††††††††† But it is qualified by the statement that harmonization is consistent with the purposes of the Food, Drug, and Cosmetic Act.And, of course, there is no purpose section in the Act, but it is understood that the main purpose of the Food, Drug, and Cosmetic Act is to protect the public health.

††††††††† (Slide)

††††††††† Also, FDAMA states that, "FDA should support USTR in efforts to move toward acceptance of mutual recognition agreements relating to the regulation of drugs, biological products, devices, food additives, and color additives in the regulation of good manufacturing practices between the European Union and the United States."

††††††††† This provision is restricted to good manufacturing practices, but all of the products that FDA regulates are covered, most all of them.It is between the FDA and its counterparts in the European Union.

††††††††† (Slide)

††††††††† Turning to regulations that relate to international harmonization, there is a regulation that covers food standards in Section 130.6, called Review of Codex Alimentarius Food Standards.In 1997, FDA proposed, or at least published it in advance notice of proposed rulemaking that ‑‑ stated that it was planning to amend these requirements.

††††††††† These requirements deal with just commodity standards, Codex commodity standards, and not the general standards that ‑‑ the so-called horizontal standards, for example, the standards that cover animal drug residues that we are dealing with today.So in this ANPR, FDA was going to amend these regulations to incorporate procedures to deal with the horizontal or general subject matter, Codex regulations.

††††††††† There has not been a proposal yet, partly, because our Center for Food Safety and CVM are trying to determine the level of resources that would be required to enact this kind of a procedure, particularly, if it, as it deals with the retrospective review of existing Codex standards; and also CAFSN is looking at their policies with regard to food standards.

††††††††† These are so-called recipe standards for different food products.They have not, even over these number of years ‑‑ it is a very difficult issue, and there has not been much progress in that area yet.But it is something that could obviously affect how we will ‑‑ if we go ahead and propose something, it would possibly affect how we would deal with Codex standards in setting these import tolerances.

††††††††† Part 26 is a regulation that we implemented as a result of implementing the Mutual Recognition Agreement.In the area of pharmaceutical GMP, the MRA, so-called MRA agreement between the European Union and the United States, one annex of which covers pharmaceutical GMPs, and includes veterinary drug manufacturers, veterinary drug GMPs.

††††††††† There is a transition period as part of that agreement.But we thought that agreement was so significant and placed a number of FDA resources in this area, that we thought that it was appropriate to propose the agreement.

††††††††† It is the first time that in an international agreement that deals with FDA regulated products has gone through rulemaking.So we basically codified the international agreement in the area that covers FDA products.

††††††††† Here is another example of draft guidance that has not been finalized yet in the area of equivalence criteria for food.There are a number of issues there that we are trying to deal with, particularly, the Center for Food Safety, that are very difficult issues, and much is the concern is based on concerns about how many agency resources will be required to do these kinds of equivalence assessments.

††††††††† (Slide)

††††††††† Let me just turn quickly to what other ‑‑ what my knowledge of what other agencies do, as far as looking at Codex ‑‑ in particular, Codex, the existence of Codex standards in their areas, or in the case of APHIS, the existence of standards under the International Office of Epizootics.

††††††††† APHIS, in their veterinary services, sanitary international standards team, works with the OIE on international standards for diagnostic tests, vaccines, in the safe international trade in animals.

††††††††† It is my understanding that APHIS does consider OIE standards when it develops U.S. requirements, but that if there are differences they usually do not provide an explanation for the basis for those differences.

††††††††† And, again, this is a concern about the number of resources that would be required to look at all of those differences and to explain the scientific basis for those differences.

††††††††† The same is true with the Food Safety and Inspection Service.They obviously need to be aware and are aware of existing international standards in areas where they develop domestic standards, but they do not take the initiative to go a step further to explain why if their standards are more stringent, why that ‑‑ what the basis of that is.

††††††††† The EPA is different, at least in the area of their current review of pesticide tolerances.This is based on legislation in 1996 called the Food Quality Protection Act.

††††††††† Under that legislation, the Congress required that EPA consider Codex standards in the area of pesticide residues, and also required that if there were differences between EPA's tolerances and Codex tolerances, then it had to be explained what the basis of those differences were.

††††††††† So this has been a huge effort by EPA.They have relied primarily on the private sector petitioning EPA to provide that information, but it is still to review all of that information and they have had some problems.

††††††††† (Slide)

††††††††† So, in summary, FDA's primary goal with regard to its international harmonization activities is to preserve and enhance its ability to accomplish its public health mission including maintaining high standards of protection, enhancing regulatory effectiveness, and increasing worldwide consumer access to safe, effective, and high quality products.

††††††††† (Slide)

††††††††† Trade agreements permit, obviously, permit the establishment of, and enforcement of measures that provide a level of protection considered appropriate by the importing country.Measures may be more protective than international standards, but they must be science-based and serve to effect the importing country's chosen level of health protection.

††††††††† Where consistent with consumer protection purposes of the Food, Drug, and Cosmetic Act, FDA must harmonize requirements and seek appropriate reciprocal arrangements based on determinations of equivalence.

††††††††† (Slide)

††††††††† FDA's regulations satisfy the obligations of NAFTA and WTO because they are non-discriminatory, solidly grounded in science, and based on what the United States has chosen as the appropriate level of protection.

††††††††† So, with that, if anyone has any questions, I would be happy to entertain them.

Questions and Answers

††††††††† MR. SMITH:Yes?

††††††††† DR. WOOD:I know that VMAC and the questions before us deal with policy.And, yet, in your presentation, you raised the concerns at several points about the ability of the agencies to respond in terms of staffing to the needs for harmonization and all.

††††††††† So I guess this is just a general question.But, I mean, what are the ‑‑ will there be agency issues in terms of responding to any of the import tolerance questions that we answer here that we need to be aware of, or are we in an area again of another unfunded mandate or something?

††††††††† MR. SMITH:Well, our response to date is primarily questions that have been raised as potential trade barriers, questions that go to our U.S. trade representative, or the Department of Commerce questioning the scientific basis for some of our requirements, for example.And, of course, those agencies come to FDA.

††††††††† And, with regard to resources to do that itself, without considering any kind of additional program, particularly, any kind of retrospective review of existing Codex standards, for example, that kind of program in my mind would place a huge burden on FDA, and I do not know that it would be an effective use of our resources.

††††††††† It is going to be difficult just dealing with import tolerances that come down the pipe to ‑‑ obviously, we will consider the existence of Codex standards.But if we had to explain why our standard was more stringent, that would involve a lot of resources.

††††††††† I do not know if I can talk to the center with regard to whether we are going to have resources to do that kind of work.But I think I can say that if there were a judgment from you folks that we needed to be doing something like EPA has to do, which I do not think they would do unless Congress had required them to do it, essentially, in legislation.

††††††††† I think if we had to embark down that path, we would be relying on the private sector to do a lot of the work obviously.But just to check and make sure that if they claim that what tolerance they want is the same as the Codex tolerance, there is a lot more effort in pesticide residues.

††††††††† Codex does not have that many animal drug tolerances set, not as many as pesticide tolerances, but it would still be a significant burden.And I suspect to have resources dedicated just to responding to trade disputes mediated by Commerce and USTR, that is going to take a lot of effort by CVM.Thank you.

Seafood:Safety & HACCP

by Dr. Kim Young

††††††††† DR. YOUNG:Thank you, Aleta.I will do my best to get us back on time, because I know the lunch time is coming up and people are starting to get hungry.

††††††††† Chairperson Langston, CVM members, guests, my name is Kim Young.I just recently became the deputy director for the Division of Compliance with the Center of Veterinary Medicine.

††††††††† And, before that, before I came to CVM, which was last October, I was the aquaculture specialist within FDA's Center for Food Safety and Applied Nutrition Bulks of Seafood.I also did a lot of work with the Seafood HACCP with that position.

††††††††† (Slide)

††††††††† One important commodity that will be affected by import tolerance is agriculture.Aquaculture is different than your meat and poultry, being that aquaculture is regulated by Food and Drug Administration, on the farm by CVM in regards to the drugs used, and also by the feed that is fed to the fish; and then, from the farm, to the consumer, to the Center for Food Safety and Applied Nutrition overseas, the food processing.

††††††††† So, to give you some background on aquaculture, my presentation today will view first an overview of the global aquaculture production.I will get into the countries which export aquaculture products to the United States; and I will touch bases into what the FDA's concern of global veterinary drugs used in aquaculture.

††††††††† (Slide)

††††††††† To begin with, what I would like to do is give you the definition of aquaculture, as defined by the Food and Aquaculture Organization of the United Nations.The definition is:The farming of aquatic organisms including fish, mollusks; mollusks being your oysters, clams, mussels, scallops; crustaceans, that would be your shrimp, crayfish, lobsters; and aquatic plants.

††††††††† Farming implies some form of intervention in the rearing process to enhance production, such as regular, stocking, feeding, protection from predators.And then, it goes on from there basically explaining that it does not matter whether the aquatic organisms are commercially or privately owned.

††††††††† (Slide)

††††††††† On the global side of things, in 1999, which is the most recent figures I have, 32.9 million metric tons of aquaculture products were destined for direct human consumption.In other words, this figure does not include the ornamental fish that are grown, nor does it include the aquatic plants that are grown in aquaculture.

††††††††† In recent years on a global basis, the aquatic industry has been growing by approximately 9.2 percent per year.If you look at that today, one in every four finfish that you consume is from aquaculture; and every one in three shrimp that is consumed ‑‑ this is on a global view of things ‑‑ are from aquaculture; and that in the year 2007, FAO predicts that 50 percent, over 50 percent of food fish that we will be consuming will be from aquaculture.

††††††††† (Slide)

††††††††† This slide will give you a better perspective.This graph shows how the aquatic industry (in green), how it has been growing during this past decade, and how the commercial, or the wild card industry has been pretty much flat for the past decade.Again, go along with what FAO predicts, that in the year 2007, if the green and the blue columns will be equal.

††††††††† (Slide)

††††††††† Now, most of the farm seafood comes from Asia, which produces about 90 percent of the global volume, and approximately 82 percent of the value of aquaculture products.This continent's main finfish production is carp, which has not developed a market here in the United States as of yet.

††††††††† One concern FDA has is with a large majority of the aquacultural production, representing the last two bullets, that most of the production is in developing countries, which do not have the elaborate drug approval process that we have here in the United States, if they have any approval process at all.

††††††††† (Slide)

††††††††† The top 12 countries that produce aquaculture, the principal producers, this is 1998, again, with the FAO was the source of the information, the top 10 actually are from Asia.

††††††††† As you can see, China is number one with 68.7 percent of the aquaculture grown in that country, because it is followed by India, Japan, Philippines, Indonesia, South Korea, followed by Bangladesh, Thailand, Vietnam, North Korea.United States is 11, and then followed by Norway, being 12.

††††††††† Again, I want to emphasize we are looking at the countries that produce most of the aquaculture in the world.

††††††††† Now, here in the United States, the per capita consumption of aquaculture products is 15.6 percent.This is based on the National Fisheries Institute, which is an association in the United States that tracks the consumption of the seafood.

††††††††† And, based on the data from NFI, and also other reports that are published, along with conservative estimates on my part, I figure that approximately five pounds or 32 percent of the total seafood consumed is from aquaculture.

††††††††† And based again on data taken conservative estimates, I figure that 3.8 pounds of the 15.6 pounds is actually imported from other countries, and which it represents about 24 percent of the seafood that we consume here in the United States is aquaculture that is imported.

††††††††† (Slide)

††††††††† Going over the top 10 products consumed in seafood, see what I have outlined in yellow, shrimp, salmon, and catfish are aquaculture products, principal aquaculture products, where figuring that shrimp and salmon both are approximately 75 percent aquaculturally grown of what we consume here in the United States; and catfish, which approximately 100 percent of what we consume of catfish is aquaculturally grown.

††††††††† So what I did was base my figures on ‑‑ or my consumption of what is aquaculture and what is imported based on those three commodities, or those three species.I did not include other products that we import, such as tilapia, trout, striped bass, what we import, or what we consume.

††††††††† (Slide)

††††††††† The major aquaculture products that are exported to the United States will be salmon and shrimp, which is actually 90 percent of the over 44,000 aquaculture shipments sent to the United States in one year representing salmon and shrimp.

††††††††† And, as the previous speaker had on the graph, the number of imports are growing quite fast.Other products that import, the mollusks, tilapia, and trout, striped bass, frogs, catfish, and crayfish.

††††††††† (Slide)

††††††††† What I want to do on this slide and the next slide is just to show you where we are importing our products from, our aquaculture products.This is over a period of one year.We have 62 countries exported aquaculture products to the United States.

††††††††† As you can see, they ‑‑ wide ‑‑ it was a quite range in there infrastructure, government infrastructure, and their abilities to determine the drug approvals.

††††††††† What I have outlined in yellow are the countries that have exported over 500 shipments to the United States during a one year period.Bangladesh is a low income country, as described by FAO, and it exports shrimp, trout, and striped bass to us.

††††††††† Canada, their main product that they export to the United States is salmon; Chile is salmon; Honduras, principal product they send to us would be shrimp; India, shrimp; Indonesia, shrimp.

††††††††† (Slide)

††††††††† Mexico, shrimp; Norway, big exporter os salmon to us; Philippines, shrimp; Thailand, shrimp; and United Kingdom, which is salmon from Scotland.Again, I just wanted to emphasize the wide range of countries with wide range of government infrastructure.

††††††††† (Slide)

††††††††† One benefit of import tolerance is that will allow approval of tolerances for drugs in seafood species that are currently not raised here in the United States, at least, of any significance.

††††††††† Since these species are not being raised here in the United States, the drug companies have no economic incentive to pursue FDA approval for a drug being dispensed in these species.

††††††††† Examples of major farm species that are not commonly marketed in the United States are your carp, which is widely grown in China; your grouper, which is grown in Hong Kong; and cod, which is in major development right now in Norway.

††††††††† (Slide)

††††††††† Examples of drugs being used in farm aquaculture.On this slide and the next slide, I have listed the name of 33 drugs that one Asian country has approved for use in aquaculture.For those of you that are knowledgeable in pharmacology, you may question how a country can allow some of these drugs to be used.

††††††††† I have highlighted five drugs that are based on CVM's present knowledge will not be given import tolerance.These drugs are chloramphenicol, flumequine, furazolidone, your oxolinic acid, and malachite green.

††††††††† The good news is this country current exports only a few aquaculture products here to the United States.And also, in the United States, we have a hazard analysis and critical control point regulation for seafood, which I will touch bases with later.

††††††††† And, as a result, any drugs that have been used in this foreign country, Asian country, they make sure that none of that product is being exported here to the United States.

††††††††† (Slide)

††††††††† The drugs that are currently approved for aquaculture ‑‑ as you can see, there are only six.You have your chorionic gonadotropin; your formalin solution; you have your tricaine methanesulfonate, also known as MS-222; oxytetracycline; sulfamerazine, which is approved, however, is presently not marketed by the drug company; so you have your sufadimethoxine/ ormetroprim combination.

††††††††† So those are the only drugs currently approved here in the United States.

††††††††† (Slide)

††††††††† With Seafood HACCP, this is an area that is being overseen by the Center for Food Safety Applied Nutrition, part of FDA, and in here the misuse of veterinary drugs in aquaculture is a concern through the agency, and is reflected in this Seafood HACCP regulation.

††††††††† In 1997, the agency implemented the Seafood HACCP regulation.It requires all processors ‑- these are processors domestically and foreign ‑‑ that they must develop a HACCP plan for those drugs or those hazards which are reasonably likely to occur. We have identified that drugs used in aquaculture are a reasonably likely to occur hazard.

††††††††† The HACCP program consists of seven principles which I have listed here.First is the hazard, where a firm must identify the hazard, and the hazard being unapproved veterinary drugs in aquaculture.These could also be mentioned unapproved.It could also be misused of approved drugs.

††††††††† Where would a firm determine or control this hazard is at, for example, receiving to ensure that the farm that they are receiving their products from are using drugs correctly, that they have records.

††††††††† Critical limits would be no drugs above tolerances, tolerance levels; and you get into monitoring procedures, corrective actions, verification procedures, and where records have to be kept by the processing facility.

††††††††† (Slide)

††††††††† How do we current enforce this, the HACCP regulation?

††††††††† Well, under the regulation, all importers have to ensure that the seafood products that they import have been processed under the same standards as required domestically.

††††††††† This includes the foreign processor being required to document that the raw fish that they have received has not been treated with an FDA unapproved drug, and that an FDA approved drug has been used properly.

††††††††† The FDA does perform verification of foreign compliance with these regulations.For one, we do ‑‑ FDA does do foreign inspection of the foreign processors, and also of the producers.

††††††††† We review the HACCP plans at the importer, where the importer must keep records of what is happening overseas to ensure the food safety.We also have a drug testing program going on.

††††††††† We do have import alerts.An import alert is where, if we find that a foreign processor is not in compliance with our regulations, or we do some drug testing and we find that their residues will put the product from that firm on an import alert, whereby, that product is not allowed into the United States until that foreign entity can show that drug residues are not there, or that their HACCP plan or their implementation of HACCP is fully in place.With the drug residues, we have the import alert 16124; and for the HACCP plan implementation, we had 16120.

††††††††† (Slide)

††††††††† So what are we doing for drug testing?

††††††††† Currently, we have few drugs that we are testing for.We were testing for chloramphenicol in shrimp; flumequine in catfish and shrimp; malachite green in catfish; piromidic acid in shrimp; oxolinic acid in catfish, salmon, and shrimp; and oxytetracycline in shrimp.

††††††††† The Center for Veterinary Medicine currently has approximately 20 drugs that is in ‑‑ that they are determining methods, some stages of development.So we are working on having more methods for testing in seafood.And as they are determined, they will be put into the program for testing of foreign products.

