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**BREAKOUT GROUP DISCUSSION - AVIAN**

**February 23, 2000**

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**WELCOME AND INTRODUCTION**

Dennis Wages 3

**DISCUSSION/QUESTION/ANSWER** 6

**KEYNOTE: \"\-\--\" Indicates inaudible in transcript.**

**BREAKOUT GROUP DISCUSSION - AVIAN**

(2:02 p.m.)

CHAIRMAN WAGES: All right. We are going to go ahead and get started, if
you will. My name is Dennis Wages, and I am the moderator for the Avian
Breakout Group. As a moderator, I wanted to kind of lay some ground
rules I guess, if you will, and let you all know that my background is
not about pre-approval studies, nor experimental models or anything
other than the knowledge of the species that we are dealing with.

And hopefully my input would be more in a practical sense when you start
looking at comparison of in vitro versus in vivo versus field studies.
Plus, I guess we drew straws and I lost, and that is why I am moderator.
But I will be giving the summary of this group\'s information tomorrow
at the summary portion of the program.

We are not looking for a consensus, but if consensus points do arise,
those will be emphasized in the summary; however, we will try to take
all points that are presented and give them in the summary. But again,
if I can emphasize certain portions of our program because of consensus,
we will be tickled to death.

We have got some technical difficulties going on here. We are going to
try to allow about an hour per question. We have got about six hours for
the breakout sessions, and we are going to try, give or take, to spend
about an hour per question. Some, it appears, will take longer, and we
will modify that, and then hopefully, that will give us about an hour
tomorrow to either summarize or, if, in fact, we have other questions
that arose during our conversation or dialogue, we will include those.

We are going to keep on track the best we can, and we want to stimulate
dialogue the best we can. But I am going to be one to intercept a
monopoly on the conversation extremely fast. I want as many people to
give their opinions, and we want to stimulate discussion between
individuals. But we don\'t want a filibuster to start, and the moderator
will take very straightforward procedures to stop that.

We have a microphone use. We have got a lady that is recording the
entire thing. So at first we are going to try with her microphone. She
has kind of got a portable microphone that is on her table. Hopefully,
just speak loud enough and clear enough and that will be as far as we
need to go with microphones.

If it appears she cannot record the information, we have a portable
microphone, and we are going to have to probably use this front row to
have people speak into it. So try to speak loudly and clearly, and we
should be okay.

Jeff Gilbert will be our CVM scribe who will be putting things on
PowerPoint for us, which will be the focus of what I will present in our
summary tomorrow. I want to represent you and the group much more than I
want to represent me. That is very important to me.

And then, David Grau will be the facilitator from CVM, and I am going to
turn it over to him to make a few comments and then we are going to get
started on question one. David.

DR. FLYNN: Can I just make a point?

CHAIRMAN WAGES: Yes.

DR. FLYNN: Based on the last session I guess, we wanted to try sort of
add some questions to this list, and I think one general question that I
think was brought up among a number of people at the panel discussion
was the basic objective question in terms of the \-- you know, what is
the primary objective or objectives of these studies.

So that may be a good starting point, to spend some time talking about
that first before moving on to some of the other questions that are
there that are a little bit more detailed. I was just kind of giving
that message to everyone.

CHAIRMAN WAGES: The objectives of pre-approval studies in general?

DR. FLYNN: Right.

CHAIRMAN WAGES: Okay.

DR. FLYNN: Thank you.

CHAIRMAN WAGES: David?

CO-CHAIRMAN GRAU: My role is just to insure the process that we will be
using today. But also, to start off with, are there other questions,
time permitting, in addition to the now six that we currently have, that
you all would like to address either later this afternoon or tomorrow
morning?

So, in addition to the five questions as you see in your agenda and now
this initial question about objectives for outcomes on pre-approval
studies, what other questions would you like to see this group address?
If you don\'t have them in mind right now, as we go along, please feel
free to raise those questions that you think would be important to take
a look at.

And what we will do is I will ask Jeff to, please, make note of those
questions. And then, hopefully we will make time to address as many of
those questions as we can tomorrow morning. So, are there any right now
that you can think of that you feel aren\'t adequately addressed either
in the agenda or by this first question?

DR. FEDORKA-CRAY: Excuse me. Other questions? Is that what you are \--

CO-CHAIRMAN GRAU: Yes. Other questions that you would like this group to
take a look at.

DR. FEDORKA-CRAY: Perhaps I would just raise the \-- some of these
questions already seem to be, the ones that I would approach, a given
model that was already developed. And it would seem that one of the
things that we would have to do besides define the objectives would be
then to define a model and then to say whether there were positive or
negative aspects associated with it.

I mean, one of the first questions was the positive aspects of study
concepts presented. You know, there were so many different kinds, you
know, hundreds of questions presented and need to be addressed, and
there were no \-- and there is not a cohesive focus. So, to me then, you
would have to not only define objectives, but focus and define some type
of model that then we can defend and give the pitfalls and the positive
points associated with that.

CO-CHAIRMAN GRAU: So are you suggesting that this group first comes up
with a model? Or, after all the discussions, propose a model based on
the conversations that ensue over the next five hours?

DR. FEDORKA-CRAY: I guess the way I would look at these \-- because some
of these also don\'t seem to fall in the order that I would think would
be necessary to define some of the parameters associated with that \--
would be to look at objectives and then to define a model and then to
list the positive aspects of the model, such as the data gaps, and then
to list a proposed series of steps to achieve the model dynamics. And I
think that if that can be done in five hours, that is a tremendous
accomplishment.

CHAIRMAN WAGES: But don\'t you think, Paula, that we need to know the
objectives, what we are trying to get at, prior to \--

DR. FEDORKA-CRAY: Right. I said the objectives first. So the first thing
was objectives.

CHAIRMAN WAGES: And then the most appropriate model that would come
close to answering those questions.

DR. FEDORKA-CRAY: Exactly. Yes. I said objectives first.

CHAIRMAN WAGES: I am sorry. I missed that.

CO-CHAIRMAN GRAU: Other thoughts on what was just proposed?

DR. KRUSHINSKIE: My understanding of these questions \-- I thought these
were just sort of to start the dialogue, but not necessarily to go
through, lock-step, through these? Or is that not the \--

CHAIRMAN WAGES: These were \-- my understanding is they were placed in
our agenda to try to cover these. They were CVM\'s best shot at what
they wanted to answer, knowing that it would stimulate other avenues of
dialogue.

DR. KRUSHINSKIE: I think Paula\'s point is well taken, that we don\'t
have a model to discuss.

CHAIRMAN WAGES: I know.

DR. KRUSHINSKIE: We need to do that, and then these are good questions
to ask about a particular model. And maybe the idea, when they wrote
this up, was that there would be more of a concrete model together by
the time it got to this point.

CO-CHAIRMAN GRAU: Right. Something that the group could reflect on
during the conversations.

DR. GILBERT: Can I add something to that?

CO-CHAIRMAN GRAU: Yes. Go ahead.

DR. GILBERT: I work in that pre-approval studies working group. Indeed,
we are hoping to get input from outside about what is the best model.
You know, we are relying on you guys, the experts, to tell us is there a
model, Paula, that we could follow. If there is, please, the mike is all
yours. We have some ideas in mind, but again, we wanted to get everybody
else\'s opinion on what they would be first.

DR. WEBER: Didn\'t I hear that perhaps overriding \-- at least in the
discussion as initially presented \-- was the rate and extent of
resistance development as a result of the use of the antibiotic in say
enteric bacteria? That was one objective that was a starting point for
his presentation.

CO-CHAIRMAN GRAU: Right. So that would be one of the objectives. So does
that sound like \-- going back to Paula\'s suggestion, what do you
think? Does that sound reasonable?

CHAIRMAN WAGES: So, once we go through the objectives of a pre-approval
study, then we would look at the appropriate models that potentially
would put us in line to meet those objectives. And then, if and when we
get through that, then we could go and answer questions appropriate to
specifically a model that we feel comfortable with to answer the
objectives.

Is that what I hear you saying? Is that the group\'s wishes?

VOICE: Yes.

CHAIRMAN WAGES: Okay. Well, we have had one comment already of the
primary or a major objective being the rate and extent of resistance
development. Do we want to expand on that anymore? Or is that \-- that
is kind of broad in my estimation, but \--

MR. : Dennis, don\'t we have to include in this, in the objective, what
the outcome \-- how we are going to use the results from whatever model
is set up to make a decision as to whether this drug is approvable or
not?

If this is a pre-approval study, then the study, or studies, must be
pivotal to the approval of the product. So we have to define what it is
we are looking for that will tell us whether a product can be approved
or not and under what conditions.

DR. FEDORKA-CRAY: Yes. I think maybe we are \-- I mean, the way I see
this is I am almost looking at it as if they are walking in the door \--
if you are walking in the door with an application, the first thing you
would do is you would look at the compound. The objective would be to
define the class of antimicrobial and the potential risk resistance
mechanisms that would be associated with it. You know, that we would
already know or that we wouldn\'t know.

DR. KOTARSKI: I agree with Paula. You need to know the spectrum of the
activity of the drug and you need to know \-- having known that
perspective, identify what are the potential resistance mechanisms; of
known mechanisms.

DR. MEVIUS: Is that an objective?

DR. FEDORKA-CRAY: To me, that would be objective one.

MR. : My concern is there is questions that would \-- we could maybe
find answers for that would be nice to know and we should know about the
product. But I guess, from an industry standpoint, I want to know what
it is that we have to do and what questions we have to answer to get the
product approved.

DR. FEDORKA-CRAY: But if you don\'t go in there, don\'t you think \-- if
you go in there with that information right up front to a bunch of
reviewers, that that will lay out the scenario for the thought process?
I mean, to me you would want to have it as tight as possible so that you
wouldn\'t leave any room for them to wonder where you were coming from.
I don\'t know.

MR. : Right. I don\'t know how that helps them make a decision to
approve it. That is my point.

DR. MEVIUS: The objective will still be study rate and extent of
resistance development. And then, during the process, the first thing
you will want to know is what are the mechanisms \-\-- spectrum of what
is existing in the field already and then we will go on building the
model and study what the effect is.

I think also you should include in the objectives study rate and extent
of resistance development of a given dosage, because you are studying at
a dosage regiment, and it is not just the product because \-- well, when
you are talking about dose optimization. If the dosage regiment \-\--
effects on resistance selection. So I think it should be more defined
and relate to a dosage.

You are licensing a product in a given dosage for regimen and \-- for
the specific regimen you want to have a pre-approval study done or a
pre-approval study is done.

CHAIRMAN WAGES: Yes, sir.

DR. LUTHER: Lonnie Luther, with the Office of New Animal Drug
Evaluation. I have been with the pre-clearance arm of FDA for 25 years.
We traditionally and statutorily been asked by Congress to show safety
and effectiveness of a new animal drug product. We have done that
primarily in the target animal, with concern for \-\-- indication for
use and the dosage; frequency and duration of dose.

But now we come to a new hurdle, and that is the demand of the public to
show that antibiotic resistance isn\'t transferred to other parts of our
environment. Primarily to human health care. So our overall riding
mandate there is to protect the public health.

So I think one of the first questions you have to ask is what is this
new hurdle, and that is why we are here, to discuss what kind of data,
pre-clearance, data should CVM ask for on this new animal drug
evaluation or ask for for a new poultry antibiotic. And what kinds of
information will allay the public health concern.

I don\'t know if that helps, but I think our objective really here, in
terms of antibiotic resistance, is to have at least a defined study that
will demonstrate that the public health is not compromised.

CHAIRMAN WAGES: Excuse me. He has his hand up. Go ahead.

DR. WEBER: One of the issues there where this is important \-- but also,
that after this is learned, is what to do with it, and I think there are
further decisions that need to be made on the management or resistance
dealing with it that come after you learn certain aspects. So there are
going to be management decisions in terms of post-approval that might
come from this information, and that was discussed in the last time.

As far as the amount and the dosage and duration, is it not possible
that you might have more resistance develop at some suboptimal dose? In
other words, if you go ahead and you kill all the bacteria or you make
some effect at the full dose, but if it is suboptimal in some animals or
half the dose or someone is not using it, in fact, you may get more
resistance development at the dose than you would at the full dose.

So there are issues about what is \-- what doses should you study, and I
think that was one of the questions. If you study it at the full optimal
dose and PD/PD the outcomes, that you might find an actual \-- an
optimal dose to deal with the resistance development.

If you want to get a handle on \-- like Dr. Anguelo said about finding
the genes that might be occurring with this, you might wan tot develop
that through some other in vitro studies or some sort.

CHAIRMAN WAGES: Yes. Go ahead.

DR. MEVIUS: First I will respond to you. Then I would like to respond to
you. I think this should be one of the purposes \-\-- optimize dosage
regimen \-\-- would be in a model \-\-- for the period you are going to
look at.

So I think the dosage for it, or the minimum dosages are really the
highest and the lowest dosage in the \-\-- should be included.

And to come back to you, I think probably the health issue is an
important basis of this discussion. But if you want to have a study done
to really get some answers, you need to have years of research with a
lot of molecular epidemiology, and the first step in this potential
public health research whether there is resistance. Yes or no.

If you can define dosage regimens for \-\-- would minimize the challenge
of selection of resistance, and it would also minimize the chance of
public health concern. So there is no way of giving a simple model of
answering public health concerns, because it is very, very complicated.
It depends on the bacteria and the resistant genes and there is a lot of
very specialized work \-\--

DR. GILBERT: Let me just add one point there. Yes. There is no simple
way. But is there a way we can proceed with now, knowing that it may
take 10 years or whatever? Or a lot of molecular work in the genetics
and in vitro and everything. That is going to take a long time.