††††††††† (Slide)

††††††††† We also have a database for drugs and chemicals used in aquaculture.Right now, we are gathering information on that.The Center for Veterinary Medicine has engaged the services of a contractor to collect drug usage data from foreign countries that export to the United States.

††††††††† The data includes information such as the types, amounts, and use patterns of drugs and chemicals used in the countries, in a foreign country's aquaculture industry.As the information is gathered, a human food safety risk assessment will be conducted.

††††††††† (Slide)

††††††††† The FDA used the results of this project basically to prioritize the monitoring of the drugs and chemical residues in the edible tissue of imported aquaculture products.When I say edible tissues, that would be the flesh and the skin of the finfish.

††††††††† We will use the information to prioritize the development of methods to be used in monitoring programs.I would say we have approximately 20 methods that we are developing now.

††††††††† If we find that there is a drug that is being used that we do not have queue, we will change our priority to get a method for determining residues of that drug in the flesh; and provide a basis for promoting discussions with foreign countries regarding the hazard concerns identified by the risk assessment.

††††††††† (Slide)

††††††††† So how do we encourage the import tolerances for these countries?

††††††††† The driving force, basically, would enforcement of our current regulations.Actually, this year we have increased foreign inspections.We have increased drug residue testing with additional drug methods in place.

††††††††† And also, not allowing current or future shipments from firms not complying with the regulations to be imported into the United States will create the need for foreign countries to send us data for developing import tolerances.

††††††††† (Slide)

††††††††† In summation, the demand for seafood in the United States and the world cannot be sustained right now by the wild catch alone.Aquaculture is becoming more and more important.Aquaculture must now and even more in the future provide a significant portion of the fish consumed in the United States given that:

††††††††† (1)FDA unapproved drugs are used in foreign countries.We have established that.

††††††††† (2)The U.S. is importing more and more aquaculture products.

††††††††† (3)That FDA's role is to protect human health.The agency needs a regulatory means of assuring that possible drug residues in aquaculture are safe.

††††††††† Mr. Chairman, and VMAC members, we look forward to hearing your thoughts on how the FDA might best regulate import tolerances.Thank you for listening.Any questions?Yes?

Questions and Answers

††††††††† DR. WAGES:Do we currently export any fish to any other countries?And, if so, who to?

††††††††† DR. YOUNG:We are major importers; we are also major exporters of seafood.With regards to aquaculture products, what we are exporting ‑‑ it is not ‑‑ I am trying to think myself what are our aquaculture products ‑‑ not that much at this time that I can think of right now.We were exporting some catfish.However, the market for ‑‑ the dollar exchange, et cetera, has dried up that market for the catfish industry.

††††††††† DR. WAGES:The reason I ask is if we have three listed drugs that we use ‑‑‑ to the United States, it was not listed on your international use of drugs.

††††††††† I was wondering if we exported fish, how do they view, or what tolerances are set, or how do they set their tolerances on importing drugs that are not used in their country?

††††††††† DR. YOUNG:We are working with them trying to develop equivalencies with the foreign governments where they will go along with what, how we are enforcing our regulations.

††††††††† For seafood, the biggest one right now is the seafood HACCP regulation, in which we send the certificates saying that the firms here in the United States are following the compliance.

††††††††† We only send those certificates when we know we have been to the firm, their HACCP paper work, et cetera, that they are in full compliance.This also, the domestic process in their HACCP verification, goes to the farmer to ensure that drugs are not being misused.

††††††††† DR. GLENN:I have a question regarding the ‑‑ let's see, the drugs for which you said we will not receive U.S. import tolerances.I assume those are the ones that are not approved for use in the United States?

††††††††† DR. YOUNG:Correct.They are not approved here in the United States, correct.

††††††††† DR. GLENN:And you are testing for drugs in muscle tissue of various aquaculture species that are being imported.What level is acceptable in that testing process?

††††††††† DR. YOUNG:Okay.Those drugs that we are testing for, no residue is acceptable, zero tolerance.

††††††††† DR. MACDONALD:Recently, in the last couple of months, the EU has banned the importation of shrimp from three Asian countries because of chloramphenicol residues.Has this affected your operations for those three countries on monitoring shrimp?

††††††††† DR. YOUNG:We are, let's say, we do monitor.We have increased our monitoring for shrimp for chloramphenicol in shrimp.We can always do it more.But, as of yet, to my knowledge, I have not heard that we have any positives for the chloramphenicol in shrimp.

††††††††† DR. MACDONALD:Excuse me.To put that, the importation of seafood into perspective, I was told that the importation of seafood, both aquaculture and wild caught, currently in dollar volume ranks number three on the importation into the United States with oil first, cars second, and seafood third, is that right?

††††††††† DR. YOUNG:Correct, that is what I have heard also.But the United States is also one of the ‑‑ we fluctuate between first and second for the main importer of seafood into the United States, but that can also include your fish meals for fish for non-human consumption.

††††††††† DR. PARKHURST:As a point of clarification, when you are doing, who does the inspections, like the foreign inspections, and the drug testing?

††††††††† DR. YOUNG:The foreign inspections, we have a cadre of investigators that do go overseas for inspection.The drug testing, we test that ‑- we collect the samples at our borders, and it is done by FDA.

††††††††† DR. PARKHURST:Would it be reasonable to have the importer be responsible for some of that?

††††††††† DR. YOUNG:Under the HACCP regulation, the importer needs to verify that the product is safe that is coming into the United States.They can do the testing themselves.We will look at what they ‑‑ they have paper work to see how they are ensuring safe food.

††††††††† The product is under import alert that it is covered by the import to do the testing.But what we are doing, FDA verifies that the HACCP is being implemented correctly.So we are testing to ‑‑ for means of verification.

††††††††† DR. MACDONALD:On the HACCP, does the HACCP business go all the way back to the pond, or does it start at the port?

††††††††† DR. YOUNG:Okay.The HACCP regulation has written stops at the processor.In other words, it starts at the processor by the regulation at receiving.However, it indirectly affects the aquaculture in that the processor has to ensure that the drugs used on the farm are to be used correctly.

††††††††† DR. GLENN:So could you clarify that?The HACCP, seafood HACCP is on farm HACCP, is that what you said?

††††††††† DR. YOUNG:Well, the regulation starts at the processor.It starts at the processor.However, the processor has to address any hazards that are reasonably likely to occur, and having drug residues is a reasonably likely to occur hazard.So they, at receiving, they have to make sure that any product that they take through their doors has not had any unapproved drugs or misuse of approved drugs.

††††††††† So, even though our regulation does not go back to the farm, the farm is affected by the processor itself whether they want to do business with them or not.

††††††††† DR. LANGSTON:As clarification, I know many of the industries in the United States have voluntary online inspection.When you say inspection of the plant, it is really their HACCP cooperation and testing of tissues?It is not an online inspection as APHIS would perform here?

††††††††† DR. YOUNG:Okay.For HACCP, it is regulation.They must ‑‑ it is not voluntary.You have two programs out there.You have the National Marine Fishery Service, which has a voluntary HACCP program, which deals in some other aspects of HACCP, and also for firms that want ‑‑ this is the domestic side of things that want to go with food lunches, they have to be in the voluntary.

††††††††† FDA, it is mandatory, and we do spot inspections.This is where HACCP has helped us, and where before when we did inspections, it was just a ‑‑ what was the firm doing at that time we were there,

††††††††† Now, with HACCP the firm needs to have records.We looked through the records to ensure that they have been following good manufacturing practices or good procedures 365 days a year.

††††††††† DR. WOOD:But, again, those HACCP programs are only in domestically produced?

††††††††† DR. YOUNG:It is required both domestically and foreign ‑‑ for foreign.The way we verify is a little bit different where domestically we can go to the domestic firm processing facility at any time.Foreign is a little bit different where we need to go through foreign governments before doing inspections.

††††††††† With this seafood HACCP regulation, we are going to the importers.This is the first time we go to the importers and look at their records, where mostly the importer will have the foreign firm's HACCP plan on site.We would look at the HACCP plan to ensure that they are looking at the hazards that we feel are reasonably likely to occur.If their HACCP plan is not in compliance, then we will put them on an import ‑‑ import alert which I referred to.

††††††††† DR. LANGSTON:I wan to make sure I am clear on this.So both domestic and foreign have FSIS inspectors?

††††††††† DR. YOUNG:Okay.This is not an FSIS.This is food and drug.They are not there all of the time, we do have a cadre of inspectors ‑‑ cadre of inspectors that do foreign inspection.So we will go over there and look at their HACCP plans in the firms to ensure that they are in compliance with FDA's regulations.

††††††††† DR. LANGSTON:And domestically?

††††††††† DR. YOUNG:And, domestically, the same thing.We have our inspectors that go to the firms ensuring that needing our regulations.

††††††††† DR. LANGSTON:Okay.When I said online, I was referring to FSIS.That was the confusion.

††††††††† DR. YOUNG:Okay.

††††††††† DR. WADDELL:Which agency is looking at bacterial contamination of imported fish?

††††††††† DR. YOUNG:Okay.The FDA is at acrobic.You are looking ‑‑ referring to salmonella listeria, et cetera, FDA does.

††††††††† DR. KOCHEVAR:Are there any microbial resistances used with fish?

††††††††† DR. YOUNG:That is getting in an area that ‑‑ I mean, those are problems.So when you start to ask specific questions on that, I am not up on all of the issues to be able to fully address you there.But there are problems, yes, or concerns, I should say.

††††††††† DR. LANGSTON:Any other questions?

††††††††† (No response)

††††††††† DR. LANGSTON:Thank you.

††††††††† DR. YOUNG:Thank you.

††††††††† (Applause)

††††††††† MS. SINDELAR:Thank you, everyone, and the hotel's restaurant is located on the lower level.If you walk around to the right, there are stairwells, as well as an elevator, to go down.And it is called Papa John's Restaurant.And there is, for the VMAC members, a room called the Hideaway.So it is recessed in the back for the VMAC members.Thank you.

††††††††† (Whereupon, the meeting was adjourned for lunch.)






(1:07 p.m.)

††††††††† MS. SINDELAR:We are going to get restarted.And I would like to introduce to you, John Prucha from FSIS, USDA.It is a real pleasure to have him here with us this afternoon.

Compliance with Tolerances for Imported Meats

by Dr. John C. Prucha

††††††††† DR. PRUCHA:Okay.Thank you.Good morning ‑‑ good afternoon.My name is John Prucha.I am the assistant deputy administrator for Program Coordination and Evaluation, Food Safety and Inspection Service, U.S. Department of Agriculture.

††††††††† With me today, are two of my colleagues from FSIS who I would like to introduce to you:

††††††††† Mr. Clark Danford, who is sitting back there.Clark, raise your hand.Right.Clark is the executive assistant to my office, and he developed and organized my presentation today.

††††††††† And Rita Kishore.Rita is the principal scientist in FSIS, who plays a key role in designing the National Residue Program, which I am going to mention to you today.

††††††††† (Slide)

††††††††† As I think you know, the Food Safety and Inspection Service is the agency in the federal government responsible for meat and poultry inspection.The purpose of my presentation today is to briefly explain how USDA enforces animal drug tolerances in meat and poultry products that are presented at U.S. ports of entry for import into the United States.

††††††††† Specifically, I will explain how USDA's Food Safety and Inspection Service enforces U.S. import requirements through the reinspection of imported meat and poultry products.

††††††††† (Slide)

††††††††† First, I would like to call your attention to the word "reinspection."It is important for you to understand that all meat and poultry products that enter the United States originate from countries with meat and/or food regulatory systems that have been determined by FSIS to be equivalent to the U.S. system.

††††††††† Thus, every pound of imported meat and poultry product has been inspected and passed by a foreign food inspection service before it is shipped to the this country.In addition, the competent of the foreign government issues a certificate that accompanies the product.

††††††††† This certificate guarantees in writing that the product has been produced in full compliance with all U.S. import requirement.At the U.S. port of entry, FSIS conducts a reinspection of this product as part of its ongoing verification of continuing foreign country equivalence.After the product passes reinspection, it is then released into U.S. commercial channels, and, in essence, becomes domestic product.

††††††††† (Slide)

††††††††† During calendar year 2000, a total of 30 countries exported meat or poultry products to the United States.Most of these countries are relative low volume exporters.

††††††††† (Slide)

††††††††† The overwhelming majority of meat and poultry products, a little bit more than 85 percent, comes from just three countries:Canada, Australia, and New Zealand, three highly developed countries with equivalent meat and poultry inspection systems that are very similar to the U.S. domestic system.

††††††††† In fact, the United States, Canada, Australia, and New Zealand, hold periodic quadrilateral meetings to coordinate joint positions on food safety issues, and discuss equivalent measures to address public health concerns.FSIS plays key role, a key and important role in these equivalence discussions.

††††††††† (Slide)

††††††††† I think it is important for you to understand how FSIS makes equivalence decisions concerning foreign food regulatory systems including programs for monitoring and controlling chemical and drug residues in meat and poultry.

††††††††† Currently, FSIS recognizes 34 countries as having equivalent systems for regulating meat and poultry products.As I said earlier, 30 of them are current exporters.We do not certify individual foreign slaughter or processing establishments for export to the United States.

††††††††† Rather, FSIS requires the foreign competent authority, generally, the chief veterinary officer, to certify which establishments meet all U.S. import requirements.

††††††††† FSIS can trust the foreign competent authorities establishment certifications, and the health certificates that accompany each shipment of product exported to the United States because we have previously evaluated their foreign meat and/or poultry inspection system, and found it to be equivalent.In matters of equivalence, I must hasten to note, FSIS policy can be summarized as "trust but verify."

††††††††† (Slide)

††††††††† An equivalent foreign food regulatory system is one that provides the same level of public health protection achieved under our domestic system of meat and poultry regulation.The system's approach to equivalence holds foreign governments accountable for their food regulatory program and provides a basis for FSIS to trust the health certifications that provide us.

††††††††† Foreign inspection system equivalence is initially determined and periodically verified through an evaluation process.Central to that process are what we call the triad components of equivalence.

††††††††† (Slide)

††††††††† They are document analysis, which is an examination of the official issuances of a foreign food regulatory system.And, in particular, the documents have set forth its sanitary measures.

††††††††† Another component of the triad is on-site audit, in which FSIS visits the foreign country and verifies that it is delivering the program described in its official issuances.

††††††††† A third leg of the triad, port of entry reinspection during which FSIS reexamines meat and poultry products from each country that exports to the United States.

††††††††† The first two components, document analysis, and on-site audit, are used to determine the equivalence of a country when it initially applies for eligibility to export meat or poultry products to the United States.

††††††††† Thereafter, FSIS adds the port of entry reinspection component to complete its equivalence triad.It is interesting to note the recurrence of these three components.

††††††††† (Slide)

††††††††† A major document analysis is performed when a country first applies for an equivalence determination.The documentation submitted by a foreign country for an initial equivalence evaluation includes a full description of its food animal husbandry practices to include veterinary drug usage, the National Residue Control Program in place toensure compliance with government standards, and laboratory results of samples tested.

††††††††† Thereafter, document analyses occur as necessary when new sanitary measures are applied to their inspection system either on initiative of the foreign country, or in response to a new FSIS import requirement.In other words, it is an as-needed event.

††††††††† (Slide)

††††††††† Similarly, an extensive on-site team audit performed before a determination of initial equivalence is made.The purpose of an initial equivalence audit is to verify that the foreign government is delivering the program it described in its inspection system documentation.

††††††††† Initial equivalence audits include visits to farms and feedlots, a discussion of veterinary drug practices, and an on-site review of laboratory practices and competencies.Thereafter, system audits are conducted at least annually in each country that exports meat or poultry products to the United States; thus, audit are, for the most part annual, events.

††††††††† (Slide)

††††††††† Port of entry reinspection by comparison of frequency is conducted each and every day on each and every shipment of imported meat and poultry at dozens of foreign entry points all along the parameter of the United States.So reinspection, you see, is a continuous daily activity.

††††††††† (Slide)

††††††††† Today, as this meeting is being conducted, FSIS import inspectors are conducting verification reinspections on some part of the nearly four billion pounds of meat and poultry products that are imported annually.

††††††††† Another point I would like to make concerns a manner in which reinspection is conducted.

††††††††† (Slide)

††††††††† Presently, every imported meat or poultry shipment is checked by FSIS at a U.S. port of entry to ensure that the paper work is complete including the health certificate which is essentially a government-to-government letter of guarantee that the product has been produced in full compliance with all U.S. import requirements.

††††††††† Every shipment is also examined for obvious transportation damage, or overt signs of spoilage.Under our current system, certain shipments are randomly selected for additional reinspections as directed by our automated import information system, which is a computer system that generates import reinspection tasks for our inspectors and records their findings.

††††††††† For example, one shipment of boneless beef might be selected to be thawed out and examined for blood clots; another shipment may be sampled for analysis of certain chemical residues; while still another shipment might be examined to make sure the listed net weight is accurate.

††††††††† When a shipment is selected for chemical residue reinspection, FSIS takes a sample of the product and conducts laboratory analyses for violative levels of certain veterinary drugs or pesticides.

††††††††† (Slide)

††††††††† While FSIS does not set the tolerances for these residues, we do enforce them to the best of our ability.

††††††††† (Slide)

††††††††† For example, in the case of veterinary drugs, FSIS commonly draws samples of animal muscle tissue during port of entry reinspection, analyzes those samples for residues using tolerances determined by the Food and Drug Administration, and takes regulatory action against violative product.

††††††††† The basic criteria for FSIS regulatory action is stated in our code of federal regulations as follows:

††††††††† (Slide)

††††††††† "Animal drug residues are permitted in meat and meat products if such residues are from drugs which have been approved by the Food and Drug Administration, and any such drug residues are within tolerance levels approved by FDA unless otherwise determined by the FSIS administrator and listed herein."

††††††††† (Slide)

††††††††† In cases where FSIS finds the residue of a veterinary drug, which has not been approved by FDA, and thus has no established tolerance, our long established policy is that the meat or poultry tolerance is zero.

††††††††† (Slide)

††††††††† When a violative veterinary drug residue is found by FSIS during port of entry reinspection, several things might occur.If the product sample was taken and analyzed by FSIS before the shipment is formally presented for reinspection, as if often the case when an importer wants to hold the product until it clears residue analysis, we would mark the violative product as "'refused entry,'" and cause it to be removed from the United States under the control of the competent authority of the exporting country.

††††††††† (Slide)

††††††††† If the product had not been held pending laboratory results, again, this is the importers choice, it would subject to recall and destruction or diversion into non-human food, into non-human food use, just as if it had been produced domestically.

††††††††† The violative product could not be returned to the country of origin or shipped to any other country because it is adulterated under U.S. law and FSIS would not certify it for export.

††††††††† So you can see that import tolerances for animal drugs are taken very seriously by FSIS, and our enforcement activities can have a substantial impact on U.S. meat and poultry importers, as well as on foreign exporters.

††††††††† It would, however, be disingenuous of me not to mention some constraints on our ability to monitor for veterinary drug residues in imported meat.One limitation is the fact that some drug tolerances are set only for organ tissue.Most of what FSIS seize at port of entry is muscle meat.

††††††††† As I stated earlier, FSIS policy is that the residue tolerance in meat is zero if no acceptable level has been determined.Practically speaking, if we did find the residue of an approved drug in muscle meat, we would consult on a case-by-case basis with FDA to determine whether the level detected should be considered violative.

††††††††† Another very significant constraint on FSIS import residue monitoring is the fact that we have finite chemical laboratory resources measured both in capacity and capability.

††††††††† And, as managers, we must apportion those resources appropriately to both domestic and imported products.The tool we use for making those resource decisions is our National Residue Program.

††††††††† (Slide)

††††††††† The FSIS National Residue Program is the principal mechanism for monitoring and controlling the presence of violative residues in meat and poultry products.

††††††††† The National Residue Program has several goals.It is a tool to enforce U.S. law and the residue control regulations issued by the U.S. Department of Agriculture, FDA, and the EPA.As such, it seeks to build and maintain consumer confidence in the safety of our nation's meat and poultry food supply.

††††††††† By its existence as a national monitoring tool, it serves as a deterrent to drug abuse in food animal production.It is a mechanism for the assessment and communication of human exposure to chemical residues.And, in the domestic arena, it provides FSIS a means to verify residue control measures in the production of U.S. meat and poultry products.

††††††††† (Slide)

††††††††† National Residue Program resources are distributed across several different analytical components.The monitoring, special projects, surveillance, and enforcement components are part of the Domestic Residue Control Program.We can set those aside today except to note that most National Residue Program resources are devoted to domestic purposes.

††††††††† (Slide)

††††††††† For example, in the year 2000 National Residue Program, FSIS apportioned 84 percent of its laboratory samples to domestic components, and 16 percent to the import component, which is what FSIS implements during port of entry reinspection.By way of comparison, it is interesting to note that imports make up less than 5 percent of the total U.S. meat and poultry consumption.

††††††††† (Slide)

††††††††† Planning for the import residue plan begins concurrently with domestic planning and is carried out in four phases.They are:Phase I, during which compounds of public health interests are identified and ranked; Phase II, where compounds are selected for inclusion in the program; Phase III, in which compounds are paired with product classes; for example, certain antibiotic residues in a certain species of food animal; and Phase IV, when the samples are allocated.

††††††††† (Slide)

††††††††† Phase I in National Residue Program planning is an annual meeting of the Surveillance Advisory Team, an interagency committee composed of members from USDA, FDA, EPA, and CDC, Center for Disease Control and Prevention.

††††††††† The Surveillance Advisory Team generates a comprehensive list of chemical residues of public health concern in meat and poultry and egg products.The compounds are then ranked for relative public health concern using techniques and principles from the field of risk assessment.

††††††††† (Slide)

††††††††† In Phase II, compounds and compound classes are chosen from the ranked list for inclusion in the annual National Residue Program.The selection line is drawn at a percentile in the Phase I ranking list, based upon public health concerns.

††††††††† However, some of the selected substances might not be included in the final National Residue Program, due to nonavailability of laboratory resources.In other words, FSIS must apply non-public health criteria at this point to select compounds and compound classes for the final National Residue Program, based upon laboratory capacity and capability.

††††††††† A further cut is made between domestic and import sampling with a substantial majority of sampling allocated to the domestic program.This is entirely logical and appropriate.

††††††††† (Slide)

††††††††† Keep in mind that all imported products have already been inspected and passed under an equivalent foreign inspection system that has implemented an equivalent National Residue Program.Thus, a National Residue Program Import/Residue Program of the United States is a secondary verification constructed for inclusion in the FSIS port of entry reinspection system.

††††††††† As such, it is part of our larger equivalence verification process that I discussed earlier, which includes document analysis, specifically, a review of each exporting country's annual residue program plan, and annual on-site audits to verify implementation of the plan.The National Residue Program annual planning process continues in Phase III with identification of compound and product class pairs.

††††††††† (Slide)

††††††††† What actually happens is a matrix of product and compounds is constructed.Products such as fresh beef, processed beef, fresh pork, et cetera, are listed on one axis, while drugs or drug classes are on the other.

††††††††† At each intersecting product drug class square, a mark is placed to indicate its status in the current National Residue Program.This is simply an exercise to match up drugs with the animal species they can be used in, and display the sampling status of that pair in the current National Residue Program.

††††††††† (Slide)

††††††††† Finally, National Residue Program planning is completed in Phase IV, where sampling resources are allocated.For the import residue plan, this involves some calculations.You may be pleased to hear that I will not go into all of these calculations here today.

††††††††† In essence, a formula has been developed to allocate samples.The formula incorporates product class as a percentile of total imports, and the drug ranking scores developed in Phase I.Resulting scores determine the number of import samples per year by product class and substance.

††††††††† These samples are then allocated on a country-by-country basis depending on their level of imports in each product class.The results of National Residue Program import residue planning is a four column table, and example of which, from the 2000 National Residue Program, has been included in your handout.

††††††††† You might want to refer to it at this point.It is in the back of the handout that you all have.You should have a list of tables back there.No, it is not in there.It is the handout that was in the back of the room.Do you all have one of those?You will see some tables.

††††††††† You do not have one?Clark, could you grab?Yes, they were in the back there.It is not that difficult to follow along.But if you have one, it makes it a little bit easier.

††††††††† (Distributing handout)

††††††††† DR. PRUCHA:Okay.This is pretty simple.But you will see that the columns are titled, "country, product, compound, and number of samples."It should be in the back pages of that handout.

††††††††† (Slide)

††††††††† The country column is a list of countries that are active exporters of meat and/or poultry products to the United States.The year 2000 import residue plan listed 30 countries.

††††††††† (Slide)

††††††††† The product column lists product classes.In the 2000 plan, they ranged from as few as one product class per country to as many as 17.

††††††††† (Slide)

††††††††† Most of the meat and poultry product imported into the United States is fresh meat, and that of course is mostly what we sample for residue levels.Thus, tolerances for fresh muscle tissue are important to our import reinspection program.

††††††††† (Slide)

††††††††† The compound column lists the drugs or drug classes selected for import residue testing.In 2000, they were the same as those selected for the domestic program, but FSIS could select different compounds for sampling during import reinspection.

††††††††† An interesting point that I would like to make is that FSIS presently does not test imported meat or poultry products for animal drugs that are used in foreign countries, but are neither approved nor banned in the United States.

††††††††† We simply do not have the resources, nor, in many cases, the methodology to so.But, keep in mind, as I discussed earlier, that we have previously determined that the foreign country's National Residue Program is equivalent.We do conduct annual on-site audits to verify that the annual residue plan is being carried out as described in the foreign country.

††††††††† (Slide)

††††††††† The number of samples column is really the bottom line.In year 2000, FSIS sampling ranged from a minimum of eight annual samples per compound, per product class, per country, to a maximum of 220.Most samples were at the eight per year level.

††††††††† (Slide)

††††††††† In closing, you have heard today how FSIS enforces animal drug residue tolerances in imported meat and poultry products through random sample monitoring of products during port of entry reinspection.

††††††††† The sampling program we administer during import reinspection is one part of our equivalence triad, with additional verification provided through review of each country's annual residue plan, and annual on-site audits to observe foreign residue control programs in operation.

††††††††† The goal of FSIS is to verify that every country exporting meat or poultry products to the United States has an equivalent residue control program.While exporting countries are not required to have a residue control program identical to ours, they must demonstrate that the program they have provides the same level of public health protection achieved domestically.

††††††††† (Slide)

††††††††† (Phone rings)

††††††††† Okay.With that ring, that concludes my presentation.That was perfect timing wasn't it?Thank you very much.And I would be happy to answer any questions that you might have.

Questions and Answers

††††††††† DR. PRUCHA:Yes, sir?

††††††††† DR. WAGES:Question.If a country is importing beef, or, let's say, any product ‑‑

††††††††† DR. PRUCHA:Any meat product?

††††††††† DR. WAGES:Any meat product, yes.And they are using something like chloramphenicol, which is illegal in this country.

††††††††† DR. PRUCHA:Correct.

††††††††† DR. WAGES:We will have the potential to check or chloramphenicol prior to it coming into the country, in the U.S.?

††††††††† DR. PRUCHA:Well, actually, that drug ‑‑ our laboratories do have the competency.

††††††††† DR. WAGES:To do that?

††††††††† DR. PRUCHA:To do that.But we have not included, as an example, specific example, we have not included that drug in our import reinspection sampling.The point I was making is that there is a number of reasons why we do not do that, and I touched on a number of those reasons.

††††††††† We put our emphasis on the country's monitoring program, the exporting country's monitoring program.And, as evidenced by the documents that they submit to use annually, which are verified by our auditors when we send them to the foreign country.

††††††††† DR. WAGES:Could you explain the slide, the not equal to/equivalent?What did you mean by that slide again, a couple of slides back?

††††††††† DR. PRUCHA:That was the whole gist of what I was trying to explain to you all, is that ‑‑

††††††††† DR. WAGES:I understand but ‑‑

††††††††† DR. PRUCHA:That we do not require a foreign country to have a mirror image, exactly the same so-called sanitary measures.All of the laws, regulations, et cetera, et cetera, they can have in place alternative but equivalent control programs for assuring us that the product coming into the United States has the same level of public health protection.

††††††††† When it comes to, for example, a drug like chloramphenicol, the tolerance is zero.So we look in their in their programs, and we look in their inspection system for all of the things that they are doing to assure us that the meat in the box that is coming to the United States contains no residue levels of a disallowed drug.

††††††††† So that is what I meant by that slide, that ‑‑ let's see if I can back this up.That is the one you are talking about?

††††††††† DR. WAGES:Yes, you have got to remember I played so much football without a helmet.

††††††††† DR. PRUCHA:Right.So the point is that the foreign ‑‑ we look to the foreign country to have equivalent controls."Equivalent sanitary measures," that is the jargon, but we do not expect them necessarily to have the same exact controls, or sample exact measures.But the outcome, the output needs to be the same.

††††††††† DR. WAGES:And you clearly do not check every lot of meat coming in?

††††††††† DR. PRUCHA:No.

††††††††† DR. WAGES:So, let's say, a drug is banned in the United States; the tolerance in that country is a tenth of a part familiar.

††††††††† DR. PRUCHA:Correct.

††††††††† DR. WAGES:They have verified that in their own testing?

††††††††† DR. PRUCHA:Yes.

††††††††† DR. WAGES:But, at the United States level, with that banned drug, the tolerance is zero.

††††††††† DR. PRUCHA:Correct.

††††††††† DR. WAGES:You would have to check that product to ensure that it was zero tolerance wouldn't you, or would you not?

††††††††† DR. PRUCHA:Well, keep in mind that there is four billion pounds of product coming in.So we are not going to be able to sample every one of those pounds.So our emphasis is on looking to see that there is appropriate preventative measures and control measures in the exporting country.

††††††††† We do that through looking very closely at the exporting country's annual National Residue Control Program, and how they are executing that program.And so, once every year we get submitted to us, is the plan for the upcoming year, and the results from the previous year.

††††††††† We look very carefully at what that data shows us.And, in addition, we go on-site with our auditors to verify that how they are carrying out that program, and they are just not graphiting in the results.That is essentially our program.

††††††††† DR. HOLLAND:I would assume that the exporting country has responsibility for trace backs, if there are positives, and things of that sort.

††††††††† DR. PRUCHA:Correct, that would be part of their National Residue Program.So if there ever is an indication that there is a positive, for example, we would look very closely to see what that country is doing in response to that finding.

††††††††† DR. HOLLAND:So you do have a mechanism in place in that a habitual abuser is not getting more product into the country?

††††††††† DR. PRUCHA:We would look to see how the foreign country deals with that sort of a situation.Again, that is the information that we look for in their plan when they submit it to us every year.And that is the kind of information that our auditors are charged with verifying when they go to a foreign country to conduct their audits.

††††††††† DR. HASCHEK-HOCK:I have two questions.One is a follow up to what was asked previously.Foreign countries are expected though to certify that the products are in compliance with USDA tolerances?

††††††††† DR. PRUCHA:Correct, with every shipment, there is a health certificate which is, like I said, essentially, a government-to-government letter of guarantee that the product has been produced in full compliance with all of our requirements.

††††††††† You see, just to comment on that, I think there is basically only two countries in the world, the United States and Canada, that have simply one system of meat and poultry inspection.

††††††††† Most of the countries of the world have a system in place to meet the requirements of their trading partners, and then they have a domestic system, and some countries even have two or three systems.

††††††††† That is why it is very important to us to be sure that those particular plants that are, in fact, exporting product to the United States are in fact operating in full compliance with all of our requirements, so we look for that guarantee from the competent authority.

††††††††† DR. HASCHEK-HOCK:My second question is:When you talk about the types of inspection or reinspection, you mentioned formulation sampling.Can you expand on that a little bit?What do you look for in that?

††††††††† DR. PRUCHA:I am not sure I am following you.Did I use the word "formulation?"I just gave a number of examples.And what I intended to do was give you just a number of examples of what might go on at import reinspection, and, in addition to collecting samples for residue analyses, but there are a number of other activities going on.

††††††††† DR. HASCHEK-HOCK:Okay.

††††††††† DR. PRUCHA:And that is probably what I saying I think.

††††††††† DR. HASCHEK-HOCK:I guess I was looking at it from drug formulation.But do you mean like ‑‑

††††††††† DR. PRUCHA:Labeling of the product.

††††††††† DR. HASCHEK-HOCK:Labeling?

††††††††† DR. PRUCHA:Correct, I was just using that as some examples of everything that we spot check the product for.

††††††††† DR. LANGSTON:In part, one of the questions we have asked us to address whether or not certain good agricultural practices may result in a different safety factor, one of those being route administration.

††††††††† We know that IM repository injections tend to give longer residue profiles at the injection site.How do you presently handle a situation where you may take one sample from a box of meat and it very high in that one sample, but not in the others, say, that one sample that was very high was likely an injection site?

††††††††† DR. PRUCHA:Well, the truth is that we hardly ever find positive on imported residue analyses.If, and when we do find a positive, we take that very seriously, so immediately we would consult with our colleagues in the Food and Drug Administration, as well as get on the phone with the competent authorities in the exporting country.And, essentially, we would take that on a case-by-case basis.

††††††††† One of the things that we do do, if we do find, if we ever do find a positive, that any ‑‑ the next 15, we just ‑‑ that is just an arbitrary number, but the next 15 shipments are held and tested for ‑‑ and not allowed to enter the country until the analyses are completed.

††††††††† So we would not expect to see a scenario as you just described. If we did find any positive, we would be very concerned, especially for a drug that had zero tolerance.

††††††††† I do not know.Rita or Clark, if you ever want to add anything to my comments, just grab the microphone.Yes, sir?

††††††††† DR. MACDONALD:I was looking at your plan in Denmark.For this 2000 plan, there were 220 samples either taken or scheduled for arsenicals.That seems like a big number for a compound that is not approved in Denmark for swine.That was for a cause obviously.It was a reason for that.

††††††††† DR. PRUCHA:I am not sure why that number is.Help.Do you have a comment on that number, Rita?

††††††††† DR. KISHORE:No, I do not know.I am looking at the number and it looks like a misprint on there.

††††††††† DR. PRUCHA:I could only speculate why that number is that high, and I can research that and give you a specific answer to your question.I do not know.We may have found a positive, and that would trigger extensive follow up sampling.

††††††††† DR. MACDONALD:Okay, thank you.

††††††††† DR. PRUCHA:I will get back to you on that, with a specific response.

††††††††† DR. KISHORE:It looks like a misprint to me when I look at that.

††††††††† DR. PRUCHA:That would be a good answer.

††††††††† DR. WADDELL:You list on the chart, on the table, on most countries just antibiotics.What test or analysis is done on the sample for antibiotics?

††††††††† DR. PRUCHA:Grab the microphone, Rita.

††††††††† DR. KISHORE:Okay.For antibiotics, we do antibiotics by bioassay.It is a seven plate assay, and the same assay is used for domestic sampling also, and it tests for a wide variety of antibiotics in there.

††††††††† DR. PRUCHA:Did that answer your question?

††††††††† DR. WADDELL:Yes.

††††††††† DR. PRUCHA:Thanks.

††††††††† DR. WAGES:And the exporting company when they certify a shipment of meat to the United States, do their residue tolerance ‑‑ do they certify that their residue tolerances meets our standards or theirs, meaning that if they had ‑‑ if we had a product ‑‑ again, I am back to if they had a product used in their country that is banned in the U.S., but their residues were a tenth of a part per billion in meat, would they certify that it is lower than that, or would they lower ‑‑ would they certify that it is zero for us?