Our alternative would be probably just to shut down and say no until we
figure this out. But we want to proceed. We don\'t want to, you know,
block development discovery. We have got companies that have products
that want to come down the pike. Is there anything that we can start
with now and say this is our best guess in February of 2000, as far as
what kind of study we can put together to get these drugs through?

DR. MEVIUS: You are asking me?

DR. GILBERT: I am asking everybody.

MR. : I guess, if you look at things that way, where we want to get
things going again, then I think you get back to where you have the
compounds, you characterize resistance, you look at \-- you do these
types of things and you beef up your post-monitoring, your NARMS; you
beef up your NARMS. You do this kind of information based on what you
have determined are the mechanism in those things.

I am not sure you will have all the studies or \-- if you go back to
dose selection, you know, first of all, I am not sure if you will ever
have the study to really \-- once something gets out into the market, to
really say what is going to happen and get out of the market.

I think you have to understand a compound and know what you are looking
for once it gets out on the market, but you really need to beef up NARMS
and do those types of things.

CHAIRMAN WAGES: Yes, sir?

DR. WEBER: One of the objectives I thought I heard, and it sounded like
a good one, is if you are allowed more than one, is to begin in these
studies to collect some information on potential mitigation strategies,
like knowledge about the time for the resistance to subside or diminish.
Again, that is part of the rate and extent; to see if part of the
information on the decline aspect, as well as repetitive dosing.

So I think that \-- if that is a broader subset of the rate information,
I think that is going to be important in terms of potential downstream
mitigation strategies. For example, I believe the \-- one of the models
being considered now in some of the studies we are seeing is extended
dosing and removal from dosing and re-dosing. So there are two or three
aspects that are currently being looked at in terms of resistance
development and decline.

CHAIRMAN WAGES: But, from a practical standpoint, in poultry, the
re-dosing won\'t be an issue. I can tell you \-- count the number of
re-dosing that occurs in the field after an antibiotic has been used on
very few fingers. So we are getting into a thing that is theoretically
great for somebody in the laboratory to look at how resistance occurs,
but we are not going to be multiple dosing chickens in the field. So why
should that be an integral part of how something gets approved or, you
know, a claim put on.

Maybe I am missing something. You are looking at the guys who has got to
defend all this.

DR. WEBER: But isn\'t that a subset that might be useful in other
species and not particularly useful here because of what you just said
in terms of the dosing regimens you actually use.

DR. KRUSHINSKIE: You also have your judicious use guidelines. The
judicious use guidelines of antibiotics addresses the appropriate
mechanism of using antibiotics to control resistance issues, as well as
retaining the efficacy of those products.

The other question I have \-- when you started talking about looking at
dosages, that you are going to look for resistance or controlling dosage
or dosage, maybe I am not understanding it, but it sounds like one
dosage is the dosage that is efficacious against the target organism,
period. That is what the products are licensed on.

If I am using batril (sic) to treat E. coli., I want the dosage that
treats E. coli. Whether that creates resistance in camplyobacter or not
isn\'t really pertinent to whether that should be licensed for the
treatment of E. coli. If that under doses camplyobacter and creates a
resistance issue, that is a concern.

But in looking at testing for release, are you going to take every
camplyobacter and salmonella glove lot and determine what the optimum
dosage is and control resistance development in each of those species?
And then which dosage are you going to license for?

If it is 10 times higher to control resistance in camplyobacter than it
takes to treat E. coli., it is not cost effective for me to treat E.
coli. with this drug. See what I am saying? Most don\'t really
necessarily go hand in hand.

CHAIRMAN WAGES: Paula, go ahead.

DR. FEDORKA-CRAY: I think that is the crux of the situation here. Maybe
you can present it as sort of a main focus and then the subset or the
other information that we have to know that helps to provide information
for public health.

But I agree. It is the dose that would be indicated for the target
pathogen and why look at other doses, if that is what the approval is
based on. But, at the same time, I don\'t think that it would be bad to
have other studies going on say, you know, in support of measure and
whether \-- to understand. And whether that is done by the company or
that is done in a research situation where we have other labs or
programs supporting it, I think those are different models that you
would be talking about looking at different doses, multiple doses,
because you are going to get caught in a situation here when you can\'t
get all the parameters looked at in a timely manner to get anything
through.

DR. KRUSHINSKIE: I don\'t think they are all going to come together to
be one \-\-- one uniform dosage.

CHAIRMAN WAGES: And you are really looking \-- from a practical side of
things, it is more like a therapeutic uses. I am not going to go put my
money in the stock of the company that is investigating growth promoting
antibiotics to go in food animals. So it is a therapeutic regimen.

The bottom line is, in my mind, and the problem or the questions at
hand, is does it, by the therapeutic use of this product effect the
potential zoonotic pathogens in their course of exposure during a
treatment regimen. Is that not really the bottom line on what we are
worried about?

You know, in poultry it is camplyobacter and salmonella as a result of
treating E. coli. with a fluoroquinolone. Correct? And so \-- pardon me?

DR. MEVIUS: It is not just \-\-- because it is also present of resistant
genes in commensal flora that can

become \-\-- so it is more complicated.

CHAIRMAN WAGES: Correct. I agree with you. And the potential transfer of
that. And then, I guess what boggles my mind is I don\'t see how we are
going to sit here in six hours, versus 25 hours, and establish a study
that could answer those questions.

DR. MEVIUS: But if this should be part of the development of \-- whether
it is a new drug or a new formulation of an old drug, in the development
the company also takes this into account; that the dosage regimen should
not only be effective, but also should have the least potential for
resistance selection.

For instance, Virginiamycin used for control of posterior enteritis as
you presented yesterday. That is therapeutic use or that is mixed in the
feed. But also, if it is longer term use, it could very well be the case
that strategic use in shorter term at higher dosages would have the same
therapeutic effect of posterior enteritis and less effect on resistance
selection. So this is the point I am making.

CHAIRMAN WAGES: I understand. But also, you have to look at the big
picture of what the pharmaceutical companies are up against. You know,
they spend their research dollars right now defending use instead of
investigating new use, you know. And to put enough hurdles in front of
the pharmaceutical companies, you\'re looking at all the drugs that is
going to be approved for food animals in the United States. And if you
don\'t believe that, I will sell you some land in Florida.

DR. MEVIUS: I think the categorization here in CVM will be very
important as \-- thinking about which drugs are going to be categorized
as category one \-\-- I don\'t know really which other drugs will be
category one, and maybe the guidelines or the general rules for category
two drugs can be quite different.

That is not so really relevant. That is not a direct public health
threat. So maybe \--

CHAIRMAN WAGES: Well, Virginiamycin is going to go into category one. So
they said.

DR. MEVIUS: Certainly. It should, of course.

CO-CHAIRMAN GRAU: Any other objectives?

CHAIRMAN WAGES: How many of what we said are actually objectives? Can we
go back and at least look and bullet what we think is objectives.

DR. GILBERT: Yes. Define a model and then defend critique; study the
rate and extent of resistance development; decide what we are going to
do with the outcome results of those studies; what sort of impact they
are going to have. You know, once we find out the bad news or good news,
then what do we?

It looks like we need to address the compound first; figure out its
spectrum of activity; study something about the mechanisms of the
genetics; focus on a dose regimen, which I totally agree with. That is
what we have been trying to do. It looks like dosing regimens is an
important issue. Beef up NARMS.

DR. FEDORKA-CRAY: I mean, I would say I don\'t think those are all
objectives.

CHAIRMAN WAGES: Yes. I would just hoping somebody would bullet the
objectives so I know what is objectives and what is explanation of
objectives.

DR. FEDORKA-CRAY: Can we get a white board in here?

CHAIRMAN WAGES: We talked about that. We wanted a sheet. I don\'t think
we have an access. Should we try? I wouldn\'t mind bulleting; go back
and get the consensus, at least in the group, on what is \-- bullet the
\--

DR. GILBERT: Well, I guess define a model. Would that be number one?

CHAIRMAN WAGES: That would be an objective. I am not convinced we have
to one, two and three them. Let\'s just say \--

MS. : The model addresses the objectives.

MS. : Right. You need objectives of what your model is going to follow.

DR. KRUSHINSKIE: If it is to study the rate and extent of resistance
development, can we take \-- in what? In the target species? Is there
any consensus opinion on what it is that we are modeling the rate and
extent of resistance development in? Is there more verbiage to that in
that guidance document?

CHAIRMAN WAGES: Well, it has been alluded to that we are interested in
the target animals and the commensals, which have the potential for
zoonosis, as well as the ones that have the potential transfer, such as
the enterococci. I mean, that is a broad stroke of all bacteria.

DR. KRUSHINSKIE: How many species in the gut? I mean, you can\'t do it.
That is what I am saying. There is 400 or some.

CHAIRMAN WAGES: Again, I am just the devil\'s advocate up here trying to
stimulate things. They will keel on E. fecum and fecalus (sic). Probably
in the enterococci and a couple of campys and a couple of salmonellas.
You know, that may be the keys. I don\'t know.

DR. FEDORKA-CRAY: Can you say study the rate and extent of resistance
development using \-- at the indicated dosage in the \-- for the target
animal pathogen, and then, you can make two define the effect or define
the resistance effect? Or define the development of resistance as a
result of the indicated use in salmonella, camplyobacter and
enterococci?

CHAIRMAN WAGES: Would everybody agree that those at least are the three
biggies that we are considered with?

DR. WEBER: You said enterococci. Right? The fact that \-- for example,
Virginiamycin \-- and I am not a microbiologist. But it is now indicated
for use in clostridium; for clostridium. What you would say is that
would be a specific indicated organism.

DR. FEDORKA-CRAY: Or that would be the target.

DR. WEBER: But if you had something that was targeted for camplyobacter,
would you not look at clostridium? Is that one to consider, in other
words, of the five that we have looked at? Or six.

DR. FEDORKA-CRAY: I don\'t know that I would make that one that I would
look at.

DR. GILBERT: Paula, what were your bugs again?

CHAIRMAN WAGES: Salmonella, camplyobacter and enterococci.

MS. : He asked if it should include clostridium. That is what the
question was.

DR. MEVIUS: How about \-\-- more general. I think \-\-- make it more
general. Food-borne pathogens, like salmonella and camplyobacter.

CHAIRMAN WAGES: But not in poultry though, and we are dealing in
poultry.

DR. MEVIUS: All right. And let\'s say indicator organisms or \-- of the
commensal \-\-- like E. coli. or enterococci, because you can choose
others as well. But, at the moment, E. coli. and enterococci are used.

DR. FEDORKA-CRAY: I think, if you don\'t define it, Dick, the way things
go here, then there is going to be a laundry list of, you know, 12 or
15.

DR. MEVIUS: The problem is, Paula, if you have drugs like, for instance,
\-\--

DR. FEDORKA-CRAY: I agree.

DR. MEVIUS: \-- the enterococci to E. coli. So what are you going to
study then? So you have to have the concept, and it should be commensal
\-\-- which is, by nature, susceptible, and then that could be used as a
model bacteria. And, if possible, maybe enterococci and E. coli.

DR. FEDORKA-CRAY: I guess I would just put in there then a qualifier
saying limited it to the two top bacteria of concern.

DR. MEVIUS: Right.

DR. FEDORKA-CRAY: Otherwise, you run the risk of \-- okay. Well, if we
didn\'t find it here, then let\'s look there. If we didn\'t find it
there, then let\'s look here.

DR. GILBERT: Who is the two top?

DR. FEDORKA-CRAY: Just like Dick said, you have to look at the \-- what
the drug is going to be \-- you know, where there is going to be some
effect and not something that has inherent resistance to it.

DR. GILBERT: I think Paula hit on something. I mean, this is your
opportunity to input. If you want solely to look at salmonella and E.
coli., tell me that. You know, is this a good list here?

CHAIRMAN WAGES: Would it be a consensus of the group to have those
organisms as it reads? Or would it be more appropriate \-- I wouldn\'t
have it, all those on there. I wouldn\'t have E. coli. on there.

DR. MEVIUS: It is important.

CHAIRMAN WAGES: Well, for what?

DR. MEVIUS: If you want to have a model study just to study the effect
of the use of a drug active \-\-- gram negatives. The problem with
salmonella, and also in camplyobacter, is it is not so easy to randomize
a sampling strategy. You have a lot of enrichment techniques, of course,
and not all animals shedding salmonella. Camplyobacter you have
selective plates with antibiotics in there. So E. coli. would be a model
bacteria by itself. By nature, \-\-- then you could study in this model
the effects of the dosage regimen on the resistance selection.

MR. : Do we know that E. coli. is a good model for salmonella and
camplyobacter?

DR. MEVIUS: You are only looking if it is a good model for salmonella.
You would also have to \-- you would always have to look at the
food-borne pathogen, because the direct risk is what is very important.
But E. coli. is just \-- you can sample it rather. It gives you the best
opportunity to objectively determine whether a dose regimen has a
negative select \-- effect on resistance selection. Just as a model.
Whether it can be directly translated for risk in salmonella in
camplyobacter there is a different, \--

CHAIRMAN WAGES: Then I am not concerned about it, if it doesn\'t
directly impact the potential for the

food-borne pathogen problem. That is what I am worried about, is getting
people sick. I am not interested in it.