††††††††† DR. PRUCHA:Well, the health certificate is filled out for every shipment.And so, they are essentially guaranteeing to us on a shipment-by-shipment basis that everything that underpins that production of that product is in place and operational.

††††††††† And so, when it comes to a specific issue of residues, the reality is that we are relying more extensively on the annual submission of the residue program, and on the annual submission of the results from the previous year.That is really where our emphasis is on.

††††††††† So they are not certifying that every ‑‑ I mean, in reality, they are not certifying that a particular shipment that samples have been taken from that from every box, for example, to be an extreme.

††††††††† They are not really certifying that every box ‑‑ that a sample has been taken from every box and the sample has been analyzed, and the finding has been in compliance with FSIS requirements.

††††††††† They are essentially certifying to us that all of the programs that we are expecting to be place and operational are, in fact, continuing to be carried out during the course of the year when we are not there to physically review and examine exactly what is going on.

††††††††† That comes back to the point I tried to make earlier in the presentation, that we do operate in in a trust but verify mode, that we go through an extensive evaluation exercise up front to develop a level of confidence that the export ‑‑ that the responsible officials and competent authorities in the exporting country are reliable.

††††††††† And so, we do operate in that mode; trust but verify.But we do conduct these various verification exercises that I attempted to describe to you.

††††††††† DR. KOCHEVAR:So does that imply that you would never approve a plan from a country that had an allowable level of, say, chloramphenicol, but if that was part of their meat inspection system to allow some level of a banned substance in this country, in their plan?

††††††††† DR. PRUCHA:We would allow them to use that drug with the understanding and the full expectation that the measures that they have in place ,underpinning the production of meat for export to the United States, are designed to assure zero tolerance.

††††††††† DR. WADDELL:Could you back up two slides, the 33 ‑‑ and on the second bullet point?

††††††††† On the second bullet point, can you think of some specific examples of drugs that would fit that, those description, or that description?

††††††††† DR. PRUCHA:I had a list of these in my brief case.

††††††††† (Away from mike) If I anticipated this question, and probably not, but I have a table with animal drugs approved in other countries, but not approved for use in the United States.And if I could just name off a few, and then I will let you see this.

††††††††† For example, Australia ‑‑ I do not even know how to say all of these.But, Closantel, which is an antiparasiticide; Triclabendazole, which is an anthelmintic; Abramectin, which is anthelmintic.Canada, we have got Dimitridazole; Denmark, Carazolol, Ciprofloxicin, et cetera, et cetera.So there is a number of these.

††††††††† (Away from mike)And then I have another table ‑‑‑.But I have another table of these countries that are giving compounds that are prohibited.‑‑‑.

††††††††† You can see that the animal husbandry practices in the urine chart, wherever the spots came from ‑‑ oh, just call whenever you want to.

††††††††† As I am sure you know that there is a lot in tropical countries and other parts of the world, there is a number of different environmental conditions and animal husbandry conditions that are a lot different than the United States.

††††††††† And so, drugs are used in those countries which there is no need to even to use those drugs in this country.So there has been no ‑‑ my understanding is because of that ‑‑ principally, because of that reason, the drug companies have not petitioned FDA for the use of those drugs in this country.

††††††††† MS. SINDELAR:Excuse me.Because all of this information is publicly available, I will need the original two pieces, and I will make copies for all of the VMAC members, as well as for public display.Thank you.

††††††††† DR. WOOD:You stated that one of the constraints you are dealing with is that some tolerances are set for organ tissues, but when you look at a muscle tissue, muscle meat, are there particular compounds where that is more true than others, or is that a general rule of thumb?

††††††††† DR. PRUCHA:Rita, do you want to address that one?I think that is a general rule of thumb.I think most of the tolerances are set for organ tissues, and not from muscle meat.

††††††††† DR. WOOD:And so, the tolerance levels then that you established for the muscle tissues are tolerance levels that are set by USDA then, or are they set by FDA?

††††††††† DR. PRUCHA:FDA.Do you have any comment on that, Rita?

††††††††† DR. KISHORE:From what I have seen, most of the tolerances are set for muscle and liver or kidney or muscle.One of the drugs that comes to mind that no tolerance has been set for muscle is telmicocin in cattle, though the telmicocin in pork has a tolerance for muscle and liver.So there are very few of those that the tolerance is not set for muscle.I think about 17 or 18 of those.

††††††††† DR. PRUCHA:I do not know what kind of a time schedule you are on.I am happy to answer questions or attempt to.

††††††††† MS. SINDELAR:Thank you, Dr. Prucha.

††††††††† DR. PRUCHA:All right.Thank you very much.

††††††††† (Applause)

††††††††† MS. SINDELAR:This is just for your information.Some of the questions that might arise following these discussions for which you would like answers to, we have asked the speakers to please stay, whenever possible, to answer any questions.So thank you.

††††††††† DR. ROBINSON:I have a couple of other comments.One is generic for the rest of the advisory committee meeting tomorrow and the day after.If you have a phone or a pager with an audible alert, please change it to vibratory or turn it off.We would appreciate it if they were not going off in the sessions.

††††††††† The second comment is that we really appreciate Dr. Prucha and his colleagues coming here to provide the FSIS perspective on import tolerances.I would like to make a point or draw a distinction for the committee.Many of the questions that you have been asking, particularly with respect to Dr. Prucha's talk, are germane to the issue before the committee.

Public Disclosure and Environment Assessment

by Dr. Mark Robinson

††††††††† DR. ROBINSON:There really are two distinct issues here; the first being the process by which import tolerances are established; the second being the implementation of the surveillance in enforcement of those tolerances.The questions to the committee really have to do more with the former than the latter.

††††††††† (Slide)

††††††††† The last comment I would like to make is that the agenda does not list the entire subject to which I am going to deal, which is actually public disclosure and environmental assessment.

††††††††† I note that there is a bit of fear in the face of the committee members that we are going to go back over ADIs, and safe concentrations, and tolerances, which is not the case.Hopefully, this presentation will be mercifully short.

††††††††† There are two questions before you.I am ahead of the game here, because the questions will be formally introduced to you at a later time.But we need to pose the questions in a shorthand in order to cover this area.

††††††††† We have no truly formal expanded presentation.But we felt that in order to deal with these questions, we needed to tell you what is the status quo with respect to drug approvals in the United States, so that you might have some basis on which to frame the questions, with respect to import tolerances.

††††††††† (Slide)

††††††††† The first has to do with public disclosure, and the question I believe is question number three, reads something along the lines of:Should we disclose to the public that we are considering an import tolerance for a new animal drug?If so, when, how, and in how much detail?

††††††††† (Slide)

††††††††† In the code of federal regulations, with respect to both NADA's and INAD's, it states that, "The existence of this file will not be disclosed by the Food and Drug Administration before an approval has been published in the federal register unless it has been previously publicly disclosed or acknowledged."

††††††††† So why would we ask this question in the first place?

††††††††† The FDA has been asked to provide a greater degree of transparency with regards to its decisionmaking.In the area of a new animal drug application or an investigational new animal drug application, we have yet to find information that would cause us to believe that disclosure of information prior to an approval would in any way be protective of the public health.

††††††††† In other words, if the drug does not get an approval, it is not going to be used in the United States.And so, we keep confidence with respect to the information of that submission until an approval is made.

††††††††† Now there may be other issues at hand, which is a subject for the committee to consider, as to whether or not we should keep with the status quo applied to NADAs and INADs for import tolerances, or whether we should go in another direction.

††††††††† (Slide)

††††††††† Similarly, the fourth question to the committee reads, in part, that:"We are considering modifying the regulations such that an environmental assessment will not be required in conjunction with an import tolerance, or the establishment of an import tolerance.

††††††††† (Slide)

††††††††† The status quo, with respect to NADAs and INADs in this country, is that actions requiring preparation of an environmental assessment include approval of NADAs, abbreviate an application, supplements and actions on INABs, unless excluded under 2533(a), (c), (d), and (e).

††††††††† So what are (a), (c), (d), and (e), you ask?

††††††††† (Slide)

††††††††† First, if the action does not increase the use of the drug, meaning, the use of the drug in this country, (c), for substances that occur naturally in the environment, (d) for low environmental exposure, and this in part would relate to minor use, minor species, consideration, where an additional approval just is not going to up the ante, (e) action on an INAD.

††††††††† You can get a categorical exclusion during the investigational phase of the new animal drug application.So, again, the question to the committee is:Should we handle this with the same ground rules as we do an INAD, or an NADA, or should we go in a different direction?And that is it.

††††††††† Are there any questions on those two subjects?Yes?

Questions and Answers

††††††††† DR. HASCHEK-HOCK:My question is:You have indicated some reasons for not disclosing prior to approval.Do you have some reasons or potential considerations why disclosure should be made earlier than approval?

††††††††† DR. ROBINSON:Me, personally, no.That is the question to the committee.Are there reasons?I have no compelling reasons from a professional perspective.Again, it is slightly different for INADs and NADAs.

††††††††† We are talking about drug use occurring in this country, and the central focus is protection of the public health.I do not know a specific argument that would propel me to consider public disclosure.

††††††††† But we felt that in the interest of what the FDA is being asked to provide, in terms of transparency, that we should at least consider this question and solicit input.

††††††††† DR. KOCHEVAR:Do you have any sense of how industry feels about that, whether they think it would be important not to have disclosure until a tolerance was set?

††††††††† DR. ROBINSON:We have at least one industry spokesperson in the public session.I will let them address that specifically.My feeling is that they probably do not care one way or the other, but they would prefer that we maintain nondisclosure for U.S. drug approvals.But I will let them speak to that.

††††††††† Any other questions?

††††††††† (No response)

††††††††† DR. ROBINSON:If not, it is my pleasure to introduce Mr. Jim Heslin, who will moderate the open public discussion.

Open Public Session

by Dr. Jim Heslin, Moderator

††††††††† DR. HESLIN:Hi, my name is Jim Heslin.I am the agency training officer.And, occasionally, I get asked to help facilitate meetings and discussion sessions including several that have occurred sponsored by the Center for Veterinary Medicine.

††††††††† I just wanted to say that the role of the facilitator is generally getting people to share their comments and perspectives.It has been my experience, particularly, here at CVM, that that is not a particularly difficult thing for folks to do.If they have a perspective, they are not shy about introducing it.

††††††††† One of the other things is I try to keep people to the ground rules for discussion purposes.I have had pretty good luck with that.There was one occasion, I think at a prior meeting ‑‑ and I do not see the person here, so I will say this ‑‑ where this gentleman was going over his allotted time and I had to sort of intervene and say, "If you would please conclude your remarks."

††††††††† Well, over the next several minutes, he used more variations of inconclusion and insummary than I have ever heard in my life, but I do not expect that to be an issue here.

††††††††† Basically, the ground rules are these:If you have a comment, come forward to one of the microphones, identify yourself and your organization.If you have a lot of information you want to enter into the docket, something that is printed, or extensive comments that you can submit later, you are free to do that.

††††††††† I have to be aware of the time, though I think we probably do have ample time here this afternoon for public comments.And, with that, I wanted to move to a scheduled presenter, Bob Livingston.

Presentation by Dr. Bob Livingston

††††††††† DR. LIVINGSTON:Hi, my name is Bob Livingston.I am an employee of the Animal Health Institute.I will try not to be repetitive because we had a very thorough introduction of the human food safety procedures for a new animal drug application.

††††††††† (Slide)

††††††††† Let me just highlight some of the points that were mentioned this morning and are of particular concern to the animal drug industry, at least the pioneer animal drug industry.

††††††††† Let me start out by saying that the primary concern for the animal drug industry is the approval of new animal drugs for use in the United States.Import tolerances are only of secondary concern.

††††††††† The first item here is that legislation specifically states that the Food and Drug Administration is supposed to use similar food safety criteria, as required for domestic tolerances.

††††††††† The comments that I would like to make on this, that the criteria used by the Center for Veterinary Medicine is very similar to that used by the Codex Alimentarius, and also to the European Union and Japan.

††††††††† There are minor, minor differences, and right now the European Union, Japan, and the U.S. are participating in a process called VICH, where they are trying to even further harmonize the preapproval requirements for new animal drugs.

††††††††† (Slide)

††††††††† The legislation also states that there may be several sources of safety data.There was no indication or guidance given on the confidentiality of data.The drug industry would encourage the center to take into account the confidentiality of the human food safety for animal drugs.

††††††††† This is an issue that is before the Codex Committee on residues of veterinary drugs right now, and we had encouraged the center to follow ‑‑ or, actually, encourage this discussion within Codex in the resolution of this problem.

††††††††† Also, very much of a concern to the animal drug industry is the setting of harmonized tolerances will promote further international harmonization of regulatory requirements for veterinary drugs.

††††††††† (Slide)

††††††††† Human food safety requirements.As pointed out earlier, obviously, you will need toxicological studies and residue studies.But we feel that it is very important to also take into account the manufacturing information, and the example was pointed out this morning by looking at different isomers within an animal drug.

††††††††† But in the consideration of the residue studies, it is critical that you have knowledge of the conditions of use of that drug.In fact, in your evaluation the human food safety of a particular animal drug, you should have access to the label as to how that drug is regulated.

††††††††† (Slide)

††††††††† Let me see if I can explain some reasoning why you need to know the conditions of use.As was pointed out earlier by Dr. Friedlander, that radiolabeled studies are required to determine the total residues of the animal drug in all of the edible tissues; from these radiolabeled studies, that you determine a marker residue, at least in one tissue, and probably more than that.

††††††††† But what is of critical importance is the ratio of that marker residue to total residue, and that ratio is dependent on the conditions of use of the drug.This ratio provides the linkage between all of your toxicology studies and the tolerance, and that ratio is dependent on how that drug was used, the dose level, the route of administration, the length of administration, et cetera.

††††††††† Another point that I would like to stress on the residue data is that Codex has recognized that for international trade, you need more than one target tissue.Typically, you have an organ tissue, but for international trade you also need a tolerance in muscle tissue.

††††††††† AHI would like to encourage that in the evaluation of import tolerances that you not only focus on muscle tissue, but you use the same procedures as if that drug was going to be approved in the United States to avoid causing problems later if some company wants to get that drug approved in the United States.

††††††††† (Slide)

††††††††† As was mentioned earlier, and in your handout material, that a withdrawal study is not required.You may not require a withdrawal study to determine a withdrawal period, but you need some idea of the depletion of that marker residue in order to establish a tolerance.

††††††††† If that depletion is not rapid enough, it may make it very difficult to establish a tolerance.And you have to remember that that exporting country, if they are going to export meat products with that drug, they have got to establish a withdrawal period.

††††††††† So I would not out and out say that no withdrawal study is required.Although you have not been presented the four questions, I ‑‑ well, two of the four you have.

††††††††† (Slide)

††††††††† I would like to provide my comments on the questions.And the first question was whether you can set a food safety tolerance based just on toxicity and residue data versus obtaining a residue data under conditions of use.It is very difficult to consider residue data without knowing the conditions of use.

††††††††† I am not clear on exactly what that question was getting to, but you cannot just take residue data out of the air and apply it to setting a tolerance.I would like to also emphasize that the Codex procedures use essentially the same criteria that are used in the United States for domestic tolerance.

††††††††† I have here that Codex uses what they call good agricultural practices or you might be more refined to say good veterinary practices.I say good agricultural practices here because some of the animal drugs are not used under veterinary control.

††††††††† The last thing that I will mention on question 1 is that you need to use the manufacturing information on the animal drug.

††††††††† (Slide)

††††††††† Question number 2 addresses one of the issues today, or later this morning we were talking about whether different formulation would lead to different domestic tolerances.And the question 2 was whether there were analytical methods that you would be able to tell whether a residue was due to the use of the drug product for which the tolerance is approved.

††††††††† And, to my knowledge, there are no practicable analytical methods to determine whether that animal drug was ‑‑ animal drug residue was due to one formulation over another.

††††††††† However, if you were concerned about the formulation, the USDA residue monitoring program will allow you to put any controls you would like on that particular drug.You could control it by limiting it to that country, and to the use of that drug in that country.

††††††††† However, you cannot get too specific, because if you want to abide by Codex tolerances, you have to recognize that Codex tolerances are not restricted to any individual formulation.They are determined based on specific formulations, but there is no restriction.

††††††††† (Slide)

††††††††† Question number 3, just addressed by Dr. Robinson, as to whether this information for a request for an import tolerance should be released to the public prior to actually setting an import tolerance.

††††††††† And, a was pointed out, there is no public release for a new animal drug approved in the United States prior to issuing it in the federal register, and there is no reason to treat an import tolerance any differently.

††††††††† In fact, you can make an argument that because a new animal drug in the investigational stage is widely used that there is more of a reason to divulge that than there is an import tolerance.

††††††††† (Slide)

††††††††† Question number 4 is concerning the environmental impact.AHI is not aware of any information that establishment of an import tolerance would have any impact on the environment in the U.S.

††††††††† And a further statement, which I will follow up, the U.S. has no obligation to control the use of animal drugs in a foreign country other than to inform the country of any specific concerns that the U.S. has.

††††††††† (Slide)

††††††††† The EPA has issued in the federal register a guideline for the establishment of import tolerances for pesticides, even though that guideline is out for comment, but that guideline is being used by EPA today.And it is interesting what is in that guideline, because I think it almost parallels the process that could be used for animal drugs.

††††††††† But, EPA, they use existing data to the greatest extent appropriate.They make a statement in the guideline that they will use Codex tolerance or publish a notice for public comment explaining the reasons for the deviation.This is actually in the Food and Drug Act, as a result of the Food Quality Protection Act.

††††††††† (Slide)

††††††††† Some more comments on the EPA guideline.The EPA specifically requests residue data representative of the pesticide use in other countries that export food to the U.S.

††††††††† Repeating what was already said, and this is verbatim out of their guideline, "The agency had no authority to regulate pesticide use in other countries.It is the EPA's policy to harmonize as tolerances with the levels established by Codex if protective of public health."

††††††††† (Slide)

††††††††† The last, in addition to ensuring public health, EPA emphasizes that their setting of import tolerances are in compliance with all of the international obligations that the United States has such as the WTO agreement, the so-called SPS agreement.

††††††††† I think it would be very instructive for CVM to thoroughly consider the EPA guideline, and it was encouraging that in the advance notice of proposed rulemaking that they said that they would consult with USDA and EPA in developing these regulations.

††††††††† I do not know if you have time for questions or?

††††††††† DR. HESLIN:I think we probably have a couple of minutes.

††††††††† DR. LIVINGSTON:Any questions?

Questions and Answers

††††††††† DR. LANGSTON:I have one relative to confidentiality.I suppose when I looked at this from the viewpoint of establishing import tolerance, let's say, if a country put forth as the sponsor to get this drug tolerance set.And, obviously, if they generate the data, they can do what they want to with it.

††††††††† But I had kind of presumed that they would go to the drug company and request information, and that that company would probably provide it so that it would promote the use of their product more perhaps by being allowed to export more.

††††††††† Where do you foresee an instance where the company would resist that?Could they be coerced to give information they did not want to give?In other words, when would it be an issue of confidentiality?

††††††††† DR. LIVINGSTON:I think, in general, the company would be more than cooperative in trying to get an import tolerance because you are promoting the use of their product.

††††††††† One of the areas that they have run into problems where that is not true in Codex is that when a company starts developing a new animal drug product, they have an idea of how extensive of a market they want for that drug, in terms of what are the conditions of use that they want to get approved?

††††††††† One of the problems you run into is that once an ADI is established, it is kind of like a bank account.And so, when you get an approval, you use a certain amount of that ADI.And a company that owns the data, they should have control about where that drug is being used so that there is some ADI left over for them for further development.

††††††††† The case and point here is a drug company may want to develop a drug for many species.However, if a third party came in and said, "I want to develop that drug for a dairy application, just by the fact that you are setting a tolerance in milk, you may us up all of the ADI to the point that that would limit the development of that drug by the company that owned it."

††††††††† So, in general, I do not think you are going to have much of a problem.But when you are talking about confidentiality, you should go to the company that owns that data and inquire if there are any problems, and whether they would support use of that import tolerance.

††††††††† DR. HESLIN:Okay, thank you.

††††††††† DR. LIVINGSTON:Thank you.

††††††††† DR. HESLIN:Okay.The floor is now open for additional comments.

††††††††† (No response)

††††††††† DR. HESLIN:Okay.No one at this point has any comments they wanted to enter?Yes?

††††††††† MR. HATHAWAY:My name is Mike Hathaway, and I represent the Catfish Farmers of America.I would like to raise a couple of questions:One is I have not noticed any particular logic for having an approval for a drug for an imported product, or for residues of it, that is not also approved for use by a domestic industry.

††††††††† An example might be an antibacterial, which may have therapeutic uses in the U.S., it may be used abroad, but I fail to see the health difference in having a residue of a product in a food product that is all right for an imported product, that is not all right for a domestic product.From a food safety issue, it does not seem to make sense.

††††††††† The other issue is that, with respect to the additional approval process, this additional approval process of drugs that are not or could not be approved in the United States.I have not seen the logic in not subjecting an imported product containing a residue to the same kind of requirements that are used for approval for a product in the United States.

††††††††† Simply saying, that the U.S. government or FDA may have requirements that are difficult for the imported product to meet, if they are not a worthwhile requirement for the U.S. product, they should not be imposed; if they are, then they should be imposed on imports as well.

††††††††† A few questions on resources.(1) I think we have had information from Dr. Young and probably it is common knowledge to many that imported seafood is, based on the year 2000 numbers that I have available, would indicate that about 68 percent of what the U.S. consumes is ‑‑ seafood that is consumed is imported.

††††††††† If we can also assume that the greatest risk of exposure to U.S. consumers is from the countries that have the largest number of importations.And I would say first that the data I have got is that there are several countries that have more than a thousand shipments per year, Chile, Ecuador, India, Indonesia, and Thailand; 500 to 1,000 includes Bangladesh, Honduras, Mexico, and the Philippines; and 100 to 499 include China, Taiwan, and Vietnam.

††††††††† If these are the countries of greatest potential risk, why aren't the resources for equivalency agreements being dedicated to those countries so that we have not simply a question of the U.S. taxpayers and industries having the burden of paying for inspection here, which we all know was inadequate, when we could be, and should be imposing a burden of equivalent inspection in food safety on the countries that cause the greatest potential risk to the U.S. consumers.

††††††††† I am not aware of any WTO requirement or NAFTA requirement that makes us absorb that cost on the import side.And the difference between what is done in the meat and poultry issue and the seafood issue is really very startling.

††††††††† It appears that we devote 14 percent of our resources for inspection of meat, if I am correct, to 5 percent of consumption.I am not sure what the numbers are for seafood, but I suspect it is vastly different.

††††††††† And, in fact, I would guess that we probably have far more inspection that is worthwhile inspection in the United States than we have in any foreign country.Because if you do not have the right through an equivalency agreement to do an inspection without the diplomatic permission of the country that you are going to, it does not seem to me to be likely to be worth very much.

††††††††† So if we are going to have a foreign inspection, I know the Office of Seafood says we do have foreign inspectors.I have not seen data on inspections in foreign markets that would indicate that those inspections are anything close to what the U.S. ‑‑ or inspections in the United States are, particularly, in these countries that provide the largest health risk to the U.S.

††††††††† So I think as a question, one, is that if we need more resources to foreign inspection, we should impose that requirement on the foreign governments and on foreign processors in the same manner it is done really indirectly I guess by the Department of Agriculture for meat and poultry.

††††††††† In other words, the foreign governments have to show the United States that they have an equivalent system that protects U.S. consumers, and in the absence of that they do not.I know this is not a forum necessarily for resources.

††††††††† But if we have a problem, and we do, with respect to imports, should we not address the problem where it is most likely to occur?And should we not impose those costs on the countries that are benefitting from exports to our market in the same way that we impose those costs on U.S. producers for serving this same market?

††††††††† I think that is all I had.Thank you.

††††††††† DR. HESLIN:Okay, thank you.Does the committee have any questions of clarity for this speaker?

††††††††† (No response)

††††††††† DR. HESLIN:Okay.Anyone else have comments that would like to offer?

††††††††† (No response)

††††††††† DR. HESLIN:Okay.If you are waiting because the agenda says there is a session after break, if you are waiting for the break, maybe you should comment now.Because I have a feeling, absent any other comments, we are going to take a break, and then Dr. Sundlof will move forward.

††††††††† (No response)

††††††††† DR. HESLIN: Okay, thank you.

††††††††† MS. SINDELAR:Thank you.We will take a 15 minute break, and Dr. Sundlof will then present the questions to the committee.

††††††††† (Whereupon, the meeting was adjourned for a short break.)

††††††††† MS. SINDELAR: And I will let Dr. Sundlof present the questions to the committee.Thank you.

Presentation of Questions

by Dr. Stephen Sundlof, Moderator

††††††††† DR. SUNDLOF:All right.We are going to move into the questions that were posed to the committee on the issue of import tolerances.Let me just give some housekeeping notes here first.

††††††††† It was asked if we get through the questions and the committee can reach consensus this afternoon, can we just move everything up.And part of the problem is that we have speakers that are supposed to be speaking tomorrow afternoon on the next issue.

††††††††† They would not be available in the morning.Some of them are coming in tomorrow morning.And so, what I would like to suggest is that the committee get as far as they can.

††††††††† But we will say any of the final answers, we will go around at least one more time tomorrow morning, make sure that everybody has had a good chance to sleep on it and is ready to make their final discussion points tomorrow morning.

††††††††† One of the other questions that I have been asked during this time is all of the presentations that were given this morning, and the Powerpoint slides, and all of that, will that information be available?

††††††††† And I have talked to Aleta Sindelar and she assures me that all of the materials that were presented today will be available on CVM's homepage tomorrow; and the information that gets presented tomorrow will be available on Thursday, et cetera, so that everybody should have fairly rapid access to the information that was given out today.

††††††††† What I will do then is I will read the questions, and I will take the questions one at a time.The committee will then be allowed to discuss the issues.By the way, the committee has access to anybody in the audience who they think would have information that could help them if you get stuck.

††††††††† So, feel free to ask questions of the FDA or to any of the presenters that gave out information with the exception of Dr. Prucha, who I think has already left.So, with that, I will read the issue, and then the question is up here on the screen so you can also see it.

††††††††† We set tolerance based on an acceptable daily, or allowable daily intake, and the relationship between the marker anilide and total residue.To establish a tolerance, we consider conditions of use including the formulation, dose, and route of administration, and manufacturing features including drug potency and purity.

††††††††† Regulatory agencies outside of the United States and international organizations may use different or additional factors to establish maximum residue levels.The factors used by these regulatory agencies may include different edible tissue consumption factors or animal husbandry standards such as good agricultural practices.

††††††††† The effect of considering these factors may be a different tolerance value than the value established only on the basis of human food safety data, as presented in Section 1(b) of the advance notice of proposed rulemaking.

††††††††† So the first question for the committee is:There are different approaches that we could use to find a safe import tolerance.We can look at toxicity in residue data and build in a conservative safety factor alternatively.

††††††††† We could also review conditions of use such as good agricultural practices, route of administration, and dose, which may result in a different safety factor or factors.Additionally, we could consider manufacturing information such as that required for a domestic application which could also result in a different safety factor or factors.

††††††††† Which approach is preferable?And I turn it over to the committee.

Committee Deliberations

by Dr. Cory Langston, Moderator

††††††††† DR. LANGSTON:Okay, just a comment before we begin.Everyone here was picked for their expertise, but not necessarily in the same area.In fact, some of the people are probably more attune to the second issue of pathogen load and less toward residues and vice versa.

††††††††† So if any of us make any comments that someone else is unfamiliar with the term, acronym, the lingo, feel free to just chime up.No one seems particularly shy here anyway.

††††††††† So, with that, I will open it up.And does anyone have any particular comments or issues they would like to see resolved?

††††††††† (No response)

††††††††† DR. LANGSTON:I wanted to add something relative to clarification on the question, Steve.When you say we could look at toxicity and residue data and build in a conservative safety factor, is that more or less saying that we can do it the way we are doing our domestic application, or what is different about that particular option?

††††††††† DR. SUNDLOF:It is my understanding that that pretty much mirrors the present way that we establish tolerances here in the United States.But does anybody from CVM, who may have helped craft that question, have any additional information?

††††††††† Am I substantially correct or ‑‑ yes, Dr. Robinson.

††††††††† DR. ROBINSON:I think that part of the intent there was to express that if we only look at the toxicology and the residue chemistry data, absent any other information, that we would tend to be a little bit more conservation actually than we would with a full package in a new animal drug approval in the United States.

††††††††† So it would really be to add additional safety factors to cover any uncertainty that we might have with respect to the issues, the underlying assumptions that I illustrated of, particularly, of chemistry and manufacturing controls.

††††††††† DR. KOCHEVAR:If the processes were not substantially the same for domestic and foreign, wouldn't it become sort of a back door for companies to have a product to gain access to this market in a way that would not be equitable?

††††††††† In other words, I am still bothered by the GMP and GAP part of this, the fact that in the process that is envisioned there really would not be any way to safeguard the purity, identity, all of those issues about the product that is being evaluated.

††††††††† So I guess the question I have, and this would be just from a public safety point of view, why wouldn't the process be pretty much exactly the same as it is for domestic?

††††††††† DR. GLENN:And I had the same question.

††††††††† DR. HASCHEK-HOCK:My comment was that apparently there are at least 34 countries, at least to my understanding, that where the U.S. feels fairly comfortable on equivalency, if not identical practices.I assume that they have looked at differences.

††††††††† Is it correct that they have looked at how the toxicity and residue data are presented and evaluated and feel comfortable that these are equivalent to U.S.?

††††††††† Should there be some difference in what is required between those countries and countries where equivalency is not considered similar to the U.S.?

††††††††† DR. SUNDLOF:Again, I am going to ask CVM folks if they can address those issues.

††††††††† DR. LANGSTON:While they are considering who is going to get up and talk about that, in clarification, Debbie, are you saying that basically because of manufacturing processes, a residue is not a residue?

††††††††† DR. KOCHEVAR:I guess more that you could establish a certain standard.And then, if you are going to assess a product as it came in, that you would not be sure that what you were checking in that product when that particular drug was given to the animals, yield that that made, would be the same process that you would get if the same drug was given to another animal just because of the variation in the product.

††††††††† In other words, there is not an assurance that the drug was manufactured in a way that would allow you to predict residues in a standard way every time.Does that make sense at all?I may have strayed here from a logic.

††††††††† DR. LANGSTON:No, I think it does, in the sense that if you have differences in formulation that result in a different absorption rate, you might have a different metabolic profile and associated different total residue profile.

††††††††† But, relative to that, this is a question for someone else though at CVM.When we are doing NOELs in the rodent and other mammalian species, in that NOEL established all the dose of the parent drug without taking into account the toxicity tolerance by the ratios of the various metabolites.

††††††††† So, yes, there might be a difference, but we are already discounting that difference when we are looking at establishing NOEl.Am I incorrect about that?So if someone could answer that, and then we will answer the other question.

††††††††† DR. SUNDLOF:Dr. Friedlander, I think you spoke this morning about ‑‑ I think it was you, who spoke about that we consider all of the metabolites equally toxic to the ‑‑

††††††††† DR. FRIEDLANDER:We do consider all of the metabolites equally toxic to the parent, unless they are demonstrated to be otherwise.And in dosing the toxicological species, we anticipate that the drug is undergoing metabolism; that the rat or the mouse is being exposed to all of those metabolites, and that the toxicity profile we are seeing is essentially the complete picture.

††††††††† When we go over to the food animal, what we are looking to see is that we have not missed anything in terms of a metabolite that is in the cow, and maybe is not formed in the rat, in which case, we would say, well, the rat has not seen everything that cows make.

††††††††† And since people eat beef, people will be seeing something that cows make that the rats did not make and we will have an incomplete picture.If this were to happen, we would be looking at sending the package back to have some additional assessment made to sort of pick up that missing metabolite and look at it to see if there were toxicological concerns there.

††††††††† DR. LANGSTON:Yes, but let's say at a given dose in the rat, at a point in the study where the metabolism was such that three-fourths of the parent compounded and metabolized, one-fourth remaining drug, and this was associated with ‑‑‑ toxicity; and you went to the cow and you had the opposite scenario of three-fourths parent, one fourth metabolite, you really are not going to change your NOEL based on that.

††††††††† It is the same metabolites.You are still drawing the toxic effect from what's occurring in the rat though, am I correct?

††††††††† DR. FRIEDLANDER:Correct.And for the food safety part, we would not be particularly focused on any toxicological manifestations in the food animal.That would be the purview of the target animal safety group.They would focus in on that component.

††††††††† DR. LANGSTON:So, in light of that, that is where I have a problem with these subtle changes in absorption rates and formulations.Granted, huge effects should be taken into account for, but we are still not addressing them at the very basic level of the NOEL.

††††††††† DR. KOCHEVAR:And this may be a very minor issue.But if a drug is not manufactured according to certain standards, is there anything else in there besides the active ingredient, which is what we would be looking for, that also could potentially be harmful to people when they ate the meat?

††††††††† I mean, I guess, it is just a question of quality standards for the product even if it is not the actual residue for that drug.And that may be a minor point.I do not know.

††††††††† DR. LANGSTON:I hate to keep having this dialogue with Debbie.But I do not know.Well, I will just close.

††††††††† DR. WOOD:Just so I am curious, to Deborah.I mean, what is it then that you are arguing for?Is it something that is different in terms of ‑‑

††††††††† DR. KOCHEVAR:No, I guess drugs that are manufactured in this country have a requirement for GMP.They have had to come out of a facility.And so, when you do characterizations of those drugs downstream, then you pretty much know what you have because that is part of the approval process.

††††††††† If a drug came in from another country, and what we were looking at was the marker residue, which, as Cory points out, you know, and the bottom line, it is either there or it is not.And, as long as the metabolites are all accounted for, then that probably addresses that issue.

††††††††† But I guess my concern from just a public health point of view is, are there other things in that pharmaceutical that make their way into meat?

††††††††† I mean, it is almost like packaging for a piece of food.I mean, you look at everything that goes into the packaging to see if it has some adverse effect on the food.So it is probably not even a drug issue anymore.It is a formulation of that drug, and the quality standards used when that occurs.

††††††††† DR. LANGSTON:I think, to some degree, that overlaps into question 2 that Dr. Sundlof will be talking about, whether or not you can tell a different formulation, one from another.

††††††††† And, certainly, if there is a different vehicle or excipient that is used in a formulation, perhaps, we could follow that to tell it is product A versus product B.

††††††††† Whether or not it is harmful, I would presume most are on the GRAS list, the generally recognized as safe.But if that were not the case, it would become an issue, and I am not sure how you would deal with it.

††††††††† And there have been those instances, for example, I think tryptophane, there was an instance where some sort of byproduct got into tryptophane and caused eosinophilic myositis in humans, but they still do not know what that was.But I have really no way to suggest to overcome that is the problem.

††††††††† DR. WOOD:I, too, I guess share the concern about purity, strength, and the active ingredient formulation, and all.Is that more an enforcement question, or is that a question that can be dealt with as ‑‑ I mean, is that a USDA question, or is that an FDA question, I guess is what I have been wondering?

††††††††† DR. HASCHEK-HOCK:No, we are talking about some specific issues here.I think the general thing that we need to be concerned about is that the safety data and the tolerance that is set meets the current standards for domestic tolerances.

††††††††† And whether it is up to us to determine exactly what needs to be done to achieve that, I am not sure if we can address all of the specific issues.But my feeling is that the important thing is that we do have the same level of safety in the tolerance that is set based on the data as we have with our domestic tolerances.