DR. MEVIUS: But E. coli. is not really different from salmonella. If you
have a very clear situation in E. coli, it will also be the case that
less \-- the more difficult to study and determine in salmonella.

(Simultaneous conversation.)

CHAIRMAN WAGES: Whoa. Hang on. Go ahead.

DR. KOTARSKI: I agree with Dr. Mevius; that E. coli. and salmonella are
so alike in their chromosomes that E. coli. is a good \-\-- organism for
salmonella, but I have a \"but.\" And that is the exposure of the drugs
in chickens. The number of bacteria that are exposed to the drug and
places that they are exposed to the drug may be different than
salmonella.

So, from that standpoint, the drug distribution and the drug/bug
interaction for E. coli. may not necessarily be a good model. So maybe
we could think about \-- you know, advise the CVM to think about the
most appropriate organisms in context of the spectrum of activity and
the drug distribution. We are looking at the top two of the most
important organisms. In other words, you have a depend clause in there.

CHAIRMAN WAGES: Let\'s just stop right now and let\'s just look at \--
with those four up there, let me have a show of hands. Who wants to see
that number two stay as it is with those four organisms represented.
Raise your hands.

(Show of hands.)

CHAIRMAN WAGES: Okay. And the ones that want to see, I guess, E. coli.
taken off of there and have those three organisms?

(Show of hands.)

CHAIRMAN WAGES: Okay. So we don\'t like any of those. What is the
alternative? Now, Paula. Go ahead.

DR. FEDORKA-CRAY: Thanks, Dennis. How about if you say indicated use in
food-borne pathogens, such as salmonella and camplyobacter or those
designated as most important for that \-- at that moment in time? Or
those designated most important, in addition to commensal pathogens. Or
commensal bacteria, limited to the two top as indicated? Like Sue says,
for bug/drug interaction, such as E. coli. and enterococci. You know,
that puts all your qualifiers in it.

DR. MEVIUS: We have to keep in mind that E. coli. is not just model
bacteria. We include enterococci as a potential carrier of resistant
genes transferring genes to other populations. E. coli. is also a
population carrier \-- potential carrier of resistant genes transferring
through zoonotic bacteria or through pathogenic bacteria. So that is a
second reason why I think E. coli. should be included.

It is the same sort of information as the enterococci. Enterococci by
themselves are not zoonotic. It is the potential carrier of genes \-\--
case for E. coli.

Always the food-borne pathogens is relevant, if the drug has a gram
negative spectrum, otherwise, include one of the two indicator organisms
or whatever you want to call that.

DR. GILBERT: If one or the two were both there for all time, could that
be a standard, you know, that we could apply even handedly to everybody
and not worry about it over time? Ten years from now if we said, oh,
look at the guideline and do salmonella or E. coli., would that be
sufficient? Would you be satisfied? Or would the public be satisfied
knowing that the studies were done in those organisms? Or, is it the bug
du joir?

DR. WEBER: Could one look at the spectrum of activity that you develop
when you \-- to see where important inhibitions might lie? I am just
throwing it out.

(Pause.)

CHAIRMAN WAGES: So, do we need to complete this number two more?

DR. FEDORKA-CRAY: Would it be food-borne pathogens, such as salmonella
and camplyobacter.

DR. GILBERT: And take out E. coli.?

CHAIRMAN WAGES: Or E. coli. or and E. coli.?

DR. FEDORKA-CRAY: No. Salmonella and camplyobacter and commensal
bacteria.

CHAIRMAN WAGES: Take out E. coli.?

DR. FEDORKA-CRAY: No. And commensal bacteria, such as E. coli. or
enterococcus. Or two of the most important bacteria indicated at the
above bug/drug combination.

MR. : But shouldn\'t it \-- I could be terribly off base on this. To me,
I think this is a lot of stuff that would be great to know in looking at
these two things. But still, shouldn\'t we be choosing the bugs based on
the risk to human health?

If we look and we say we are going to choose camplyobacter, shouldn\'t
that be chosen based on \-- you know, if you are going to choose which
ones you are doing, shouldn\'t it be chosen based on the risk to the
public? You have to work that in somehow. I mean, there has got to be a
reason why you investigate it. It has to be based on a risk, if you come
up and say you are going to protect human health. I just throw that out.

But, if you look at the risk assessment of it actually happening and \--

DR. WEBER: That comes later.

DR. MEVIUS: That comes with the probability of the real risk, which is,
we know, very, very low.

MR. : Then you generated all of this information that is nice to have
and nice to know and you find out later down the road that the risk was
negligible? It is very complicated. I just throw that out about, you
know, you do all this and then you say, okay, here is all this
information. But, in the overall scheme of things, how do we relate it
to the risk?

DR. FEDORKA-CRAY: That is the whole thing that everything is \-- that is
the million dollar question. Why are we doing this whole thing?

MR. : You know, through every stage you have to keep asking yourself.

DR. MEVIUS: That is why \-\-- categorizing also groups of
antimicrobials. Which are the most important ones and which are \-- for
which it is not important when you show selection of resistance. If you
have selection of resistance \-\-- and salmonella, then that can be very
important, but \-\-- so the categorization has to be included. That is
very important.

DR. KRUSHINSKIE: I agree with that. Really, it is going to be an
exercise in spending a lot of money and time if it is not a significant
drug for human medicine. It is a bacitracin \-\--

(Simultaneous conversation.)

CHAIRMAN WAGES: Excuse me. No. Hold it.

DR. KRUSHINSKIE: \-\-- a big use in human medicine. I can see, for the
category one drugs, it is very important.

CHAIRMAN WAGES: Okay. Richard, go ahead.

DR. CARNIVALE: You mentioned before you thought this was related
primarily to therapeutic.

CHAIRMAN WAGES: Correct.

DR. CARNIVALE: I guess I am a little confused then why we are talking
about enterococcus and maybe commensal bacteria, because I had an
understanding that CVM had never really had a concern about therapeutic
antibiotics really affecting commensal organisms to any great degree. I
guess I thought that issue was mainly related to the continuous feed
additive type.

CHAIRMAN WAGES: But I think what we are doing is \-- in my mind, is this
the potential for any pre-approval drug that might have a gram positive
spectrum? If somebody came out with an oralseptive (sic) that was going
to go into the system, we would have to have enterococci. That would be
a bigger player now. Right?

DR. CARNIVALE: Even for therapeutic.

CHAIRMAN WAGES: Yes. Wouldn\'t it?

DR. CARNIVALE: Well, I am asking the question. I guess I just \--

CHAIRMAN WAGES: I mean, because it is gram positive. I guess i looked at
this as global. I know we are shooting down the fluoroquinolone
therapeutic avenue. This is probably a joke, but this is a pre-approval
for potentially any antibiotic, which will never happen in poultry, but
we are going to do this anyway.

MS. : But is the pre-approval process for every category, drugs that go
in any category?

CHAIRMAN WAGES: I would think it would be. And I don\'t know the answer
to that. I would ask CVM. But, to me, it would be modified. I mean, if
you are looking at a category three drug, you know, I think you are
looking at \-- these studies would be not as severe as something that
was potentially a two or a one drug.

DR. GILBERT: They may not be required at all. If it a low \-- you know,
never going to be used in humans and low, potentially you could make the
case that it be waived.

CHAIRMAN WAGES: Go ahead.

MS. : I am just reading from Dr. Flynn\'s first summary statement on
pre-approval study objectives. He does state resistance \-- pre-approval
study objectives. Resistance, how rapidly does decrease susceptibility
emerge rate, which is what is the magnitude \-\-- susceptibility \-\--
zoonotic pathogens in the animal\'s intestine tract.

The third relative point is germane to what we have to use in every
case. This is not all uses. Classes of drugs will require most
resistance \-\-- pathogen load studies. The second bullet on this issue.
\"Certain uses and classes may not require pre-approval studies,\" and
that relates to the category one, two, three high/low \-\--

CHAIRMAN WAGES: Okay. That would be my understanding.

MS. : So what we are tailoring here though is for category one. Is that
what \--

CHAIRMAN WAGES: Well, I think that is where the most potential for
concern is.

MS. : Can we limit this to category one?

CHAIRMAN WAGES: We can do anything we want to.

DR. WEBER: To what extent is the resistance development an issue with
the longevity of the drug use itself no matter what class? I mean, you
know, as far as its efficacy. Actually, I think we will shed some light
about potential longevity of the drug. At least at the doses suggested.

CHAIRMAN WAGES: Well, I don\'t think it matters. When has a drug every
been pulled off, except for the old neomycin and terramycin (sic)
because they didn\'t work? They are still there. Neomycin and terramycin
in most E. coli in broilers don\'t work, but they are still out there
with claim on it.

DR. WEBER: \-\-- using them \-\--

CHAIRMAN WAGES: Too expensive. No. It is too expensive to use them.

DR. KRUSHINSKIE: But it is also behooves the drug company to understand
how rapidly resistance develops to their product for the target organism
because why would you spend \"x\" number of dollars to develop the
product if it is going to be \-- would lose its efficacy in six months?

CHAIRMAN WAGES: Is that something they would do though normally? Or
should it be required in a pre-approval study? Yes. They are going to do
it anyway.

MS. : But that information \-\--

(Simultaneous conversation.)

MS. : I have a question. If we approve a drug for \-\-- bacteria, \-\--
as indicated \-\--

CHAIRMAN WAGES: Pardon me? You have to repeat that, please.

MS. : Okay. If we approve a drug

against \-\-- positive bacteria, then we use all those gram negative
bacteria as an indicator \--

CHAIRMAN WAGES: Your target organism would change, number one, if you
were dealing with gram positives. Correct?

MS. : Yes.

DR. MEVIUS: You have to relate to the spectrum of your specific
antibiotic, otherwise it shouldn\'t test irrelevant.

CO-CHAIRMAN GRAU: How are we doing? How are we doing? I just want to
check in with you and see because we are about an hour into it and \--

CHAIRMAN WAGES: I am totally confused.

CO-CHAIRMAN GRAU: Right. One of the things I am thinking of is the need
to scope this, which is really the nature of the conversation. Scoping.
How broad? How narrow? What do you want to focus on? Can you have one
study model for everything? And, if not, which one/ones would be most
impactful, relevant, desirable to look at over the next, now, five
hours? We started at six.

So, you guys are \-- again, not to rub it in \-- the experts, and I
certainly am not. That is why I am checking in and asking how you would
proceed at this point, being that the ultimate objective of our session
has now become to come up with a suggested study model. How are we
doing?

CHAIRMAN WAGES: Yes, sir?

MR. : I would say go back to what is being referred to here, which is
the framework document, as it exists, to eliminate the necessity of
describing concepts, and the questions here do not relate to models.
They relate to concepts, study concepts. You have a class three \-- a
category three drug, which is \-\-- potential. You probably are not
going to have a pre-approval study. So we don\'t need a study concept.
Get rid of the stuff that you don\'t need to talk about here and then
get into the stuff you do need.

CHAIRMAN WAGES: I can\'t answer your first question. We are not breaking
until 3:30. That is the only thing I can tell you.

DR. KOTARSKI: Well, if we focus on defining objectives and then a first
stab at a model for category one drugs, we can always build onto it for
the lower categories.

CHAIRMAN WAGES: Dennis? You have that look. You\'re thinking.

DR. COPELAND: It seems to me we still have to come to grips, first, with
what we are going to do with whatever we come up with. What is the
objective as far as the approval process is concerned? Where does it fit
in? How is that going to help us make a decision on what to do with that
drug? If we don\'t know that, then I don\'t know how we can design a
model where it is going to \--

CHAIRMAN WAGES: Is the pre-approval studies an avenue to categorize the
drug into one, two or three? Okay?

MR. : No.

CHAIRMAN WAGES: Why not? No. Seriously. If we use pre-approval studies
to identify the mechanism of resistance, the potential cross resistance
occurring in human drugs, et cetera, why isn\'t that study an objective
to help characterize or categorize that drug in the framework document?
That has been bugging me all day.

And I don\'t see why those pre-approval studies would not have an
objective to do that. Okay. That is all I know about it.

MR. KOTARSKI: My understanding \-\-- the category one, two and three are
an identification of the \-\-- so they drive the level of testing that
needs to safely approve that drug. So therefore, if it is a category
one, it means that it is an essential drug in human medicine; and
therefore, if a sponsor wants to go forward with that particular drugs
\-- we will say it is \-\-- I want to take \-\-- and I want to put it
into the animal population.

If I do so, I better have strong reasons to say that that is not going
to have an impact on resistance emergence in human health. I have to do
all those studies to do that, whatever they might be. But the studies
mitigate whether or not you can go forward.

CHAIRMAN WAGES: Claire, you are smiling. Is that good? No?

DR. LATHERS: That is not it. We are listening.

CHAIRMAN WAGES: Yes. But we need a little input on some perspective at
least. We will tell you if we don\'t buy it.

DR. LATHERS: Okay. I think, in terms of categorization, the question is
do you categorize them and then do your studies? Or do you do the
studies and use that to determine the categories? Is that what you
asked?

CHAIRMAN WAGES: That is what I asked.

DR. LATHERS: Clearly, the framework document is telling us that category
one are drugs that are essential to human use and not necessarily going
to be duplicated \-\-- so we need to protect them. So now you are back
to that initial question that you kind of brushed off that someone asked
earlier about what is the relevance to public health. Human health. And
here we are.

We are balancing this overall public health need with the animal need,
which brings you back to the question is it therapeutic needs in terms
of animals or in terms of antibiotic \-\-- so it is not an easy answer.
You have to decide, as a group, what you think is the best type of
protocol that you might \-- and I think what I am hearing is that it may
change, depending on what you are looking at.

CHAIRMAN WAGES: Paula had her hand up. She is falling off back there.

DR. FEDORKA-CRAY: Now I am getting confused, because I don\'t think that
\-- I think that you would have to know what the category is, the
potential category is, from the get-go.

If it is a class of drug \-- if it is a fluoroquinolone, I think you
have a pretty good idea where that is going to fall as far as a category
goes, because you can\'t do enough of studies to \-- well, let me put it
this way. I think you can design all kinds of studies to give you the
answers that you want. Then, depending on where you would want to
classify it, that that might not satisfy \-- that may not be rigorous
enough.

Or someone else might say, well, if you did it this way, then we know
that you would probably get this, and so, do this to make sure that you
\-- you know, you get yourself caught into it and you have to 500
permutations. So I think that you know already whether it is a category.
I think we have to go from the idea that we know what it is.

DR. LATHERS: All right. So Paula\'s suggestion is that we start with the
categorization.

DR. FEDORKA-CRAY: And this would be a category one.

DR. KRUSHINSKIE: But some of them, like Virginiamycin, is not a direct
human drug, and that is where the conflict stems.

(Simultaneous conversation.)

CO-CHAIRMAN GRAU: Let me just \-- can I \--

DR. KRUSHINSKIE: But \-\-- itself is not. So now it is a tier three drug
that is actually \-\--

(Simultaneous conversation.)

CHAIRMAN WAGES: Okay. We have to \-- the facilitator has got some input
and then I want to ask Mike to go ahead.

CO-CHAIRMAN GRAU: I just had a question. Is there a distinction between
the premises one makes, the criteria that one uses for the study itself
and then there is the study model? And the question is what do you want
to focus on during these discussions? Because we are doing both.

And I am not saying it is not necessary. I am just saying that there are
two things out here. Is it to address the model? Is it to address the
criteria or the premises behind the development of a model or use of a
certain model? Is it both?

MR. : It has got to be the latter.

CO-CHAIRMAN GRAU: Okay. Whatever you all \-- you know, do you want to
say what you are thinking?

MR. : No. I think you have to address the premises on the model.

CHAIRMAN WAGES: Mike, go ahead.

MR. : Thanks, Dennis. I was just going to clarify. In my mind, as a
sponsor, I think what I heard now \-\-- we pretty well have an idea of
what category we are going to fall in when you start off. Because, if we
don\'t, if we are going to follow the path of, well, we will do some
studies and then we will figure it out, it is too late.

What I hear the assumption is is that for the exercise we are in right
now is let\'s assume we can categorize from the start. So the sponsor
and the center would sit down, at the very beginning of a project, and
say, well, we believe this falls into say a category one, and so
therefore, as a sponsor, I go away and I have a pretty good idea of what
I am going to have to do.

One piece of that, in poultry, would be whatever we design here. So I
just wanted to clarify, in my mind, where I thought we were going.

CHAIRMAN WAGES: That is where I think we are going, but I am not going
to guarantee anything at this point in my life.

DR. WEBER: What I think I heard Bill saying is that while we haven\'t
had a statement about the framework document and the categories, I think
I heard him say that they might not \-- studies may not be required for
a category two. But let\'s assume, at least for this discussion, that
this work will be required for category one and category two and to what
extent.

You know, whether or not you include the \-- if category one throws out
the feed use drugs or not. You know, that apparently is part of that
discussion in terms of the policy development. And I agree with David;
bringing us back to the focus.

If you are in category one or two and you need to do resistance work,
\--

CO-CHAIRMAN GRAU: What do you do?

CHAIRMAN WAGES: What are you going to do?

DR. WEBER: Now you are looking at the objectives. Should we look at the
appropriateness of the model?

CO-CHAIRMAN: Right. So you might want to start off of what you all were
saying, which is category one, category two as a premise. So what should
be included in a pre-approval study to indicate what you have up there.

DR. KRUSHINSKIE: Could I make a suggestion for modifying objective one?
Study the rate and extent of resistance development in selective micro
flora in the target animal, poultry. The second one addresses food-borne
pathogens and commensals. Would not the first to be to look at the
resistance development in the target pathogen?

CHAIRMAN WAGES: Target pathogen. Yes.

DR. KRUSHINSKIE: Or is that just assumed to be done?

CHAIRMAN WAGES: No. I think that should be done.

DR. KRUSHINSKIE: Because those two are redundant the way they are. First
it states it at one and then it restates it at two.

CHAIRMAN WAGES: Target pathogen or the target animal. Just take out
target animal. Put poultry. We are in poultry. That is the only thing I
am convinced of. We are in poultry.

(Laughter.)

DR. KRUSHINSKIE: And then number two is the

food-borne pathogen commensals.

CHAIRMAN WAGES: Okay. Sir?

DR. MEVIUS: Nobody is really happy with the pathogen level studies, but
\-\-- objectives \-\-- think it should be in the objectives or not? You
have to deal with it. Or is that up to us?

DR. GILBERT: Yes. I mean, pathogen load is an important question. When
you put the drug on there, is it going to cause the animal to shed? Like
the 558-15 studies were originally intended to look at. I think Jean
Cooper probably told you something about our history on that. So
pathogen load is an objective. Is it an important objective? Is that
what the experts say?

CHAIRMAN WAGES: Well, we have heard both yes and no in the previous \--
yesterday and today.

DR. MEVIUS: The rate and extent of resistance development. Something
else \-\-- general conclusions \-\-- yesterday was that the studies are
so \-- you can vary the studies; that it is very difficult to conclude
something from that. Maybe we can make a short conclusion that this is
not something to focus on.

DR. GILBERT: Pathogen load.

MS. : Is it all those pathogens or the target pathogens?

DR. FEDORKA-CRAY: It doesn\'t matter if you don\'t have resistance
developing in \-- I mean, the idea isn\'t \--

DR. GILBERT: If there was no resistance developing in the resident
salmonella, but, all of a sudden, the birds were shedding it like a
fiend, that would be a bridge we would have to cross. And I don\'t know
the history of the all 558.15 studies and where each one of the drugs
that we all know about went through there and what the impact was. If it
increased the pathogen shedding a lot, problems.

DR. FEDORKA-CRAY: But, Jeff, in a way that is like double jeopardy,
because you are talking about a resistance issue. And then you are
saying, well, there is not a resistance issue, but there is a pathogen
load issue, and it seems like that should almost be a separate concern.

DR. GILBERT: We actually had originally set this up to do a couple of
days of resistance and a day of pathogen load, and I think the way it
got whittled down is pathogen load got sort of shoved to the back for
right now. But that may be the subject of another workshop in the
future. I don\'t know.

DR. FEDORKA-CRAY: So what happens if you don\'t have resistance, but you
have pathogen load? And what happens if you have pathogen load at two
logs, but you don\'t have pathogen load \-- you know, if you have
pathogen load at one log, but you only have a two-log reduction. I mean,
we don\'t know what pathogens.

We don\'t know how pathogen load impacts human health outcomes. There is
no information to say how that impacts human health outcomes.

DR. GILBERT: So we should not assume that just because the birds are
shedding with salmonella it is going to have any impact at all?

DR. FEDORKA-CRAY: I think that we don\'t know how. That is right,
because I don\'t think that we can define the impact on human health at
this time to say that \-- you can\'t design enough of those studies in
this model to cover both of those. Those are two entirely separate
questions. You can\'t do that.

MR. : Does it affect transfer between \--

CHAIRMAN WAGES: Pathogen load? Is that what you are talking about?

DR. FEDORKA-CRAY: No. I mean, any time you have more bugs in the
environment you are going to have a greater risk of exposure. But if
they are not resistant bacteria, you know, \-- I mean, you can\'t design
the study to say, okay, you are either going to have to look at one or
the other really.

Now, you will have some idea of what the drug is doing, and those are
the types of pieces of information, I think, that you can use to build
other studies that you might want to use to support say continued use of
the drug. Or you might have someone come back and say, well, can you
treat the dose so that you can increase or decrease the pathogen load a
little bit.

But if we know that in the program now we have very little coming out on
carcasses, and we \-- and I can tell you that, you know, when you have
clinical disease occurring, especially salmonella, immediately, within
24 to 48 hours, you have anywhere between five and six logs per gram of
feces being shed in the environment, which then goes down to, you know,
very low negligible levels for weeks on end.

So you can\'t \-- that is \-- I don\'t think that is a relevant issue at
this point in time, because there is nothing to support that at the
slaughter end right now. There is nothing at all to support that. Zero.

CHAIRMAN WAGES: So what statement do we want to make about pathogen
load? Right now it is a separate issue. It is not relevant in the
pre-approval study for the resistance issue?

DR. FEDORKA-CRAY: It is not relevant for the

pre-approval.

CHAIRMAN WAGES: Put that down.

(Laughter.)

DR. FEDORKA-CRAY: I think let USDA worry about that.

CHAIRMAN WAGES: Put that down.

DR. GILBERT: That is Paula, P-a-u-l-a?

DR. FEDORKA-CRAY: Send money from Washington down. No. Don\'t put that
there.

(Laughter.)

DR. GILBERT: You shouldn\'t have said it, Paula.

CHAIRMAN WAGES: Paula, can I have your cards so I can pass them out to
the people?

DR. FEDORKA-CRAY: Dennis, I am on so many lists now it doesn\'t matter.

DR. GILBERT: Are you soliciting for more work, Paula?

CHAIRMAN WAGES: We are not doing too bad, because we have already listed
the pathogens to be focused on in

pre-approval study, which was one of the questions. We have answered a
good question.

And now, considering the pathogen load, and one of the questions was
factors considered when you are trying to model pathogen load. We have
pretty much put that to rest. But one area that we might jump to is what
are all the considerations when modeling for the development of
resistance.

That is one of the questions that was actually incorporated with the
pathogen load. What factors should we consider when trying to model
resistance development? Are there any thoughts on that?

Well, it is 3:15. If that is a good stop, let\'s go ahead stop for 15
minutes.

DR. KOTARSKI: One comment on the objective pathogen load is a separate
issue. Until a link can be made to human food safety or human health
safety? A link to what?

DR. MEVIUS: (Away from mike.)

DR. GILBERT: What was that?

(Simultaneous conversation.)

CHAIRMAN WAGES: Do you want to take a 15-minute break now and let\'s say
in another hour 15 minutes instead of a big 30 minute one? So let\'s be
back here at about just a little bit after \-- 3:35 to be back, please.

(Whereupon, a brief recess was taken.)

CHAIRMAN WAGES: Okay. We are going to go ahead and get started. We
basically answered one of the questions concerning pathogen load, and
basically, we have come to the conclusion that it is not appropriate to
be considered in pre-approval studies, and that is what we will convey
tomorrow.

MR. : So it is really not separate then? It is just pathogen load not
relevant in pre-approval. Right?

CHAIRMAN WAGES: Well, and then process it separate. Or do you want
separate out of there?

MR. : Yes.

CHAIRMAN WAGES: Why don\'t you want it in there?

MR. : Because, if you say it is not relevant in the pre-approval
process, it is not relevant in \-- I just don\'t think we need to say
separate. I mean, for the record, we don\'t want to get \-- we don\'t
want to have to rehash this later, do we? So it is not something we want
to discuss separately. It is just not relevant.

CHAIRMAN WAGES: My impression is we have a consensus around here.

(Simultaneous conversation.)

CHAIRMAN WAGES: Whoa. We all can\'t talk at the same time. It doesn\'t
work. Not in my playhouse.

I thought it was the consensus of the group that pathogen load was not
relevant to the pre-approval process, period, and that it is not \-- we
are not going to consider it in this process, period. End of report. Is
that not the consensus of the group?

MR. : The point I wanted to make is if you say that, you might want to
say why. That is all.

MS. : On the other side you could say somebody should have to tell us
why it is relevant. Why should we have to defend that it is not
relevant? Why does CVM think that it is relevant to pre \-- with
resistance?

DR. GILBERT: Statutorily it is in the regs right now, 558.15. It is on
the books. Why or why not we don\'t care. It is in the law.

CHAIRMAN WAGES: Is that for therapeutics? No. That is for growth
promotants. Correct? Maybe we need to go up in the first part of this
and say, look, we are talking about therapeutic antibiotics here.

DR. GILBERT: Therapeutics only.

CHAIRMAN WAGES: Okay? So, maybe back up here in the front we need to
start tomorrow and say, look, we are looking at therapeutic
interventions here and not growth promotants, because the pathogen load
concept, with what maybe you are talking about and what was just related
to me is growth promotants. Is that not correct?

MR. : Can we restrict this to just therapeutics? Or isn\'t this supposed
to cover both? I mean, I recognize, in reality, you are probably not
going to see anymore growth promotants in poultry, but

DR. MEVIUS: I think you should not restrict, but the presentations have
shown that pathogen load studies have so many restrictions it is very
difficult to do any conclusions. The conclusion that was drawn is
actually valid; that we shouldn\'t focus the attention on it. I would
suggest not just to focus on therapeutics.

CHAIRMAN WAGES: I would probably agreeing with that in thinking and not
restrict it. Then, do we need to qualify the pathogen load statement? I
mean, I don\'t have a problem saying it is irrelevant. Next question. We
will go on about our business.

DR. CARNIVALE: I think the document could apply to both, because there
may be drugs that are proposed in the feed for control of disease, for
example. Not necessarily growth promoters, but are longer term
treatments. That is possible.