††††††††† DR. GLENN:I would also like to support that.It seems to me we have a very specific mechanism to establish domestic tolerances for human safety.Why would this body deviate from that and say we are going to do it differently and have a different level of safety?

††††††††† I am sensitive to this issue of regulatory burden and international harmonization, however.I did hear that this morning.But when you get to the science, if we have accepted this domestic tolerance setting procedure, why do we want to deviate from that for?Could someone explain that to me?

††††††††† DR. HASCHEK-HOCK:That was not exactly my point.My point is we want to reach the same endpoint.But if we have countries where we do accept their current practices, then it would seem that we do not have to go back to look at their ‑‑ how their toxicity data was arrived if the GMP are accepted by the U.S., that should be enough for us ‑‑ if it is accepted by the U.S. in general, then that would not need to be addressed from the raw data.

††††††††† But, basically, and to me, and that was my question before, you know, have all of these aspects been looked at, say, in the 30-some countries that have been determined to have equivalent practices to the U.S.?

††††††††† DR. LANGSTON:Clarification on that, Steve.When you are talking about GMP, really, the company that produces the drug where we are having a residue discussion really, you do not have access to making them the GMP in their manufacturing do you, only if they are wanting to market to the U.S.?

††††††††† DR. SUNDLOF:That is correct.We cannot inspect them for GMP compliance.But I think part of the question is that ‑‑ one of the parts of this question is, additionally, could we consider manufacturing information such as that required for domestic application?

††††††††† And it may be we may be able to require from the importing country that they ‑‑ that we would deny an import tolerance unless we had some assurance that the drugs that we are considering were approved under the U.S. good manufacturing practices standards, or something that we consider to be equivalent.

††††††††† DR. KOCHEVAR:And I think that is what I was trying to get at a little while ago, is that if you are starting with a product that you have some assurance has been made under those conditions, then you have a degree of safety that you do not have if you do not have that assurance.

††††††††† DR. LANGSTON:I would tend to agree that if you can get assurances of GMP life practices, then you should be able to judge your residues relatively similarly across lines.

††††††††† DR. MACDONALD:Cory, on establishing an import tolerance, it is obvious that the way to go is to go ahead with the documentation criteria that currently is in place in the United States.Somebody wants an import tolerance, the pathway is very, very clear.I disagree with that.I think that is a totally valid way to do it, and probably the only way to do it.

††††††††† My only comes up is the situation where drugs that are not approved in the United States for which an import tolerance is not going to be provided, what do you do in those cases to handle the use of those products, and that tissue ending up coming into the United States?

††††††††† How do you evaluate those drugs short of saying, no, we will not import tissue from creatures that were fed the following list of drugs period?

††††††††† Okay.How do we assess, or how do we evaluate the case where they were used, and how do you come up with a way to evaluate the risk to the consumer under those circumstances, i.e, a sulfonamide is used that is not approved here but is available and is used in another country?

††††††††† How do you evaluate that tissue in terms of importation?Do you just flatly say you cannot import it?Do you set some sort of a value based on your knowledge of the other members of the class?How do you deal with that?

††††††††† The straight import tolerances, as far as I am concerned, you deal with it the same way you deal with it on a contemporary application.In the United States, the only thing you do not do is worry about the efficacy portion of it.But the safety portion, which we are focusing on, is the same.Those are the rules.

††††††††† But what do you do when you are presented with a situation, as the FDA is, USDA is, of tissue that has been fed another drug, or a drug for which this has not been done?How do you set a number?

††††††††† DR. ANDERSON:I may have misunderstood this morning.But I thought they said that in that case what their criteria was, zero tolerance.So they were not refusing to accept the meat.They would accept it, but it was a zero tolerance level.Is that your understanding?

††††††††† DR. LANGSTON:Clarify me then.Because my understanding was, in that instance, where it was not approved but used elsewhere, that we would still have access to their raw data so that they would still be doing the carcinogenicity studies, the rodent toxicity studies, et cetera, and we would be looking at those.And if it was not adequate data, either in numbers or quality, we would revert back to a zero tolerance.

††††††††† DR. KOCHEVAR:But isn't there another class?I mean, there was the class of banned substances like chloramphenicol, and those were zero, not getting in, no matter what.But then, like you, I thought the ones that we do not have here, but they are not the end, you had the possibility of submitting the data and trying to get a tolerance for it.

††††††††† DR. MACDONALD:Well, if you are looking at ‑‑ pick a class like the sulfonamides, many members of the class, many of them are used in various states.The data that you are looking for to establish a tolerance is not available.I mean, the tox studies are not there.

††††††††† If they are there, they were done in the '60s, probably are incomplete.It is just not an adequate package.But what do you do when the situation happens?To me, that is the concern.As far as the question on how do you do an import tolerance, that is a slam dunk.

††††††††† DR. WADDELL:I was under the understanding that, take a banned drug like chloramphenicol, those products can still be imported to the U.S., as long as they are zero tolerance.That is the question I have is, you know, I mean, how can we ban a drug here, and then allow it to be used even with a zero tolerance?

††††††††† I mean, why don't we have the drug available here, then it would have the same zero tolerance for American animals?

††††††††† DR. LANGSTON:I do not disagree with that, and that was kind of what the gentleman with the fish industry pointed out.Unfortunately, I think we are getting into an area that I do not think our committee has any prerogative over.

††††††††† Debbie, I do not disagree with you, but I do not think we can address it.Did you have anything else?

††††††††† Back to your question, Alexander, that is a problem.There are either one or two approaches I would view either of the ‑‑ straightforward.You just cannot approve it.You have to generate the data.I have considered whether or not it would be possible to go back and look at regression correlation for things that did exist within a class.

††††††††† For example, how does the LD50 for that compare to the NOEL for known drugs?I am using LD50.It could be certain safety factors; it could be therapeutic index; it could be anything like that.

††††††††† But it is a little iffsy, and I am a little uncomfortable with it, but that is about the only thing I can think of short of requiring the studies.I probably would require the studies.

††††††††† DR. MACDONALD:Well, you know, this is what I do.And, in terms of retrieving the data necessary to do these evaluations, in many cases, the data does not exist.If it did exist, it is no longer available, not because somebody wants to hit it, it is just not available anymore.

††††††††† And so, contemporary drugs that were focused into the animal health industry where this information is available, that is probably drugs in the last 25 years targeted specifically for the animal health industry.

††††††††† A lot of the drugs you saw listed on the fish slide were drugs of opportunity.These are drugs that you can go up and buy.They are available and people use them.That does not particularly mean they have any blessing, or any data, or anything else to go along with it.That is just the way it is.It is not here, it is there.

††††††††† DR. KOCHEVAR:I guess I had a question of the FDA folks.

††††††††† Do you think the major people who would be interested in this, the countries who would be interested in these, would be for those products that are for diseases that we do not have, like you were saying with Australia, so that it is not a question of something tried to get approved here and did not get approved, was deemed unsafe, or has been banned here, like chloramphenicol, but it is just a product that just flat does not exist here because we do not need, that those would be the major people who would be interested in import tolerances, or major cases?

††††††††† DR. SUNDLOF:That was the original impetus for the legislation that led to import tolerances, but I do not think that that specifically excludes us from setting import tolerances for drugs that for which there might be a market, and for whatever reasons the pharmaceuticalcompany did not pursue an approval in the U.S.So I think you have to consider both.

††††††††† DR. HASCHEK-HOCK:I would just like to make a comment on inadequate data.I do not think that there is any way that the U.S. should go ahead and accept inadequate data.I mean, we are looking at public safety and if the data is not there, I do not see how we could approve and set tolerance levels for that.

††††††††† DR. MACDONALD:No, I agree with that.I do not take issue with that.My only comment is you saw the list of drugs.Okay.I mean that did not ‑‑ you did not make it up.I mean that came from a use pattern of some sort, and they are gearing up to do a monitoring program based on what they can gather for the intelligence of usage for these drugs.

††††††††† DR. LANGSTON:So, Dr. MacDonald, you obviously have considered this.So your view is that they would need to do the extra studies if it was going to be approved.Am I paraphrasing that?

††††††††† DR. MACDONALD:Well, I think that to do what the U.S. requires, to do what the EU requires, to do what Japan requires, to do what Australia requires, and what is required by JECFA, the review committee for Codex, you need adequate toxicity studies, and the list that Dr. Robinson presented is the list, the studies that Dr. Friedlander presented are the list in all of those cases.

††††††††† And if you do not have all of the points on that list, you have to struggle to obtain a ADI and an MRL.I mean, there are certain experimental things that you might not be able to do in these limitations.But, fundamentally, if you do not have those studies, plus an array of genotox and microbiological profile, it is not going to fly in any of those venues.

††††††††† DR. LANGSTON:I tend to agree.I do not think it should.As clarification as to what else we are discussing, the next sentence says, "Alternately, we could also review conditions of use such as a good agricultural practices, route of administration dose, which may result in a different safety factor or factors."

††††††††† I am trying to remember if someone did mention that perhaps this is in there because, relative to good agricultural practices, the way a drug is used, it might actually be a lower tissue limit, which, if you applied that, would say that they are not following good agricultural practices if they are coming up higher than we want them to.Therefore, they set the residue limit based on what is a good agricultural practice rather than the food safety data.

††††††††† Did I hear that correctly, Dr. Sundlof, that is why that sentence is kind of in there?

††††††††† DR. SUNDLOF:I think so.I would like to get some clarification from some of the CVM folks.

††††††††† One of the issues that got discussed this morning was that certain countries establish their tolerances or MRLs based on the ADI first.It is a function of the ADI.

††††††††† But if the actual use practices would result in tissue residues which are much lower than the ADI-based tolerance, than various countries will lower that tolerance to be consistent with the label indications, with the label usage directions.So that is one of the issues here.

††††††††† The other may be another issue.And, again, I would defer to CVM folks, who are closer to this, would be that, do we assurance that the countries for which this drug is being use are enforcing their own good agricultural practices, such that the drug is available with certain label indications, but in practice it is being used in a way that is much different from what is actually in the label.

††††††††† Is there somebody from CVM that would like to speak to either of those?Dr. Weber.

††††††††† DR. WEBER:Just to reinforce what I think I have been hearing here is that, for example, the JECFA, which has MRLs that are widely adopted by Codex, and some of those even wind up in the EU.The toxin residue packages are, in recent years, virtually identical to what we see.

††††††††† We often and usually wind up with, in many instances, the same ADI.But, as Dr. Sundlof was pointing out and the chairman here also pointed out, the good agricultural practices is an issue where we differ in how we would set a tolerance here, as opposed to the MRL that they ultimately adopt.

††††††††† We, as a practice, embody or use virtually, in most instances, the entire ADI, based on what the sponsor wants and wants a partition, especially if they see milk or eggs or other things, as was mentioned earlier; whereas, the EU ‑‑ and you see this coming through in JECFA quite a bit ‑‑ they take that same ADI and say, you do not need a zero day withdrawal, or one day withdrawal.

††††††††† It is a therapeutic drug.A four or five day withdrawal consistent with returning to the herd or something like that is adequate.They will go out and pick the MRL, the tolerance at something beyond zero or one day withdrawal, which is the zero one day withdrawal can be totally consistent with the ADI.

††††††††† It is consistent with the safety of the compound; whereas, applying what is called general good agricultural practice, they might pick a factor of two less than we might.Again, it is within the ADI.But, again, they may not use the entire ADI.

††††††††† So, starting with virtually the same ADI, while we believe that using up to and including the ADI, is consistent with public safety, they can pick under general agricultural practices something lesser saying for that therapeutic drug, two, three, four, and five days may be acceptable.

††††††††† DR. LANGSTON:I know I would propose that it should be based on the food safety issue, and not on good agricultural practices.If anyone would like to change my mind on that?

††††††††† DR. KOCHEVAR:Would it be the case that in considering the GAP would always make it a tougher standard?

††††††††† (Nodding of heads)

††††††††† DR. KOCHEVAR:Always tougher.So if we are happy that our standards are tough enough, and unless we are ready to toughen up the standard for the domestic side too it seems like that would be a hard way to go to include it.

††††††††† DR. LANGSTON:I tend to agree.

††††††††† DR. WOOD:Does the good agricultural practice address at all the injection site issue, and how the drug is administered?

††††††††† DR. LANGSTON:Could someone comment on that, who is more familiar with foreign good agricultural practices?

††††††††† I would think it would but ‑‑

††††††††† DR. WOOD:That would have some impact or bearing on it, but we are not addressing or dealing with the injection sites.We are looking at the tissue or the organ itself overall, right, in terms of tolerance levels?

††††††††† DR. HOLLAND:Yes.

††††††††† DR. WOOD:Right.

††††††††† DR. HASCHEK-HOCK:I mean, one of the things that is listed separate ‑‑ and this may be not quite relevant to this, but route of administration and dose would seem like there is two issues:One is what is done regularly in agricultural practice?But the other one related to residues would be how the compounds administered in development of the residue data?

††††††††† Because the current U.S. regulations are that ‑‑ my impression is that the drug, the radiolabeled drug needs to be administered, the route of administration that it would be in practice, and also close to the actual dose level that would be used in practice.

††††††††† DR. LANGSTON:That is correct, relative to determine the residue profile in a target animal, but not for determining the toxicity in the rodent species, or mammalian species.

††††††††† DR. MACDONALD:Well, all of the tox work is all oral.All the toxicity work associated with this is all oral toxicity in their lab animal species, because that is a safety evaluation because man eats the tissue.So it is an oral aspect.

††††††††† DR. WOOD:One other question that may or may not be appropriate to this issue, and that has to do with having a policy that can move and be adjusted to future policies at the FDA.

††††††††† For example, as the FDA CVM adopts a policy dealing with antibiotic resistant bacteria, and where that may factor in in some way in tolerance levels, is there adjustment or recognition of that at this point, or is that really not on the table?

††††††††† We certainly are concerned about that question.We all are.But how does that get addressed?Or is it addressed more by looking at how the country is addressing and monitoring antibiotic resistant bacteria overall?How is that question?Where is that question on the table, if at all, in these four questions basically?

††††††††† DR. LANGSTON:My view would be it would be addressed through the HACCP inspections of that country.I do not consider it a part of this discussion, but I am willing to open it if anyone does.

††††††††† DR. MACDONALD:Well, we are dealing with the impact of the residue in the tissue, its absorption in man, and its impact on man's intestinal tract.In other words, we are dealing with the residue itself.We are not dealing with the organisms in the target animal's tract.We are dealing with the residue and its impact, right?Okay.

††††††††† DR. ANDERSON:I would just like to add, I agree.I mean, I do not think that.But, certainly, any residue that end up in a human intestinal tract will add to the selected pressure which could lead to resistance, but I do not think it is a driving force for antibiotic resistance.

††††††††† DR. MACDONALD:See, what I would like to do ‑- and, of course, this is a 20 year crusade that I have ‑‑ and that is that the residue should be evaluated, not only ‑‑ well, it should be evaluated on its impact to man, on its bioavailability to systematically to man, and it should also be evaluated on its impact to the intestinal tract bacteria.

††††††††† In other words, you eat meat.The meat is digested.The supernatant has an effect, or no effect.That is what we should be looking at.We should not be looking at anything else.I will get off my soap box.

††††††††† DR. KOCHEVAR:Not to beat a dead horse here, but back to that import tolerance for banned substances.Because, I mean, that does seem like an issue that has to be dealt with either ‑‑ it is clear that it has to be a zero tolerance.

††††††††† But is it a zero tolerance coupled with the knowledge that a country says, yes, it is okay if you use this drug, but you just cannot have anything in the meat if you are going to sell it to the U.S.?Or would we not think that was the same standard as we hold our own producers to?

††††††††† And so, would you require that their HACCP plans also had the substances listed as banned substances?

††††††††† DR. SUNDLOF:Well, that is not a question that we asked the committee.But under issue number five, I think that is a good place to bring that.

††††††††† DR. LANGSTON:I think that also comes up along that same line of foreign approved drugs that, is it fair to our producers to be able to import meats into the U.S. that these producers have newer drugs that are not yet approved and can optimize their production, decrease their disease?Does it give them a competitive advantage?

††††††††† But, again, that is not one of the questions right now.

††††††††† Well, basically, I view this as three parts, based on the three sentences of the question put to us.(1) we have the existing criteria, and I have heard most people say that what we are using right now seems to be fairly adequate, why change it, as long as the data is solid and provided that the good agricultural practices probably are not too much of an issue.

††††††††† The last sentence dealing with manufacturing should be an issue, at least some sort of GMP like assurances.One thing that I have wondered about, however, before we leave this issue, and that is in policy versus implementation.

††††††††† I know we were told to concentrate on policy not implementation.But do we need to be concerned about the issue of whether you can assay these compounds in muscle, as opposed to the target tissue, or is that something else somebody else will deal with?

††††††††† DR. SUNDLOF:No, I think that is a fair issue to deal with.

††††††††† DR. HASCHEK-HOCK:Just one comment.In the first part, where mention that the current procedures are adequate, are you implying that the whole gamut of procedures that are used currently by the U.S. would need to be applied to other countries?

††††††††† Or are some things performed by at least specific countries acceptable so that the FDA does not have to go and analyze all the data from every aspect of the drug production?

††††††††† DR. LANGSTON:My view is that there ought to be some lenience in it.I do not think you need to be too dogmatic about it, as long as it is reasonable.

††††††††† DR. KOCHEVAR:Yet, by the same token, we make manufacturers here if they have a different formulation go through the whole show again.So it seems like we need to be consistent in what we require producers to do.

††††††††† DR. LANGSTON:I suppose my thinking was, you know, if they go 45 instead of 60 day on a trial, can you take that?I do not know.Maybe the answer is you cannot.Maybe you have to require a 60 day.I am open to others.

††††††††† DR. HASCHEK-HOCK:I think the formulation comes under two, but I mean it is all interrelated.But, perhaps, that should be addressed separately.

††††††††† DR. LANGSTON:Let's wait to question two for the formulation.Any other comments about question 1?We have not really talked about the issue of muscle assay, since I brought it up.Anyone have any ideas about how to handle that?

††††††††† DR. MACDONALD:Well, muscle is the tissue of trade.So, even though the target tissue might be liver and you have a method for that, what is coming into the pore is muscle.So you unequivocally have to have a method for muscle.

††††††††† I do not think that is ‑‑ I mean, the system in the United States for many years did not deal with muscle.It only dealt with the target tissue.The idea was as the animal goes through slaughter, you grab delivery, you measure it.If that is clean, the whole animal is clean.

††††††††† But, as everything gets separated, and what has been the item of commerce is muscle.So, therefore, there has to be a safe concentration, and there has to be a method for it.

††††††††† I do not think it is ideal, by the way, to have a method.I mean, in today's world the only question is money, as to cost of the assay.I do not say we can get down to ‑‑‑ number yet, but we can drive it pretty low if you really want to go there.

††††††††† DR. LANGSTON:So you are, more or less, saying that they should be able to develop the assay in muscle if needed to, if pressed?

††††††††† DR. MACDONALD:No, I think there is no question in today's technology.I am quite convinced that using the older concentration techniques that we used, coupled with current HBLC, triple quad MSMS machines, will give you the sensitivity and the conformitory data to prove unequivocally what you see is what you have got, and to do it, I say, 1 x 10-14, if you need to, maybe a little further.

††††††††† Which, you know, when you start thinking about this whole residue stuff and exposure to man and what we should be concerned about, when you get below 1 x 10-9, I mean, is there really a concern?

††††††††† See, as a scientist, as an analytical chemist, one of the things that I worry about is signal to noise, and that is seeing a signal about the noise.And, at some point here, we have to consider the biological noise that we are exposed to and relate a given incident to that biological noise.

††††††††† At some point, it is only noise; and, at some point, it is real.But I do know the model is valid.I just do not know how to make it work.But we do not address that, and we start getting down to 1 x 10-9, ‑10, ‑11, and -12, we can do it.

††††††††† There is no sweat ‑‑ not no sweat, but we can do it.The question is, is it meaningful measurement after you do it?

††††††††† DR. WOOD:Didn't we hear in the presentation and in the questions afterward from USDA that they are on a case-by-case basis already doing assays on muscle tissue, and even if the target tissue is an organ?And I was wondering, if so, how that is accomplished?

††††††††† DR. LANGSTON:Someone else can respond.My view of that would be that what they are doing is they are assaying muscle, and if it is negative, great.That still does not mean that the liver would not have been above a violative residue.

††††††††† It is only if the muscle tests positive would they pursue it.So, even though it is negative, it does not mean it is not a violative residue elsewhere, or it really would have been, the whole carcass would have been condemned even though the muscle tested negative.

††††††††† I will play devil's advocate a little bit here just to see what sort of reaction I get.But there is another option, and that is if your muscle falls below the limit of detection of your assay as it now exists, the one that is being used to detect liver or kidney, and that would be to follow your tissue depletion curves such that you go down and at the point where you begin to find a limited detection in muscle, extrapolate that back to total residue and see how far all of you are from the NOEL.

††††††††† It will be above probably your target tissue total residue.But the question then would become, perhaps, given the situation, perhaps, that safety factor was not necessary, instead 1,000 fold safety factor with 100 fold safety factor.

††††††††† Do you understand what I am saying?

††††††††† DR. KOCHEVAR:Lynn, what do you think of that?

††††††††† DR. FRIEDLANDER:I think it is important to remember that when we start talking about muscle, we are talking about muscle relating only to muscle.And I think we also have to remember that you are not necessarily chasing a number with a method as low as you could go.You are only chasing a number as low as you need to go to establish safety.

††††††††† So it is entirely possible that we could establish tolerances for muscle that would be completely consistent with the performance of the method and maintain safety without having to go to the extremes of what the method could do?

††††††††† And it is important to separate those two, because the reason you do not have to keep chasing things with muscle is because you are not implying that muscle is addressing the safety of anything other than muscle; whereas, with the target tissue, the target tissue is going to address the safety of everything.

††††††††† So you could conceivably be chasing a lower number for your target tissue because it is going to speak to all of the organs, of the edible organs, liver, and kidney, and the muscle, and the fat.And you could actually pick a higher number for muscle, because all it is going to address is the safety of muscle.

††††††††† DR. KOCHEVAR:But right now there is only one tolerance for a drug, right?In other words, there is no differential numbers on any domestic ‑‑

††††††††† DR. FRIEDLANDER:Yes, there is.There is a target tissue tolerance, and there is a tolerance in any other tissue where we have the data to support it, and there is a historical context here that probably was not brought out in the presentations.

††††††††† We have, as our definition of residue, as Dr. Robinson pointed out, we went from a no residue, zero, to a negligible tolerance of .1, to now a much more risk-based tolerance, and we have moved in terms of what tissues we have applied tolerances to, where we have put numbers.

††††††††† So, in the case of negligible tolerances, we may have a tolerance of .PP1 ‑‑ .1PPM across the board for every tissue.For some of our more modern approvals, we may have only a number for the target tissue.

††††††††† For some of our most modern approvals, we may have a number for the target tissue and for muscle, and it depends on where you are in this time continuum in a regulatory sense.It also depends on what data are available in the package.If there simply are not data to do with muscle tolerance, we have probably passed on doing a muscle tolerance.

††††††††† DR. KOCHEVAR:So that approach would not be inconsistent with what you already do for domestic tolerance?

††††††††† DR. FRIEDLANDER:No.

††††††††† DR. KOCHEVAR:Okay.

††††††††† DR. LANGSTON:Well, I would propose that that is something for you to consider overnight, especially if ADI for muscle could be taken into account for that factor.

††††††††† DR. HASCHEK-HOCK:Just one more comment on that.Since usually the muscle is much lower than the target organ, if data was not available on muscle tissue you can conceivably set it higher at the target organ, which would just have a higher tolerance, rather than perhaps not approving it because that data was not available.Although, I think it probably would need to be made on a case-by-case basis.

††††††††† DR. MACDONALD:You could calculate a muscle based on the target, based simply on consumption.Do you know what the tolerance is in liver?Do you know how much liver you are going to eat?

††††††††† Translate that to 3x, or 5x, or 6x, whatever it is, the amount you are going to eat in muscle.If the value drops that much, then that is ‑‑ you know, if push came to shove and you had to do it, that is the way to do it, because you have established it for the target tissue.

††††††††† DR. LANGSTON:Good comments.Any other comments on question 1?Again, we will delay actually your final views on this particular question until tomorrow morning.

††††††††† DR. HASCHEK-HOCK:I felt I did not get my question answered, and maybe it is something that could be perhaps answered tomorrow morning.And that is, again, on the countries where there appear to be equivalency standards, how comparable are the residue studies in good manufacturing practices?Have all of these been considered in the equivalency area?

††††††††† DR. SUNDLOF:Let me address that.Those equivalency agreements are between FSIS and the ‑‑ however many countries that they have these equivalency agreements with.It does not involve such issues as good manufacturing practice standards.

††††††††† It is basically how they conduct their inspections in the plant, what kind of residue inspection program that they have?†† Is it equivalent to ours?But it does not address the finer issues of things like good manufacturing practice and quality of drugs that are administered to animals.

††††††††† DR. HASCHEK-HOCK:How about in comparison to the European Union and WTO, and those organizations or agreements?Have those issues been addressed specifically?

††††††††† DR. SUNDLOF:Well, I will try and answer this, and maybe other folks can help me.The European Union has fairly similar standards to what we have in the United States.They virtually require the same kinds of studies.

††††††††† We are moving closer and closer towards total harmonization through the BICH process.So in the future we expect to be virtually identical in the kinds and quality of data that we require to make these kinds of decisions.

††††††††† The WTO basically is a body that resolves disputes between member countries when they have disagreements.And under the SPS agreement, the Sanitary Phytosanitary Agreement of the World Trade Organization, basically, the rules are stipulated that one country cannot arbitrarily refuse to import another country's product if it is not in consistency with that country's own safety standard.

††††††††† So, in other words, if the United States had a safety standard, but for one reason or another did not want to import something, some product that was coming from the European Union, we could not fabricate some reason why that particular production should not be allowed into the United States, if it met our safety standards.

††††††††† And, obviously, we do have some issues with the World Trade Organization regarding veterinary drug residues between the European Union and the United States, and we have used the World Trade Organization in order to try and resolve some of those disputes.But that is basically what the function of that is.

††††††††† So, for the European Union, again, I think we are fairly similar.It is where we get into some of the issues of countries that may not be as technically advanced as the United States or the European Union, where they have diseases that did not occur in the more tempered regions of the world.

††††††††† But, yet, they definitely have the need for drugs to treat some of these diseases.Trypanosomiasis is a classic example of a disease that does not occur in the tempered areas, but which is an absolute critical disease to control in more tropical climates.

††††††††† It is in those countries where we would have more concerns about the quality of the data that were used to approve those drugs.

††††††††† DR. LANGSTON:Everyone ready to move on to question 2?

††††††††† (Question 2)

††††††††† DR. SUNDLOF:Okay.Question 2 reads, just we will read the issue:

††††††††† "The tolerance established by FDA for a new animal drug approved under Section 512(b)(1) of the Act is based on data submitted by the sponsor.These data are owned by the sponsor of the pharmaceutical company, producer, organization, et cetera, that paid for the study, and is accountable for the quality of the research.

††††††††† Each subsequent sponsor seeking approval of the drug under Section 512(b)(1) of the Act must submit similar human food safety data as required to support the tolerance for their product.Each new animal drug tolerance is established for each drug product rather than the drug substance or active ingredient.

††††††††† However, the Animal Drug Availability Act allows for data for an import tolerance to include data submitted by the manufacturer to the appropriate regulatory authority in any country where the new animal drug is lawfully used or data available from a relevant international organization.Any country wanting its producers to become eligible to export to the United States could be a sponsor of an import tolerance."

††††††††† So, based on that information, the question reads:

††††††††† "Only the drug marker residue or the drug substance, not the product formulation, or the sponsor of the import tolerance can be determined by the type of analytical method that is typically used to assay imports.

††††††††† Are there analytical techniques or other approaches that would allow us to determine whether a residue is due to the use of the drug product for which the tolerance is approved?"

††††††††† DR. LANGSTON:I need some clarification here.I thought earlier it was said that there was only one tolerance set for a product.And this is saying it is a formulation tolerance.Could you explain the difference?

††††††††† DR. SUNDLOF:Right, we calculate the tolerance for each individual formulation for the drug.But, somehow, it all comes out to be the same number.I better get some residue folks to help me out with this one.

††††††††† But, generally, we look at the different formulations.Remember, we do have considerable safety factors involved.We try and make sure that whatever tolerance that we do set is sufficiently robust to take into account the various other formulations.

††††††††† So the tolerance is a relatively conservative estimate.If there are slight differences in the data from the various formulations, that pretty much gets taken into account.Dr. Robinson.

††††††††† DR. ROBINSON:To clarify, if you look at 21 CFR 556, the tolerances specified in there are for drug substances, principally, for the active ingredients.A drug product has to go through the full examination, particularly, a pioneer product, has to go through the full examination.

††††††††† And if there is another pioneer product with the same active ingredient that has been previously approved, we still have to go through the process to make sure that the previously established tolerance is the same for the new drug product.So far, we have had no situation in which there has been a tremendous degree of deviation.

††††††††† But, in theoretical case that there were, due to a formulation change that for some reason changed the pharmacokinetics or dynamics of the drug; then if that tolerance was lower for the new drug product, the existing pioneer would also get the new lowered tolerance.Okay?

††††††††† DR. HASCHEK-HOCK:Well, first of all, I think that there should not be a difference between what is accepted for domestic use, domestic tolerance and international tolerance.But does that mean that, perhaps, we do not need to look at formulation for domestic use?

††††††††† I do not know the answer to that question.Theoretically, of course, as indicated, there could be marked differences.But I think the main thing is that both are treated equally, at least in my opinion.

††††††††† DR. KOCHEVAR:Have there ever been instances where they were different, markedly different?

††††††††† You said you thought most of the time they were the same.Have there ever been cases where, in fact, you did end up lowering a tolerance because a second product was different?

††††††††† DR. ROBINSON:I think that Dr. Weber could probably speak to that better than I historically.What I am aware of is that a different formulation has in, at least one particular instance, caused us to adopt an additional tolerance, additional type of tolerance than what was already on the books for that active ingredient.And, in that case, it had to do with the route of administration.So I am not sure.Dr. Weber.

††††††††† DR. WEBER:That is accurate.What we have looked at in the past is make sure, especially where you might see, likely to see differences, is oral versus parenteral, where you get first past effect and things from liver.

††††††††† You want to be certain that one route is not inconsistent with the other in terms of what has been tested.In most of those instances that I am aware of, we often had the oral route first, which gave them more complex metabolism, which dealt with the metabolism issue.

††††††††† It also wound up with a smaller proportion perhaps of marker residue, when you went to a parenteral route, a different formulation or substance, you saw a simpler situation, where the marker might have been higher.But we stayed with the more conservative of the two.

††††††††† What we have affirmed is that the change in formulation was not sufficient to ‑‑ that we have taken into account, that it is not inconsistent with a profile that we have seen before, or the number we selected for the marker.

††††††††† DR. HASCHEK-HOCK:So what you are saying then is that practically it is mainly the route of administration.The change in formulation is because of a change in the route of administration, and is probably the route of administration that makes the difference.

††††††††† DR. WEBER:That is where we see the larger differences because of the liver versus non-first pass effects.

††††††††† DR. MACDONALD:The differences on a solution or an injectable are negligible.On a solid dosage form, however, the concerns can be quite great on the preparation of the basic drug substance itself.

††††††††† This is of great concern on the human side that the absorption studies that you do have product defined in terms of crystal structure.The presence of other crystal forms will greatly affect the dissolution rate and the absorption rate.

††††††††† On the human side of developing products, almost very, very early in the game, you have to define the crystal form that you are going to use for oral studies to define your absorption.

††††††††† The crystal form can range from a non-crystal and a morphous form, which is usually the most soluble, with the best absorption to various crystal forms with lesser absorption.The issue of the different structure, the polymorphs, is a critical aspect on the human side.

††††††††† And, while it has not been emphasized, in the early days on the veterinary side it certainly is a concern today that your product has the same crystal form and the same dissolution characteristics.And, therefore, the absorption characteristics.That is an integral part of the work up these days.So this question of manufacturing does play a role.

††††††††† DR. HOLLAND:What are the ramifications of a country being a sponsor of an import tolerance?

††††††††† DR. SUNDLOF:Well, the country would have to provide the quality of data that we would accept from a drug manufacturer's sponsor in the United States.So they would basically have to meet the same criteria that any drug sponsor would be required to provide us.

††††††††† That means, generally, that they are going to have to work with the drug companies sponsors in order to convince them to provide the information to us, so that we can establish an import tolerance.

††††††††† DR. HOLLAND:So it goes back to the pharmaceutical company?

††††††††† DR. SUNDLOF:Yes, and some of the difficulties with that are that, again, when we look to less developed countries, they may not have access to those data.They may be using generic substitutes that never had to provide that kind of information.

††††††††† So the responsibility or the onus on the country to provide those kinds of information is relatively steep, and we see this extensively in the Codex Alimentarius process, where developing countries are in desperate need to get Codex MRLs, so that they can export their food products to other countries.

††††††††† And, in many cases, they are not ever able to obtain the kind of quality of information that would allow the JECFA in this instance to establish an MRL.

††††††††† DR. HOLLAND:Well, wouldn't this have some profound effects on national versus multinational companies?

††††††††† DR. SUNDLOF:Well, again, the data are generally considered proprietary to the company, whether it is national or multinational.And it is my sense that the country requesting the import tolerance would not be able to compel the company to provide the information if they decided that they did not want to.

††††††††† Now, that may be subject to various laws in various countries, but my sense is that they would somehow have to rely on the good graces of the pharmaceutical firms to provide the data.

††††††††† DR. LANGSTON:Let me propose some options for this ‑‑ for your consideration.I have just kind of been taking notes here, things that people have said, and I have considered, to tell a formulation.

††††††††† One possibility might be a tracer within that substance, an excipient, a vehicle, et cetera, such as someone brought up in a discussion, just benzothene penicillin versus procaine.

††††††††† If you did have different tolerances set, which is unlikely at this point, but if you did have different tolerances for the two products, you could possibly assay for either benzothene or procaine.That would be one option.

††††††††† The other option would be isomeric differences.I will defer to Dr. MacDonald or others.I understand that is quite difficult to do, but possible I suppose.

††††††††† And the third would be possibly metabolic profiles, which we mentioned, where you are looking at metabolic ratios.If it goes through an oral route, it might have a higher metabolic ratio to parent compound.I would suspect that if it is a similar product and route, you would not see a difference.But if it is a different formulation and different route and/or different route, you might see that.

††††††††† So any comments on either of those three options, or any additional options to come up with an answer for the question?

††††††††† DR. HASCHEK-HOCK:Question.Are stereoisomers screened for in domestic drug approval?

††††††††† DR. MACDONALD:Yes, absolutely.I think that today's world, early in the game you have to specify the stereochemistry.Racemic mixtures are just not acceptable anymore.And, not only that, you have to ‑‑ the crystal form is extraordinarily important.

††††††††† DR. LANGSTON:How likely do you think it would be that you could differentiate a formulation based on differences?

††††††††† DR. MACDONALD:The crystal form issue is ‑‑ usually, you see that pretty quickly on a blood curve, if there are differences.The first thing you would do, you look at it in terms of dissolution.Are there any major changes on dissolution?

††††††††† There is an whole array of tests that you can do on crystal form starting with x-ray crystallography, and then looking at characteristics, behavior characteristics.But, yes, you can certainly distinguish between the two.