The other issue is we are not writing a regulatory document. I mean, we
are writing a scientific document. So it doesn\'t matter what the
regulations currently say. We are talking about this from a scientific
standpoint.

CHAIRMAN WAGES: Okay.

DR. GILBERT: I am going to take this out.

CHAIRMAN WAGES: Yes. Then take the top out.

DR. GILBERT: And do you think we need some clarification down there on
the pathogen load?

CHAIRMAN WAGES: I think we will leave it like it says, unless somebody
says different, and I think the consensus is to leave it like it is
read. It is not relevant. And if they want to take out separate, I
don\'t have a problem. Just put \"pathogen - not relevant, pre-approval
process.\" Call Paula at the USDA.

DR. FEDORKA-CRAY: I heard that.

(Laughter.)

CHAIRMAN WAGES: Okay. Involved in that question, considering the
pathogen load. If we are looking at a model situation, what are the
factors to consider in resistance development? How would our model \--
how would you put the model together to \-- well, the question
specifically reads, \"What factors should be considered when modeling
resistance development,\" period. We are not going to include pathogen
load. So, any thoughts on \-- in our model what should be considered?

DR. MEVIUS: To mimic the field situation is a suggestion.

CHAIRMAN WAGES: I am a big proponent of that, because I think that is
the real world. Hard to do. You know, difficult. Well, no. I think the
question that we need to discuss maybe is in the field situation it is
difficult to reproduce and validate that, and is that a big deal?

You know, if you mimic field situations, from a practitioners
standpoint, a poultry veterinarian, you can\'t mimic that consistently.
You can\'t mimic the percent moisture in the litter consistently, which
will effect the number of bacteria that stay in the litter that is
re-picked up. You can\'t mimic x, y and z. Does that matter? Which means
you can\'t validate it in the field.

DR. MEVIUS: You could also do it in the field, but then you will add a
lot of variables, as was said by Paula in her talk. So at least you
would have a model approach. Yes? And then post-approval studies would
show whether in the field eventually something else would happen.

CHAIRMAN WAGES: Would comparing in vivo type of experimental type models
looking at resistance in the development \-- this is a question I have
got. Could our models be established to be predictive and could we have
an adequate comparison between an in vivo experimental model?

And let\'s say the resistance exacerbates twofold or threefold or
decreases in the field situation. How would those be weighed in the
pre-approval process? Or does it matter?

DR. MEVIUS: I think in the pre-approval process you wouldn\'t have
information about decreasing or increasing resistance in the field
situation. You are doing a model study to predict something, and we
know, because of events that can occur, you would have to \-- something
to follow-up; do some follow-up.

MR. RUPP: So, when you say predict, does that mean that you are
generating data that would give us an insight to the variable in a risk
assessment? I mean, if you are going to predict something and you are
going to predict the resistance, actually a happening, don\'t you have
to take in \-- we are talking \-- you know, I keep coming back to the
human food safety issue.

I mean, is the model supposed to give scientific data for input into the
risk assessment? I don\'t know. I just throw that out there.

CHAIRMAN WAGES: Well, we are back to the original question. What is the
purpose of the model?

MR. RUPP: Well, no. But I think you need to know. I mean, that is one
thing. Those variables are \-- you need to define those. What you want
to get out of it. Right?

DR. MEVIUS: Right.

DR. WEBER: I thought we defined that earlier, the rate and extent of
resistance development.

MR. : That is basically it.

(Simultaneous conversation.)

MR. : What do we do with that information?

DR. WEBER: We are going to put into decision elements and management
decisions about how the pre and primarily post-approval activities will
unfold. We haven\'t gotten into that. We haven\'t published that aspect
of the framework, and we are not here to try to defend or project how
that is all going to be done, because that hasn\'t been completely
developed.

MR. : See, that is where I am really struggling with this thing.

DR. WEBER: A lot of people are apparently.

MR. : How are we going to design studies to show resistance development
and not know what we are going to do with that data when we have it
developed; how it is going to be used?

If it is going to be used for post-approval monitoring efforts, then why
don\'t we just put all of our effort in the post-approval monitoring,
because we know resistance is going to develop. Does it really make a
lot of difference whether it takes five years or 10 years, as far

as \-- I just don\'t understand what the pre-approval study is going to
do to help you make the decision as far as the approval process is
concerned.

CHAIRMAN WAGES: I need to make a housekeeping statement real quick. For
those of you on this side over here that are not very loud, you are
going to be asked to go to the microphone or get it passed to you to
speak up, because our person in the back is having trouble hearing some
of the people that don\'t have the voice to carry so she can pick it up.
So, just be aware. Either speak up louder or grab the mike. Thank you.
Go ahead.

DR. LATHERS: One question that we could ask is in terms of the
pre-approval studies, are they going to be part of a qualitative risk
assessment. I think that is what you are asking and what you are
suggesting. I don\'t know if you meant quantitative risk assessment or
qualitative.

MR. RUPP: When you look at what we have done already on the risk
assessment and the different variables in there, I think every single
time that you are doing this you still need to look at that overall. I
mean, just because you have resistance development, just because it has
this, if it develops very quickly, but we don\'t take into effect that
it gets to the slaughter house and it comes out the other side with
nothing, then what is the risk to human health?

I guess I always thought that these pre-approval studies were supposed
to give us more of a scientific insight into better defining and \-- you
know, to lower the probability and make the field more confident about
the assumptions and those types of things that we put into that risk
assessment.

DR. LATHERS: Jeff, I don\'t think you have added his last thought.

(Pause.)

DR. KOTARSKI: My interpretation of what you just said is should the
study have as is an objective to be used in a risk assessment of some
sort. Is that what you are saying?

MR. RUPP: I guess I am with Cope. Let\'s do this stuff, but let\'s make
sure that, number one, we are looking to see what the human health
impact is. That is why we are all here. That is why we are doing this
whole thing.

If somebody decided that we are in quandary, that something is wrong
right now, we need to know how much we are affecting human health.

DR. KOTARSKI: That is what I meant by risk assessment.

DR. WEBER: Do I interpret that to mean then that you would like to
evaluate \-- besides perhaps the resistance profile that the drug may
generate in a bug so you can actually find it after the approval. But
are you suggesting then to help with a potential risk assessment
downstream perhaps we should consider issues such as the prevalence of
the resistance in animal populations, as well as in the human, before
approval so you can monitor it post-approval?

And, in the process, be working on mitigation strategies about how you
can lower \-- and some of these studies are already designed, I guess,
to look at return to baseline and other issues involving dosing and
regimens like that.

MR. : It seems to me like good baseline data is pretty important to have
for a surveillance program.

DR. WEBER: In humans and animals?

MR. : I would think so. You know, the NARMS program is a good start. I
think it really needs to be beefed up. You know, build on that.

CHAIRMAN WAGES: How are you doing, Jeff? Are you catching the drift?

So we have a segment here that doesn\'t understand how this pre-approval
study data and results are to be used for either an advantage or a
disadvantage of the approval process. Go ahead.

MR. : I thought it was good what Lonnie pointed out. From the regulatory
standpoint, what CVM needs, and that is some assurance that we are not
going to cause other health problems. Can\'t that be addressed with a
surveillance program. You have a surveillance program in place, you have
your judicious use principles and these sorts of things.

Do you really need this pre-approval study? What does that really add to
assuring public health? I mean, if it does, fine. But I guess I am
struggling to see how that does and how that enters into the approval
process.

DR. LUTHER: I will just stand so you can hear me. I think that is an
excellent question, and I don\'t know if we are on the right course. I
can say that political pressures are real, and Dr. Sundlof can testify
to that. All of you can.

You know, we don\'t have particularly specific language in the statute
that says go do this or that. You know, we are generally charged with
protecting the public health, and we have our cousins on the human side
that think \-- some of them think that they would be fine if we didn\'t
use antibiotics in animals at all.

That is a bit of a naive view of the world. So what is our role in the
pre-clearance area? We are pressed to the wall. We needed something to
say to the world that if we approve the product \-- we have to answer to
our congressman and the consumer groups. You know, we lack something in
our arsenal to say we made the right decision. So how do we answer to
the public? How do you answer to the public that placing a new
antimicrobial in the marketplace for poultry is a safe thing to do?

To me, that is the objective and just how we answer that I am not
certain. But I do think that post-approval monitoring is an option. A
good option. You have done that with one of your products. So maybe you
can speak to that better than I.

DR. COPELAND: I think the verdict is still out. But it seemed to me
\-\-- I don\'t hear CDC saying you need pre-approval studies to
demonstrate that your product is safe. What I am hearing them say is you
need a surveillance system and a way to get \--

CHAIRMAN WAGES: Dennis, she can\'t hear you.

THE REPORTER: No. It\'s your pen.

(Laughter.)

CHAIRMAN WAGES: Excuse me.

DR. COPELAND: What I hear them saying is we need mitigation steps when
we see resistance becoming a problem.

DR. LUTHER: I just want to say that the people that have made our
pre-clearance decisions in the therapeutic area really aren\'t here
unfortunately, and most of those on the cattle side too are probably
over in the cattle group. So I don\'t have the direct experience and the
background knowledge of why we started down this pre-clearance
requirement route, but it was Dr. Sundlof\'s choice I think to require
some information.

And I don\'t know exactly what was required,

but \-- and it is in an area \-- you know, a fiery furnace so to speak.

CHAIRMAN WAGES: Okay. One more comment and then we need to get back and
focused.

DR. WEBER: I think what I heard Dr. Anguelo mention is that he saw this
as an opportunity to collect data and information, both in vitro and in
vivo. Not only on the mutation rate in bacteria, which could be in vitro
or \-- and balance that against what you see in vivo. He mentioned the
need for field studies, the resistance gene in normal bacteria. Actually
what is out there to begin with.

Also, optimal dosing rates to minimize resistance. In other words, the
PK/PD stuff so that when and if problem arises, you don\'t want to wait
for five years, when it jumps up and bites you, to say how do we address
this. So I got the sense that he felt it would be good to get this kind
of information up front. Also, to get the fingerprint of potential
resistance genes so we can look for them as they might develop.

And also, the issue of transfer. That might be useful later on. So I
think he \-- I sense that he felt that the pre-approval requirements in
this area would be good for the agency to collect the information so we
will have it at hand as we start down the monitoring aspects
post-approval. Both in NARMS and the CDC, hospital \-- you know, the
human side as well as the animal side.

I think that both sides are going to be important, and I think you are
going to see those surveillance tools hopefully increase even more as we
go forward.

MR. : To me, those are data that needs to be collected, but they are not
pivotal to the approval of the product. In other words, you don\'t make
a decision based on that data. It is data \-- it is like baseline
susceptibility data. Obviously you need to collect that before you start
selling the drug.

DR. WEBER: There may very well be the need for true baseline data. So
later on, when and if we have this discussion about thresholds or
non-thresholds, but action activities, you know, the potential for
increasing activity prior to withdraw \-- and I like the idea that Cedar
has. Opportunities to do something other than withdraw as they interact
and get that information of their subpart H in 314.

There is an opportunity for that interaction to monitor, as well as
rachet up the surveillance when it needs action, short of withdraw. I
think it is important for us to use the pre-approval side to get the
minimum information that we need to deal with these activities, both in
baseline data and information that we might possibly use in mitigations
and other activities down the line.

CO-CHAIRMAN GRAU: Let me just bring it back. The question was what
factors should be considered when modeling resistance and are there
other factors that should be considered, other things that should be
looked at, when modeling resistance?

So, as we create this model, what would you want to include in the model
that would inform you as to whether or not resistance was developing or
not?

DR. GILBERT: I think the main one we got was mimic field conditions and
practices.

CHAIRMAN WAGES: And that we got off.

CO-CHAIRMAN GRAU: That is how.

CHAIRMAN WAGES: A dose relationship? Dose and duration really.

DR. FEDORKA-CRAY: But what are you looking for? Are you looking for
disease? Are you looking for shedding? Are you looking for carrier
state?

DR. KOTARSKI: He asked us what factors we should consider, and if we are
going to set up trials, one factor we have to decide is what dose we are
going to look at, regardless of what outcome you are looking for. At
some point you have to pick.

DR. FEDORKA-CRAY: I am talking about a challenge dose for bacteria.

DR. KOTARSKI: Oh. No. I am saying just the drug.

MR. : Are we assuming feed use here or water?

DR. MEVIUS: It could be anything.

CHAIRMAN WAGES: It doesn\'t matter at this point. Generic. Route.

DR. KOTARSKI: Would it be the proposed dose? In other words, are we
talking \-- are we at a point in the drug evaluation process in which
the sponsors come forward with a dose formulation that is efficacious?
They have already identified that this is the type of formulation we are
thinking of; this is the efficacious dose.

CHAIRMAN WAGES: Dennis or Richard, when you go to CVM with a drug, with
an NADA, you are pretty confident of the class it is and the dose you
are shooting at. So yes. It would be the proposed dose I think.

DR. KOTARSKI: If we are going to be doing a field condition, this would
not be pivotal information for yes/no of drug registration. My thinking
is that if we are looking at field conditions, that is an expensive
study. We have gone a long way down the path for development. Dennis, I
am looking at you.

If we are doing a study that has got a consequence of yes/no for the
drug registration, there is a lot at stake here in terms of all of the
efforts.

CHAIRMAN WAGES: Okay. In the back, please.

MR. : I am not sure I agree with the word mimic though. Maybe develop a
model that correlates with field conditions. Maybe with enough
information we can do a battery of studies that are much cheaper or some
kind of \-- even a laboratory study that is cheaper that correlates with
field conditions to give the pharmaceutical company an idea of whether
this compound would work in the first place before they go to the
expense of running field condition studies.

CHAIRMAN WAGES: You could put them both.

MR. : I just saw something up there that said do the studies in the
field, and that may not be necessary.

CHAIRMAN WAGES: Okay. But there are areas where you have got small
40x140 houses that are very small that mimic and are actually field
conditions in a small experimental building. We have them at the vet
school. So you could mimic or simulate. I don\'t have a problem with
either one of those, knowing that the data idea is to try to pinpoint
what we are seeing in the field as best you can.

DR. MEVIUS: I agree with you. You can mimic. Specifically for broilers.
It is one of the cheapest animals to work with, so it is the easiest
animal species to mimic field conditions. So that wouldn\'t be the main
cost factor.

A very important issue was brought up by Susan Kotarski. If you would do
an approval study after the development of your drug and you have a
dosage regimen and residue studies, a lot of money is spent and then CVM
would say, well, this is not an optimum dosage regimen with respect to
resistance selection. Then you end up with a big problem.

I have been trying to make the point of dose optimization. I think you
should use these kinds of studies in the development process. Include
them in the development process. Of course, it depends on the category
your specific drug is in and what kind of specific aspects need to be
dealt with, depending on the category one or two.

So if you include it in the development process, you will have a chance
of still developing an optimum dosage regimen with respect to efficacy
and also for resistance selection.

CHAIRMAN WAGES: And you think that should be required?

DR. MEVIUS: That is an approach. For me, that is the logical approach to
come to control of resistance, because resistance will emerge. But what
we need to do is control it so it won\'t be transferred to humans. We
want to control it, and that can be done.

If you optimize dosage regimens and you do it in an earlier phase, then
you won\'t have the enormous amount of development costs. So that is a
potential; a possibility.

CHAIRMAN WAGES: Dennis. You had your hand up?

DR. COPELAND: No. No.

CHAIRMAN WAGES: Any other considerations for our model? Just for the
resistance picture.

DR. KRUSHINSKIE: Well, bird age. Species and age type of \-- I mean, if
it is intended for use in two-week old date of age broilers, you
certainly wouldn\'t want to model this in 20-week old breeders.

DR. KOTARSKI: Well, when you are doing your efficacy trials to model you
have model efficacy. You are modeling that, modeling the field
condition. So you are \-- if you are testing for efficacy and at the
same time you are monitoring for resistance emergence through a course
of therapy, automatically you pinpoint the targeted animals. Age and
that type of thing. So it happens hand-in-hand.

DR. WEBER: I guess you may want to consider a factor of withdraw time as
a possible incorporation. You want to see what the situation is at
withdraw or \--

CHAIRMAN WAGES: Does that get back to pathogen load, withdraw, or not?

DR. WEBER: It involves resistance as well.

CHAIRMAN WAGES: Okay.

(Pause.)

CHAIRMAN WAGES: Anything else? Sir?

DR. LUTHER: Dennis, I am not sure where this would fit in, but the
poultry industry has practiced a shuttle of programs. Setting drugs
aside or, you know, in geographical areas not using a certain drug for a
while.

CHAIRMAN WAGES: That is primarily cocksidious (sic) stats and not
antibiotics.

MR. : I guess I am not clear on the withdraw issue.

CHAIRMAN WAGES: I am not either, but \--

MR. : Unless we are talking about basing withdraw periods on return to a
baseline level, a micro flora level as opposed to residue.

DR. FEDORKA-CRAY: That would change over time though. So how do you know
what to mimic and what they are going back to? As the bird ages, \-\--
different flora.

CHAIRMAN WAGES: Go ahead.

DR. MEVIUS: Withdraw considerations could be that you monitor what is
happening during administration. But also, what the result would be at
slaughter. We are talking about broilers, so it is not a very long
period. And, of course, what is actually present at the time of
slaughter would potentially be transferred in the food chain. That is of
most interest.

So maybe that is not withdraw considerations, but those kinds of aspects
need to be considered. The sampling times; when are you going to
monitor. Not during administration, but look at dynamics. So, if
resistance emerges. But when it is gone at slaughter, there is no
problem. Yes?

DR. GILBERT: Clearly, our jurisdiction stops the minute the guy catches
the bird. When you think about the drugs being applied in the animal,
what happens to them after they are caught and put on the truck we
don\'t have a lot of influence over. We have been looking at sampling
times in some cases. Day 42.

DR. WEBER: But I think the reason I bring this up is the fact that some
of the protocols we are looking at now do look at cessation of drug
treatment and the effect on the resistance. Okay?

And one of the points that one can consider an important \-- I don\'t
know how it will factor in at some point. Perhaps like an injection
type. One of the time frames is if were to find it declining, certainly
that would be, I think, important information. Look at this as
information in developing these studies, where the withdraw time fits in
consideration of that resistance issue about withdraw the pressure.

I just throw it out for one of the issues in terms of the pressure or
the dosing and decline issues that are looked at in these protocols, as
well as the good doctor here showed us yesterday in the work that you
were doing.

CHAIRMAN WAGES: Can I throw something out that I don\'t know where it
fits? I just have a question. You may have the facilitator put me back
on track.

Would it matter if we are looking at the potential for antibiotic
resistance, transferring or at least getting into the food-borne
pathogens, does it matter that the product itself \-- to me it would
matter whether that product was going to a plant that was going for a
ready-to-cook meat in the grocery store or somebody would handle the raw
product, versus it going to a fully cooked product and not be involved
in any pathogens.

Is there a distinction between the potential or the use of antibiotics
in poultry when they are going to be irradiated and/or go to further
processing and cooked versus something that is going to go to raw
product? One has absolutely zero potential to get people sick and the
other one, of course, has the bacteria potential of carrying on the
carcass. Does that matter and does it fit anywhere?

DR. WEBER: Yes. You have to look at the worse case. We can\'t divide by
two and say zero and 250,000; 125 is okay. Until we get a particular
chain of events that is assured, \--

CHAIRMAN WAGES: The risk of exposure \--

DR. CARNIVALE: I hear CVM talking out of both sides of their mouth
though.

CHAIRMAN WAGES: Risk of exposure though is included in the
categorization of the drugs, and if you take the bacteria out of the
equation, you take the resistance out of the equation. You take
everything out of the equation. Do you not?

If you take the bacteria out of the equation, we are not talking about
zoonotic potential. Well, you are laughing, but that is \--

DR. MEVIUS: It is not entirely right. It was presented yesterday. If you
irradiate the food products, there won\'t be any salmonella or
camplyobacter left, but the DNA will present and transformation of naked
DNA will occur and may play a role. That is not known to \-- but that is
not the total answer. It was mentioned yesterday.

CHAIRMAN WAGES: Okay. Well, let\'s get back. I was told by the
facilitator that I got off track. So let\'s get back and focused on what
we are doing. I just wanted to get that off my chest.

DR. LATHERS: I would like to go back to a concept that Jeff added above
in terms of thresholds. I think it was when we were talking about what
would be done with the data. Right there. Yes. The question I would ask
is are we \--

CO-CHAIRMAN GRAU: Excuse me. Could we have one person talking at a time,
please. Thank you.

DR. LATHERS: The question I would ask is in terms of our pre-approval
studies and the results that we get from these studies, are they really
independent of that threshold? Or are we going to look at the
interpretation of the pre-approval study result and link these to really
an established threshold or use to establish a threshold?

It is really a question of what will happen with a threshold in terms of
the pre-approval study itself.

DR. KRUSHINSKIE: What is that threshold? Where is that threshold? Have
you measured it? Is that the pathogen on a carcass. The pathogen in the
human population?

DR. WEBER: That is the next workshop.

(Simultaneous conversation.)

CHAIRMAN WAGES: Hang on. Go ahead, Paula.

DR. FEDORKA-CRAY: I believe that the proposal or the tendency is to
think that the threshold will be measured on the human side and that is
post-approval. So really, that information that pre-approval studies \--
I don\'t see how there is even a chance that they will have any impact
for providing any information as far as thresholds and regulatory
action.

This simply has information as to whether you are going to get a product
through to even have it marketed. And the scenario I would submit to you
is that regardless of what you have pre-approval, there is going to be
post-approval monitoring activities. If they indicate something that was
missed in the pre-approval process, that is what is going to drive
having something perhaps taken off the market or having something
restricted in use. Those will also influence then the threshold.

CHAIRMAN WAGES: Paula, you have to have the threshold established before
you could have a mitigation, because thresholds are what we are going to
by to do the mitigation or intervention strategies. Is that not correct?

DR. FEDORKA-CRAY: In theory I think that would be the nicest thing to
have, but I think part of the problem is going to be where do you \-- I
mean, I think that the threshold is a whole other issue. It has nothing
to do with pre-approval studies.

CHAIRMAN WAGES: Well, let\'s get on with it I guess.

DR. FEDORKA-CRAY: Right. I think the thresholds don\'t even need to be
discussed here or anything else. I think that should be taken off,
everything from there down, because it just doesn\'t have anything to do
with pre-approval studies.

CHAIRMAN WAGES: Okay.

DR. FEDORKA-CRAY: And thresholds are totally farther down the line.

CHAIRMAN WAGES: I don\'t have to be the moderator of that workshop, do
I?

(Laughter.)

CHAIRMAN WAGES: So we want to take the thresholds \-- after PAMS, we
want to take all that off?

DR. LATHERS: Well, or move it back. That is the group\'s thinking. I
don\'t think you want to lose that thought.

DR. FEDORKA-CRAY: Well, I don\'t think it has anything \-- it is not
going to impact \-- the pre-approval studies will have no \-- will not
aid in threshold or regulatory action.

DR. WEBER: Do you know that for a fact?

DR. FEDORKA-CRAY: I think, if you put it up there like that, it has a
good chance that it will. I wouldn\'t want anything there to be implied
that hasn\'t \-- if anything, I would put up there that this information
has nothing to do with thresholds and regulatory action that may occur

post-approval.

DR. WEBER: But remember, Fred mentioned that \--

CHAIRMAN WAGES: Fred is not running this. Fred is not CVM.

DR. FEDORKA-CRAY: Fred is the wrong thing to say.

CHAIRMAN WAGES: You lost it when you said \"Fred said.\"

(Simultaneous conversation.)

DR. WEBER: I think that some of the information that you may obtain in
these pre-approval studies about the change of resistance with time or
in a population of animals or what have you, as some of the designs have
suggested, may be considered potential mitigating activities in terms of
the use of the drug.

In the general sense, I could consider that potentially to be folded
into regulatory actions that might be suggested as mitigations or
reducing risk post-approval.

CHAIRMAN WAGES: I look at the baseline information in both the human and
animal would be the one that we would observe; seeing either going
together or one impacting the other, which would be the mitigation
strategies, not just what we saw in pre-approval.

MS. : And not just what we see on the human side.

CHAIRMAN WAGES: One or the other. I would think they both would be.

DR. WEBER: Well, you can think that. The point is that information we
get pre-approval that could help mitigate both information on prevalence
or what have you and resistance information and potential mitigation
strategies and only one has been suggested, or a couple, in terms of
dosage and usage and things like that. It can effect perhaps one of
those columns. Perhaps the prevalence information in the animal side.

But that could potentially \-- as they have the potential in human
drugs, potentially affect our ability to work out a regulatory strategy
post-approval with producers or labeling or whatever else. I am just
saying I wouldn\'t rule it out; of getting information that might be
useful post-approval.

CHAIRMAN WAGES: You do know now that when you say something and you put
those two or three words ahead of your statement, you are going to lose
your credibility when you say that. Don\'t say \"Fred said.\"

DR. WEBER: I won\'t say the \"F\" word anymore.

CHAIRMAN WAGES: Paula, go ahead. Then I am going to come to a consensus
here on this threshold.

DR. FEDORKA-CRAY: I think that the implication that you could do a
pre-approval study and have that influence in some way regulatory action
post-approval is an erroneous link, because then what that would do is
that would set up the scenario for having regulatory action that might
be considered on something that may never occur on drugs that are
already approved, because that is what you are talking about.

You are talking about drugs already approved, you are talking about
drugs that are going through the approval process, and oh, if you see
something here that you might interpret for another class of drugs or
something, whether it has anything to do with it or not, then you are
going to use that as a basis for establishing some regulatory action.
There is no link there.

I think that that is \-- I think it is really erroneous to have that up
there. I mean, I just do. It is just \--

CHAIRMAN WAGES: Okay. Let\'s put it to bed. Is the threshold issue \--
does it need to at least stay up there for consideration as it states?
Should it be taken out and not be considered in the pre-approval
studies? What is the wishes? Is that the wishes? All in favor of taking
the threshold portion out, raise your hand.

(Show of hands.)

CHAIRMAN WAGES: Okay. Next. All opposed?

(Show of hands.)

CHAIRMAN WAGES: You lose.

DR. WEBER: I\'ve been there.

CHAIRMAN WAGES: Threshold will be taken out, but we did say that we
would \--

CO-CHAIRMAN GRAU: Reflect minority viewpoints.

CHAIRMAN WAGES: Yes. Minority versus one? That is really minority. Take
it out. Okay.

Are there any other factors considered in the modeling for resistance?
Let\'s get back on it, and we may have two questions answered before it
is over. Any others?