††††††††† This is something, however, you know, that the animal drug industry lags the human drug industry considerably, and there are not that many new drugs starting off in the animal site.So I do not even know whether this is truly an issue in terms of development.

††††††††† I have a tendency to use a morphous material because you get the best availability, and it is easy to do, and et cetera.

††††††††† In terms of having an analytical method that could distinguish your particular product on an isotopic ratio business, looking at the ratio of C12 and C13, that is something you might have a shot at on a bulk substance, but at a residue level that would be very, very hard.

††††††††† DR. LANGSTON:I will comment personally on the tracer issue.I threw that out for food for thought, but I kind of doubt it would be the case.You would have to have something in the compound that had at least the same or similar half life as the parent compound on metabolite.That would be difficult to come up with.

††††††††† And then if you added something beyond that, you are really adding another substance to the ‑‑ that you have to do toxicity testing on.So I tend to discount my own suggestion, for what it is worth.

††††††††† Any other comments on question 2, additional methods to address, how to detect a different formulation?

††††††††† Let's go to question 3 then.

††††††††† (No response)

††††††††† (Question 3)

††††††††† DR. SUNDLOF:Okay.The issue underlying question 3 is, we are considering how we should inform the public of the import tolerance process while also ensuring that we do not disclose trade secrets and confidential commercial information.

††††††††† So the questions are ‑‑ there is four of them.Should we disclose to the public that we considering an import tolerance for a new animal drug?

††††††††† And, if the answer to that is yes, then when upon request upon filing?

††††††††† C.How should we do so, federal register, the internet?

††††††††† D.How much detail should we provide keeping in mind that we cannot disclose trade secrets or confidential commercial information?

††††††††† DR. GLENN:It seems like this should be consistent with the new animal drug approval process.

††††††††† DR. KOCHEVAR:Just to play the devil's advocate, isn't it a little different though, because that is a new drug, it is a process by which, you know, new efficacy data and data on a number of other things is presented, whereas, these are drugs that are already approved somewhere?

††††††††† And so, they are already in the public domain some place or else they would not be coming to this country for an import tolerance.

††††††††† So, in some sense, it makes sense that if there were a component of this country that did not want a drug to be in their food chain, then the earlier they knew that, the more likely they would be to be able to be involved in that approval process.

††††††††† Whether that is a good thing or a bad thing, I do not know, but that would be the argument for putting it up earlier rather than later.

††††††††† DR. HASCHEK-HOCK:I guess I have not really heard any good reasons.Now you mentioned one about perhaps not wanting to get in the food chain, but I have not heard any really strong reasons for actually disclosing it early.

††††††††† It would seem that it would add ‑‑ I would assume that many of the drugs that would probably be ‑‑ request approval would not get the approval just because the data was not available.And so, that might be a lot more work.But if there are strong reasons for having it released earlier, I would like to.

††††††††† DR. WOOD:I would not argue necessarily for it to be early disclosure, but I do think that disclosure to the public does need to happen.But in thinking about this and hearing some of the presentations today, I think it needs to be offered in a way where then the public has a way to respond, as opposed to simply announcing that this tolerance level is being considered or has been considered.Anne, thank you very much.

††††††††† But there needs to be a format for which there could be a response.And so, in my mind that would mean perhaps then the option of it being published in the federal register with 90, 120 days, or a year for public comment before the issue was finally established.

††††††††† And, in that regard, with question C, working with a number of groups, as we all do, only a few of which love to go to sleep reading the federal register at night, I think it is important that it published in the federal register because that is the official document of government by which things move forward.

††††††††† But I think it is equally important that, at the same time, it be placed on the internet.I do know people with groups with whom I work that actually go to the CVM site at times every day to see what is new, and to monitor and follow developments on issues that are of importance to that group, so a combination of federal register with internet publication.

††††††††† And, again, the notice happening at an appropriate time, not early in the process, perhaps, when the decision has yet to be made, but at some timely point where then there is an opportunity for the public to respond, and for then there to be final action by the agency.

††††††††† DR. HOLLAND:How difficult would it be to collect historical use in some of these compounds in other countries and have that part of the document?

††††††††† DR. SUNDLOF:I cannot answer your question.It may be very difficult.It may not be difficult at all.It is certainly something we could address.

††††††††† If the committee felt that that would be important information to accompany any public announcement that FDA is considering establishing an import tolerance for drug X, and then have, in addition to that, some background information about this drug has been used in these countries for X numbers of years.

††††††††† Is that the kind of thing that you are talking about?

††††††††† DR. HOLLAND:Yes, and adverse effects, if any, that kind of information.

††††††††† DR. SUNDLOF:I think that is something that the committee could recommend.

††††††††† DR. KOCHEVAR:I think you made a really good suggestion, just some sort of provisional approval, where you have a comment period would be, you know, I think a good compromise.

††††††††† DR. HASCHEK-HOCK:The documentation that is provided in apparently what the EPA has decided is that they would ‑‑ if the tolerance limit differs from the accepted international level, then there would be information as to why a different tolerance level was set.

††††††††† And I think that that probably, at that time, that might be a good place to indicate if there are special issues that cause the tolerance limits to be set.And that might address how much detail should we provide, would seem like the information that Dr. Holland suggested, and also any special considerations might be the things that should be released at that time.

††††††††† DR. CARSON:That is what I was going to ask Richard, how specific information would be generic in nature that would be available or ‑‑ I like the idea too of some early notice.But I am just wondering how specific could you get without any proprietary problems there.

††††††††† DR. WOOD:That one I may need a night to sleep on.But I would think certainly, I mean, the concern is the matter of public health.So information that would be pursuant to what kinds of impact it has on public health, what kinds of ‑‑ what has been the experience in relationship to that residue in terms of public health would be the most important thing.So I would not think that those kinds of questions would be proprietary.

††††††††† DR. KOCHEVAR:I think interested parties would be very capable, especially on the internet, of finding information rather rapidly on a substance.I mean, it was not proprietary once they had the name of it.

††††††††† DR. GLENN:I need some clarification on this, as regards to the current activity within an NADA.I took notes here.FDA does not think disclosing information early is important to public health.

††††††††† Is there a new blueprint for expansion of this concept?And, Steve, are we adopting this into various new things in an integrated way, you know, step-wise or ‑‑ and why would we do it here?

††††††††† You know, I am just wondering if there is any negative consequences for doing it in this situation like alarming the public or something, as opposed to a new animal drug application.

††††††††† DR. SUNDLOF:I think we are pretty much constrained in the new animal drug application, as to what we can disclose and when.I do not think we have the same imposed constraints with this process, where the committee is asking for advice.If you had it to do all over again, would you disclose this information earlier, in the interest of public's right to know?

††††††††† One other thing, as long as I have got the floor here, with any of our NADAs, once we approve them, we have a freedom of information package that goes with it and it outlines the basis for our decision on what the tolerance should be.

††††††††† So it does not give specific data, but it does summarize the data that were used in saying why we came out the way we did.

††††††††† Now, I presume that we would do the same kind of thing if we were setting an import tolerance, in which there would be some kind of freedom of information statement that went out with it, that basically disclosed the basis on which we established the tolerance.

††††††††† DR. GLENN:I do not have a problem with transparency of the public.

††††††††† DR. KOCHEVAR:I think communicating with the public is one of the things we need to do very well.But I just wanted to understand if there were ramifications on the current activity of the agency.

††††††††† And, you know, you say, well, we are doing it here, but you are not doing it there, and I do not know what implications that might have.It seems like maybe the one difference there is what you were getting at, and that is there is a history to these drugs; whereas,. there are no histories really to the NADAs.

††††††††† DR. LANGSTON:Also, we have the full regulatory process looking at this whole drug from start to finish here, and we do not have control over that in a foreign country necessarily, would be another factor.

††††††††† Any other comments?

††††††††† (No response)

††††††††† DR. LANGSTON:Okay, issue number 4.

††††††††† DR. SUNDLOF:Okay.Issue number 4, we are just seeking advice.So I guess there is not a specific question here.It says:

††††††††† "We are considering amending the regulations at 21 CFR 25.33, to allow a categorical exclusion for import tolerances under the National Environmental Policy Act, if there is information that shows that establishing import tolerance does not have a significant effect on the environment.We are seeking information on whether import tolerances will have a significant impact on the environment or effect on the environment."

††††††††† DR. HASCHEK-HOCK:(Away from mike)I assume you referred to ‑‑‑.

††††††††† DR. SUNDLOF:I think that is how ‑‑ that was the intent under which this was written and not the effects on the environment of the country that would be importing animal products.

††††††††† DR. KOCHEVAR:What is the basis now for excluding most drugs from environmental impact studies?

††††††††† DR. SUNDLOF:They were listed earlier.But, basically, if we consider that the use would be insignificant to cause an environmental hazard.

††††††††† DR. KOCHEVAR:Okay.So there is not an elaborate process.It is just ‑‑

††††††††† DR. SUNDLOF:Oh, it is a pretty elaborate process.

††††††††† DR. KOCHEVAR:To be able to get it excluded, it is an elaborate process?

††††††††† DR. SUNDLOF:The company basically has to make a solid case as to how much they believe is going to go into the environment.In the human drug areas, there is a cut off limit that you would expect less than ‑‑ and I cannot remember if it is one part per billion, or 10 parts per billion, or something along those lines.

††††††††† But if you expect that the concentration in the environment would not exceed some cut off level, that that would qualify companies for a waiver for doing an environmental study.There is a number of issues that we look at.

††††††††† For instance, our drugs is going to be used in environmentally sensitive areas like in aquatic environments.Are they going to be used in CFOs, these concentrated animal feeding operations, where there may be a lot of the drug ‑‑ you know, a substantial quantities of the drug being used?

††††††††† And so, you have a very point, you know, concentrated point source where there might be environmental damage as the result of the drug itself versus situations where the drug is going to be administered by a veterinarian during the course of his practice on an animal-by-animal basis, where you would expect very little environmental damage.

††††††††† So, a lot of these issues get weighed.And, depending upon the final analysis of all of those different criteria, the company either is granted a waiver, or they are not.And they are required to provide some environmental impact data that can be substantial thousands of pages.And so, it is highly variable.In this case, the drug is not going to actually be used in the United States.

††††††††† DR. HASCHEK-HOCK:Given that only edible tissue would be imported, are there any associated issues with environmental spread of the compound?It would seem that there would be none or negligible.

††††††††† DR. LANGSTON:I cannot think of any.

††††††††† DR. WOOD:We are done with that one.

††††††††† DR. LANGSTON:All opposed?

††††††††† (No response)

††††††††† DR. SUNDLOF:Okay.Then I assume, Mr. Chairman, that we are done with issue number 4?

††††††††† DR. LANGSTON:Yes.

††††††††† DR. SUNDLOF:Okay.Then issue number 5 is please comment on any other aspects of import tolerances you may wish to raise.And I think we already heard one.

††††††††† DR. LANGSTON:I would just emphasize that we certainly have heard those about unfair practices or competitive disadvantages, these sorts of things.I think that is fair to include.Does anyone have anything else along those same lines?

††††††††† DR. KOCHEVAR:I guess I would just have a question, and it kind of came up earlier.We are going to have some discussions in the next couple of days about antimicrobial resistance, and how much impact, or how much discussion will be had by the public at large if now antimicrobial that are not approved in this country are entering our systems.

††††††††† It is true they are not entering the systems of animals that will excrete them and have resistance coliforms, and so on, and so on.But how much of an issue is that for public health concern?

††††††††† I mean, you know, it will now be in our GI tracks, and is that a significant issue?

††††††††† DR. WOOD:I would like to keep it on the table in some way ‑‑ I mean, if only as an emerging question that would be before us and before CVM as they develop policies dealing with antimicrobial approvals for new approvals in the U.S.I think that companion aspect of that needs to be looking at what kinds of impact does that have on import tolerances as well.

††††††††† DR. ANDERSON:I agree.And also, I just wanted to be clear.I am not certain that we are only talking about antibiotics that go into the human intestine, because I thought in the aquaculture talk that he had said that part of the import is in fish meal.

††††††††† So couldn't that be given to animals, and then we have antibiotics that are being given to animals and residues could be excreted into the environment?

††††††††† DR. KOCHEVAR:So I did not get that.So we are talking on import tolerances could actually be drugs that are not approved in this country that are present at some level and substances that will then be fed to animals?

††††††††† DR. SUNDLOF:Alicia raises a valid point, but it is separate from the import tolerance issue.Just to bring people up to speed, there happens to be an issue in Europe in the European Union right now in which they have traced chloramphenicol residues back to shrimp meal.

††††††††† Obviously, shrimp meal that came from a country probably, we would guess probably ‑‑ and I should not guess.So I am not going to same where it might have come from.

††††††††† But I think that would ‑‑ I mean there should not be drugs unless they are specifically added to feeds.And if we found a feeding substance that contained antibiotics or other animal drugs, that would not be considered fit for animal feed.I mean it just would not.

††††††††† We do not need any new regulations on that unless somebody ‑‑ if somebody wants to import feed that contains specific medications, they would have to go through the new animal drug approval process.They do not get by on an import tolerance.

††††††††† DR. LANGSTON:Any other comments?

††††††††† DR. WOOD:Back on the first one that you raised, and that Deborah raised earlier on banned substances, and how to handle.For me, that is not just a question of being fair to the industry, I guess, but it is also a question of protecting human health.

††††††††† And I do not know if that is really an appropriate way to handle it here, and it may be more of an enforcement question.But, I mean, the reason why a number of these substances were banned was because of the findings of the FDA that they did have a negative impact on human health or detrimental to human health.

††††††††† And, yet, we are saying there simply needs to be a zero tolerance.You can use it with your animal, but when we are importing it there is going to be a zero tolerance.

††††††††† Out of my own feeling of, I guess, skepticism, we trust that all of the drugs residues that are illegal are being caught as they come into our borders.But I am sure that is probably not always the case.

††††††††† And though we have to allow that to happen in areas where tolerances have been established, to allow a tolerance to be established on ‑‑ even a zero tolerance to be established on a drug that is banned, in a way to me, opens the door to placing human health in the U.S. at risk.

††††††††† I would rather that we not do that, perhaps, because of trade questions we are not able to ban or place ‑‑ or to ban a substance on those terms, but it certainly is a concern to me.

††††††††† DR. PARKHURST:I would have to second that, and I think it is an issue of, is there equipment good enough to detect that zero level?Because the zero level could fall getting more sophisticated equipment.And if somebody has decided that it is banned, I mean, enough work has been done, that that is an issue.And I think it would be almost falling down on our job to let it go through.

††††††††† DR. WAGES:I agree in principle, but we have got to remember that there is an import and there is an export, and countries will use a potential ban that we have and impact our exporting abilities because of, I'll say, foo foo dust.

††††††††† The things that are of concern raised for diseases, et cetera, that have no implications on human health and still can ban our products.I agree with you.I mean, I think my gut reaction is it not good enough for our animals, and there has been a concern from a public health standpoint why they were removed.

††††††††† There is no way that I would support continuing to import food that has been fed that, but it is a two-way street.We need to be careful before we recommend.

††††††††† DR. LANGSTON:I would also point out that these drugs were banned for potential public health impact.I am not aware of any proven public health impact on these.That is not to say they could not occur, and that is obviously why the FDA banned them.

††††††††† You can get into issues of whether you believe that or you do not, but for me it is a bigger issue relative to being fair to the producers, notwithstanding that perhaps it is an issue for some people.

††††††††† DR. GLENN:So just wait until we do public disclosure of that particular issue.

††††††††† DR. KOCHEVAR:So how would it work though if you were going to say we just, for whatever reason, decide it is not acceptable to import food substances from countries that say it is okay to use, for example, chloramphenicol, even though we are going to have a zero tolerance?

††††††††† What would be the alternative?Do we say to those countries, if you have a producer who wants to import food to this country, they must be certified as not using these drugs on their ‑‑ you know, in their operation?

††††††††† I mean, what alternatives would you have?Because we cannot really dictate what country X wants to ban, in terms of their drugs.But is there some in between ground that would make that feasible?

††††††††† DR. SUNDLOF:Yes, I think there is.And, certainly, under the World Trade Organization, we have set a standard, a safety standard for our country that says any use of this particular drug is inherently subjects our population to a greater risk than we think is acceptable.

††††††††† We could make the case, since that is our standard, we have set a specific safety standard for our public; that we could make the case that any country that wanted to import, did not meet our standards, and we would probably be sustained.Our position would be sustained in the World Trade Organization.

††††††††† So I think we have that capability to do that, but there may be other ways to get around that if we have some kind of adequate assurance that any products were imported in the United States were not exposed to that particular drug.I think there is probably several different options that could be used.

††††††††† DR. LANGSTON:Any other comments?

††††††††† (No response)

††††††††† DR. LANGSTON:Just a reminder then, I am sure there will be a few procedural comments after this.But we will start off first thing in the morning going through these questions, asking each of you for your opinions on them.It won't be a formal vote, per se, but we will be collecting your views on the issues.

††††††††† DR. WOOD:And then you will be summarizing where the committee stands as a recommendation?I mean, what goes to Dr. Sundlof then following tomorrow's responses?

††††††††† DR. LANGSTON:Dr. Sundlof.

††††††††† DR. SUNDLOF:We would like to get the consensus of what the committee's decisions are.So, hopefully, you will be able to have your answers somewhat sketched out so that we can go back and say this is what the committee recommended to us on each of those.

††††††††† DR. LANGSTON:I will try to put together a summary with input from the committee.

††††††††† DR. SUNDLOF:Okay.Mr. Chairman, I turn the meeting back over to you.

††††††††† DR. LANGSTON:Okay.Are there any other issues?

††††††††† (No response)

††††††††† DR. LANGSTON:In that case, we will adjourn until 8:30 in the morning.

††††††††† (Whereupon, the meeting was adjourned at 4:24 p.m.)