We want to simulate field conditions; proposed dose and duration needs
to be considered; route administration; species; class and age; withdraw
considerations as it relates to resistance specifically and the
sampling. I thought we just had sampling time, i.e., slaughter, et
cetera. It may be slaughter, but it may not be. Is that right?

(No response.)

CHAIRMAN WAGES: Are there any other factors that we should consider for
a model in looking for resistance?

DR. MEVIUS: Maybe here we are talking about the animal trial, but still,
in vitro information on resistance. Transfer of resistance.

CHAIRMAN WAGES: The mechanism.

DR. MEVIUS: Mechanism of resistance should be included in the model or
done before the model. And whether that is really predictive for the
field situation can be studied in the model. With a lot of antibiotics
the mechanisms are known. For new antibiotics it would be nice to have
information on the mechanism and whether in vitro transfer of resistance
occurs where so there is evidence of plasmid mediated. Something like
that.

CHAIRMAN WAGES: So mechanism of resistance or in vitro testing?

DR. MEVIUS: In vitro testing, mechanism of resistance, transfer of
resistance, transfer rate; those kinds of things. Yes.

CHAIRMAN WAGES: Okay.

(Pause.)

DR. FEDORKA-CRAY: I have a problem, Dick, with including transfer rate
as a pre-approval condition, because we know so little about \-- I have
a big problem with that in general because we know so little about that.
We don\'t have a very good idea about the conditions that cause that.

I mean, all of this talk about naked DNA dancing around and everything.
We have so much naked DNA around here all the time that it is hard to
believe that we are not seeing more resistance than we have. I think
that we are backing ourselves into a corner of trying to ask for
information that we don\'t have a means for even beginning to describe.
You know, it isn\'t like saying let\'s do testing for camplyobacter or
salmonella or something.

DR. MEVIUS: Right. But maybe the general concepts, whether \-- the
mechanism of resistance, whether it is chromosomal or plasmid mediated.

DR. FEDORKA-CRAY: I think that is great. That would be informative. I
wouldn\'t mind putting like some qualifiers or special considerations at
the bottom where you could say that you would look for transfer of
resistance. You know, studies should be conducted in a research setting
to define the transfer of resistance or something along those lines; so
that those would come later, but not as a part of the pre-approval
process.

DR. MEVIUS: Right.

DR. FEDORKA-CRAY: I mean, you could spend years

on \--

DR. MEVIUS: I agree. Yes.

CHAIRMAN WAGES: Then it is irrelevant. Right?

DR. FEDORKA-CRAY: It is irrelevant.

CHAIRMAN WAGES: So we don\'t need it on there.

DR. MEVIUS: No. If it is there, if we know it, it is important.

DR. FEDORKA-CRAY: It is irrelevant for a

pre-approval process. It is not irrelevant for \--

CHAIRMAN WAGES: See, I don\'t think it is, but maybe I \-- I don\'t
think it is irrelevant for pre-approval.

DR. KOTARSKI: To give you an example, fluoroquinolone resistance is \--
the most fluoroquinolone resistance that we have seen it is mediated by
mutation. Okay? There is one report of plasmid mediated fluoroquinolone
resistance. It is not well characterized, and the report occurs after
many years of fluoroquinolone use in human therapy.

So that is important information; to know that the predominant mode of
fluoroquinolone resistance comes from the chromosome. It doesn\'t seem
to be transferred that frequently. That is important information to know
generally about the compound.

Now, there are other classes of compounds or whatever that have plasmids
that transfer the resistance. For example, the vancomycin resistance.

CHAIRMAN WAGES: I think it is important.

DR. LUTHER: Was that knowledge learned prior to approval? Or how was
that knowledge acquired?

CHAIRMAN WAGES: Well, if you are talking the Israeli study on the
plasmid, that was last year.

DR. KOTARSKI: George Jacobi\'s work.

CHAIRMAN WAGES: Yes. That was post-approval.

DR. WEBER: I think it is very important information, because I think it
is \-- it goes with what the nature of the resistance is in the animal,
to be contrasted with, later on, if you can identify the nature of the
resistance in people.

If there is juncture there, I mean, you have to assume Sam\'s knowledge.
You know, that it is identical to resistance that is generated in
animals. So I think it is important to have some knowledge about the
resistance as you find it.

CHAIRMAN WAGES: I agree. But is it \--

DR. WEBER: Good.

CHAIRMAN WAGES: Is it necessary for a pre-approval study to have that?
That is the question.

DR. WEBER: Good baseline information. I believe it is.

CHAIRMAN WAGES: Okay.

DR. KRUSHINSKIE: Can I make a housekeeping point? I guess I am being
confused with the first six items. They are talking about a specific
animal model. I guess is where we have kind of evolved here. We are
looking at field conditions, proposed dose, route, administration, et
cetera. And then this last one is information that is probably important
to know, but it is not really part \-- to me, that is another topic.

One is an animal model, if we are going to do an animal model, and what
is our objective of this animal model? We listed withdraw considerations
and sampling time, but what is it that we are trying to do here? What is
the overriding objective?

Is it to measure resistance in those populations that we addressed, we
listed initially, before and after treatment? Is that what we are trying
to \-- now we are trying to put together a model that does that? I think
we are putting the cart in front of the horse here and we are mixing
apples with oranges.

CHAIRMAN WAGES: That is probably a good point.

DR. MEVIUS: I don\'t quite agree. I think trying to do an animal study
to understand what you see in animal study would be very good
information, whether it is chromosomal or it is \-- whether resistance
is linked to other antibiotics.

We saw in my kind of studies that a lot of factors effect resistance. So
it would add to the understanding. So I would think that it is important
to know prior to start such an animal study. You don\'t have to do all.
Like Paula said you can work on, for years, all the different resistant
genes that can be present. You don\'t have to define them all because
that is really scientific work for a CDC-like group. But at least know
the general concepts of resistance that makes you understand better what
is going on.

MS. : That can be a literature review basically of existing knowledge.

DR. MEVIUS: Yes. Sure. Of a new drug it should be something else.

CHAIRMAN WAGES: Dennis?

DR. COPELAND: That is what I was going to ask. And I don\'t know. I am
asking the question. If you have a brand new compounds, a brand new
class where you don\'t have literature to rely on, is this a big burden
to do this?

DR. WEBER: Ask the guy. There is one sitting right here. He can tell you
how long it takes to fingerprint a plasmid.

MR. : (Away from microphone.) I would suspect that you are going to have
a pretty good idea based on the class, which is what I think all this
started with.

MR. : My question is if we had a brand new class.

MR. : It shouldn\'t be that. It is not that difficult to clone. In fact,
if you are looking at cloning in general, it is one of the easiest genes
to clone because the selection is pretty \-\--

DR. KOTARSKI: You could take a set of isogeneic strains. In other words,
a number of different strains, different known resistance determinants.
Take your new drug if you want to get cross-resistance in those
organisms that have a known resistance determinant.

(Simultaneous conversation.)

CHAIRMAN WAGES: Okay. In our modeling we want to at least have an idea
of the mechanism of resistance. All right. Let\'s go.

MS. : In this model, which organism are we going to select as a
challenge here? Do we select all salmonella, camplyobacter, E. coli. or
\-- you know, we should select which organism we select as a challenge
study here. Say from one to seven or whatever.

MS. : Do we need a challenge organism?

CHAIRMAN WAGES: You don\'t need a challenge organism for \--

MS. : How do you monitor it then? As you indicated \-\--

CHAIRMAN WAGES: Pardon me?

MS. : Which organism as an indicator develops resistance then?

DR. MEVIUS: We have got to monitor resistant in the commensal flora.
There is no challenge organism. You look at normal flora in the animals
and see what the effect is.

DR. GILBERT: For transfer can we insert \--

DR. FEDORKA-CRAY: Transfer is not an issue.

DR. WEBER: It is not an issue?

DR. FEDORKA-CRAY: Transfer is not an issue here.

DR. WEBER: It is at some point. Whether it is right here, that is the
next step.

CHAIRMAN WAGES: Are you saying that if we are looking at resistance in a
target bacteria we are trying to treat?

MS. : Yes.

CHAIRMAN WAGES: There would need to be a challenge of that organism?

MS. : Yes. Then you can look at it and develop a resistance. Right? So
if we don\'t challenge the organisms we know, how do we look at
resistance development?

DR. KOTARSKI: When you use a challenge organism, are you mimicking field
conditions? Are those working at two different purposes?

CHAIRMAN WAGES: If you are simulating field conditions and/or \-- I
won\'t say in vitro, but in vivo in a small \-- you are going to have to
challenge. You are not going to be able to mimic. In a small
environmental house you could mimic the conditions without a challenge,
such as \-- I don\'t know the answer to that.

DR. KRUSHINSKIE: What \-\-- pathogens? What if they are not present?

CHAIRMAN WAGES: They are not in our house. Well, they are not. They are
not there. I\'m sorry, but they are just not. Go ahead.

DR. MEVIUS: You could challenge in such different ways different amounts
or organisms. That would a lot of variables. I would suggest again to
look at the bacteria that are present in the animals and look at the
effect on the present.

Whether that is a direct relation with zoonotic bacteria, that is a
different question. Look at these commensal on the gut flora in the
animals. If you are going to challenge them and then look for resistance
selection, that will be very difficult.

MS. : What about the nature of \-- the particular study that contain
salmonella or camplyobacter, but are now \-- you know, maybe the real
situation \-\-- so how can you correlate your model in the field; real
life?

DR. KRUSHINSKIE: Can you correlate the development resistance in one
species to development resistance in another? You can\'t. You can\'t
say, if it develops an enterococcus, that it is going to develop in E.
coli. and camplyobacter, because it doesn\'t work that way.

DR. MEVIUS: That is not exactly correct. Transferrable resistance
between species is a very common phenomenon and also between gram
positives and gram negatives.

DR. KRUSHINSKIE: We have higher resistance levels to camplyobacter and
fluoroquinolones than we do for E. coli.

DR. MEVIUS: That is very correct. Camplyobacter is a very different
species regarding fluoroquinolones than E. coli. That is true. That is a
problem.

CHAIRMAN WAGES: Okay. So we have got a monkey wrench thrown in here with
this challenge organism, and we need to deal with it or dispel it. One
of the two.

DR. KOTARSKI: Maybe I am thinking of the study naively. But if I go into
your house and you say, well, I don\'t see any salmonella. Okay. You
don\'t have any salmonella. But I am coming to you and I have an idea of
a dose I want to use and the point I want to refine that dose. Okay?

And I say, I want to contract with you a small study to get a better
refinement of my dose, and as I refine my dose, I want to have some
information as well about changes in resistance determinants. Now, I
can\'t measure all the commensal bacteria, but I know that this drug has
activity against E. coli and it isn\'t very active against enterococci.

So I want to know if the populations of E. coli change in their
resistance during the course of therapy for whatever this disease is.
Now, the question is to look at that disease. If I have to have a
challenge organism to get that disease to happen, I will ask. If, in the
process of treatment in that challenge organism I get resistance, does
that occur? Do I have changes in resistance for sensitive populations of
E. coli that are present in the animal? Maybe another organism. I can\'t
do salmonella. I just can\'t. But at least I have got two organisms I
looked at.

I looked at my target pathogen, I did a study and I can characterize,
during one course of therapy, whether or not there were changes, period.
That is what I am thinking, but maybe that is naive.

MR. : So what does that tell you as far as impact on zoonotic organisms,
if that is our goal?

CHAIRMAN WAGES: Whoever. Yes.

DR. WEBER: Didn\'t we deal with that in the first hour, that we are
going to look at target organisms and four or five other known
organisms? Those are all up for grabs to look at this as the potential
impact of that, and they covered the major classes and major pathogens
of concern.

If that is what the challenge is to those four or five bugs, then isn\'t
that issue? Are you just going to culture a plate with a certain level
of this disease \-- of this antibiotic on it and swab it with critical
material and see what happens?

MR. : I think the problem is, if you want to do this under simulated use
conditions, then you are relying on the commensal organisms that are in
the bird, which may or may not include the ones \-- the zoonotic ones
that you are interested in. That is the problem.

DR. MEVIUS: Well, for broilers the nice thing \-- when there are
positive camplyobacters, all animals are shedding them at high levels.
So camplyobacter can very well be present before you start. You can test
for them or you can select animal populations to be positive for
camplyobacter. Then you can also use camplyobacter as being present,
because challenging them you would add a lot of \-- well, it wouldn\'t
mimic the field situation.

CHAIRMAN WAGES: Right. Salmonella is intermittent shedders, and we have
all sorts of problems with them.

MS. : Well, you could put cedar birds in these houses too. If you had
separate models, you don\'t have a separate trial for each bug of
interest.

CHAIRMAN WAGES: Does this challenge organism need to stay up there? Or
did we actually take care of it back where we had our bacteria listed?

DR. KOTARSKI: You can put field study may include challenge \-- target
pathogen you said?

CHAIRMAN WAGES: Field studies may mimic field \--

DR. KOTARSKI: Instead of deleting challenge organism entirely, based on
your point, to say mimicking field conditions, and we put in parenthesis
\"may include a challenge target organism.\" No?

DR. MEVIUS: Do you understand what she means?

CHAIRMAN WAGES: No.

DR. MEVIUS: For instance, if postelmotisity (sic) is the target
organism, which may be not the case, then you challenge them with
pasterella (sic), then you look at what is happening at the target
organism, but also study the effect of this dosage on E. coli. and
camplyobacter if they are present. So that is the suggestion.

CHAIRMAN WAGES: I understand that. Thank you. Does that reflect what we
are dealing with here?

DR. FEDORKA-CRAY: Take out eight and move it up to one then.

DR. MEVIUS: Maybe. Yes.

CHAIRMAN WAGES: Okay. Copy it and paste it.

(Pause.)

CHAIRMAN WAGES: Okay. While he is doing that, any other factors to
consider?

(No response.)

CHAIRMAN WAGES: Do we want to review these again?

DR. MEVIUS: Maybe. Yes.

CHAIRMAN WAGES: Okay. Let\'s just go through them. Field studies may
utilize the challenge organism to better stimulate field conditions.

DR. KOTARSKI: Challenge target organism.

CHAIRMAN WAGES: Challenge target. Okay. Dennis?

DR. COPELAND: You need to clarify if you are talking about true field
studies in commercial operations \--

CHAIRMAN WAGES: You are not going to challenge.

DR. COPELAND: You can\'t challenge. If it is a simulated field
condition, like you have number two, that is a different story.

CHAIRMAN WAGES: I buy that. Good point.

DR. KOTARSKI: I am confused. There was one point when we discussed the
concept that we don\'t want to be doing resistance emergence
characterization when we are the final dose formulation. We are refining
our dose of the challenge organism. This is in a smaller study. You can
have studies where we \-- you know, we do small studies. Field
conditions implies to me a large study.

CHAIRMAN WAGES: Not necessarily.

DR. MEVIUS: In broilers a large study can be small. Broilers are small
animals. They are only \-- the processing period is only a couple of
weeks. So it is not as big as using large groups of cattle or pigs.

DR. KRUSHINSKIE: I think of it as a colony house situation with litter,
versus a pen trial or battery or something like that.

DR. MEVIUS: Not 30,000 animals.

DR. KRUSHINSKIE: I still have a problem with number eight. I don\'t k
now that you want those studies on the mechanism of resistance to be \--

CHAIRMAN WAGES: That is fine. I want to go through them all again, and
we will nail that when we get to it. Are we now better understanding the
field studies? And I am like Beth. We could have 500 birds. Or, in our
house, we could have 8,000 in a field situation on litter that is not a
true commercial situation. So, we are comfortable with one?

DR. FEDORKA-CRAY: Add target after challenge.

CHAIRMAN WAGES: Add target after challenge. May utilize a target
challenge organism? Or challenge target.

MS. : Target pathogen.

CHAIRMAN WAGES: Okay. I will be talking, so it won\'t matter. Yes?

MR. : Number one starts with number two. Simulated field conditions
(away from microphone.)

CHAIRMAN WAGES: Jeff, put a period and then put \"these may\" and take
out number two. Is that what you are saying?

MR. : I would start number one with what is in number two. Yes.

(Simultaneous conversation.)

DR. GILBERT: Okay. And then take out number two?

CHAIRMAN WAGES: Yes. And then \--

DR. MEVIUS: And then, between records, to better stimulate disease
conditions.

CHAIRMAN WAGES: Yes. We are redundant here. We have got field conditions
twice.

DR. MEVIUS: Yes. But the suggestion was in the second time you are using
a challenge for the target pathogen to simulate the disease condition,
which are also maybe the field conditions, but \--

CHAIRMAN WAGES: How about field/disease condition?

DR. MEVIUS: Very good.

CHAIRMAN WAGES: Okay. Proposed dose and duration. Are you comfortable
with that? Why have we got an asterisk behind that?

DR. GILBERT: I had it linked down to the optimum dose for resistance
considerations and effectiveness. Do we need all that? Or just leave it
at \--

CHAIRMAN WAGES: I would just put proposed dose and duration. Do you want
to emphasize \-- maybe we ought to put that back up with two. This
optimum dose for consideration and effectiveness, somebody commented
that they wanted that tagged with two. I don\'t know if it was one
person or 100.

MR. : It fits there.

DR. GILBERT: Should the proposed dose be the optimum dose for resistance
considerations and effectiveness was sort of the tenor.

CHAIRMAN WAGES: Dennis, you have your hand up.

DR. COPELAND: I just want to make sure we are all clear on the same
thing here. These are simulated field conditions where we are going to
challenge the birds with a target pathogen. So say the drug is proposed
for use against E. coli bacillosis. You are going to challenge it with
E. coli.

So we are going to look at that and we are going to look at changes in
susceptibility to E. coli, but we are also going to look at zoonotic
pathogens. Right? And we discussed that probably could easily be done
for camplyobacter. But for salmonella, there is no assurance if
salmonella is going to be there.

CHAIRMAN WAGES: Correct.

DR. COPELAND: Okay. So we are just going to forget about salmonella?

DR. FEDORKA-CRAY: No. It may be there some time. It may not be there
other times.

MR. : But how many studies are we going to do?

(Simultaneous conversation.)

CHAIRMAN WAGES: Is the focus going to be \-- I thought the focus was
still going to be the target organism, but if we can measure commensals
or the zoonotics and their presence, we would.

(Simultaneous conversation.)

MR. : There is no assurance that the target organism is going to tell
you anything about the zoonotic organism and how they react to the drug.

CHAIRMAN WAGES: They could care less whether the drug works or not of
course. That is a good point.

DR. KRUSHINSKIE: Why can\'t we challenge it with the food-borne
pathogens? Because the commensals are present. You can put cedar birds
in for salmonella, and instead of putting in E. coli, whatever the
target pathogen is, that is one study.

(Simultaneous conversation.)

MR. : You could put the cedar birds in first for salmonella, and then
you can come back and challenge them with E. coli.

CHAIRMAN WAGES: You wouldn\'t have to do that.

DR. FEDORKA-CRAY: I would just put out \-- you could put some cedar
birds with salmonella and you could put some cedar birds with
camplyobacter too, for that matter. The only problem is I wouldn\'t
introduce camplyobacter until the natural \-- and you don\'t have to do
that, because campy is going to show up by three weeks anyhow.

So I wouldn\'t even bother with campy, but you could put a cedar bird
with salmonella in there quite easily and see what happens to it.

CHAIRMAN WAGES: Which salmonella are we going to use?

DR. FEDORKA-CRAY: Now, that is a better question, and I think that gets
\-- you know, you are \-- because you can pick one that won\'t be very
resistant, no matter what you do, and you can pick one that will suck up
everything.

DR. KRUSHINSKIE: You also have some that are more invasive than others.
I am not sure if that makes a difference on re-culturing it again.

DR. FEDORKA-CRAY: No. I don\'t \-- that adds a surveillance question, as
opposed to a resistance question. You know what? I guess, to avoid all
of this though, what I would probably do is I would go out and I would
make sure I had a house that I knew had salmonella.

I mean, when we test things, when we test in the field, if we want to
find \-- like if we want to look at \-- for instance, right now we are
looking at the impact of antimicrobial use patterns on swine farms.
Okay? Well, we wouldn\'t select a farm until we went in and we knew that
we were going to have salmonella there. All right?

Okay. If you wanted to do something \-- like you have these small
housing units or something, you could go to a swine \-- I mean, if you
go to a poultry farm and, if nothing else, you can take some litter from
another poultry farm with those representative serotypes in it and put
that down in your \--

DR. KRUSHINSKIE: That adds a whole lot of variability of unknown of what
you are putting in that house.

DR. FEDORKA-CRAY: That adds less variability than trying to pick some
serotypes, because you are going to be criticized for not looking at the
right serotype.

CHAIRMAN WAGES: What are the two top isolations of human salmonellosis?
Hydleberg?

DR. FEDORKA-CRAY: Yes. Usually the top three are Tithemerium, Hydleberg,
enteritidis.

DR. MEVIUS: It is a model study. So, as a model, you could choose
tithemerium.

CHAIRMAN WAGES: That would give us something that would be relevant in
humans.

(Simultaneous conversation.)

DR. FEDORKA-CRAY: Do you use a Copenhagen?

CHAIRMAN WAGES: Most of it is Copenhagen.

DR. FEDORKA-CRAY: I would say that is not true.

CHAIRMAN WAGES: It is in poultry.

DR. FEDORKA-CRAY: No, it is not. Not when we are getting at slaughter,
Dennis. And I just gave those sheets away, or I would be able to tell
you. He has got the list. I have list of the last three years of what
the serotypes are for poultry.

DR. KOTARSKI: If we add salmonella purposely in these studies, do we
compromise our objective to understand efficacy? Because we are trying
to optimize dose for efficacy and we are trying to minimize resistance
or give some characterization of resistance in commensals.

But if you add a dimension of saying it has to have salmonella in it,
then do you compromise your efficacy component?

DR. FEDORKA-CRAY: This is where you are going to have to seriously ask
yourself do you really need pre-approval studies.

DR. WEBER: You have to optimize your dose first for efficacy. Then you
throw in the bug that she says is an appropriate. Then you are going to
look then at these studies for the development of resistance.

DR. FEDORKA-CRAY: How many studies are you going to do then?

DR. WEBER: You tell me. Give us your best shot, you know, in terms of
\--

DR. FEDORKA-CRAY: Zero. I am not saying that there isn\'t one that we
couldn\'t use. The question is it going to \-- what are you going to do
with the information? I mean, you have to know what you are going to do
with the information? And what are you going to do with the information?

If you put tithemurium in there and you get all kind of resistance out
of it and then they are going to say, no, you can\'t use it because this
makes us nervous or we get an unacceptable level, then are you going to
go back and your boss is going to say, you should have used puna, and
you are out.

DR. WEBER: We can\'t use one that is resistant to resistance
development. And I don\'t know your bug.

DR. FEDORKA-CRAY: Right. I can appreciate that. But again, you are
putting them in situations that may be aberrant that may not necessarily
reflect \-- be a true reflection and be fair to give you a fair
analysis. You don\'t want to get caught on the other side of being
criticized for being unreasonable either.

DR. WEBER: Never happen.

CHAIRMAN WAGES: Maybe tomorrow morning for an hour we will take do we
need pre-approval studies as a focused question, and maybe our first
comment in the afternoon may be to answer that question.

DR. MEVIUS: Talking about salmonella, a lot of problems are coming up,
and it seems to be a lot like the pathogen load studies. You can do it
in a lot of ways, and you can come to different conclusions. So maybe
salmonella is not a model bacteria in this kind of model to use.

We should better focus in the bacteria that are present in small
numbers, because that is the actual situation. You can work with them
and you can do, more or less, a reliable study. With salmonella there is
so many choices you will make and Paula is telling us it is not
reliable, what you will get out of it. So you can\'t do anything with
it.

CHAIRMAN WAGES: Richard?

DR. CARNIVALE: Is looking at resistance in commensal bacteria or in E.
coli or in other bacteria that aren\'t considering food-borne pathogens
relevant to the question? That is where you always fall down. If you are
looking at global health concerns, \--

DR. MEVIUS: Right.

DR. CARNIVALE: \-- then, yes, you could look at resistance. I agree. You
could measure resistance a lot easier in E. coli. But then you have to
say is it relevant to public health, and that is where the disconnect
occurs.

CHAIRMAN WAGES: And that should be the focus to answer the question of
public health, and that is why we are here. Paula?

DR. FEDORKA-CRAY: Dik, I think we are going to run into another problem
too with camplyobacter because we know now, from of the studies that we
are doing, you know, from our slaughter what we are getting. We are
getting almost 30 percent campy coli out as opposed to campy jejuni, and
we know that even within our jejuni population \-- I mean, it has been
well documented in the literature that even on the same poultry farm you
may have up to five different strains of jejuni on the same bird.

And we know that within those five different strains, what we get out
from samples, that they may have different resistance patterns. So how
many isolates of campy do we pick? Do we pick jejuni? Do you look early?
Do you look late?

DR. WEBER: I agree. It is present, but it is not one camplyobacter.

DR. FEDORKA-CRAY: It is not one camplyobacter.

(Simultaneous conversation.)

CO-CHAIRMAN GRAU: Can we reflect anything up here? That could also
reflect the conversation, which is it is complicated and there are
things that are not resolved and unknown. What could we say up here that
could summarize the multiple conversations that we have heard so that
the world could know about it tomorrow?

DR. FEDORKA-CRAY: I think that this is a really good exercise to put out
to show the complexity of the issue, because I don\'t think that people
start to realize all of the permutations that go until you start to put
it down and say, all right, now what are you going to do. Okay?

I think if anything \-- in my mind, what could be summed up from this is
this is the complexities and frustrations associated with trying to
develop a model which will adequately address a public health concern,
because of the complexity issue.

The next part would be do we need to begin to think outside of the box
regarding impact of human health from these types of studies? You know,
is this going to adequately address the problem? Quite frankly, from
what we have just said, the answer is no.

MS. : How much useful information is going to come out of this in terms
of being relevant?

DR. FEDORKA-CRAY: Enough to keep most of us in a jar, but \--

MR. : I think you need to capture the difficulty with salmonella and
camplyobacter.

CHAIRMAN WAGES: Okay. Get it up here so I can do that. Give me some
bullet points that I can say, look, we talked about simulating field
situations and we looked at trying to make that relevant to food-borne
pathogens in that field situation. Here were problems. That is what I
have to tell them tomorrow.

DR. FEDORKA-CRAY: Okay. So the first thing would be like lack \-- I
don\'t want to say inadequate supply of salmonella.

DR. WEBER: Yeah. Right.

DR. FEDORKA-CRAY: You guys don\'t believe anything.

CHAIRMAN WAGES: Salmonella is lack of positive houses consistent.

(Simultaneous conversation.)

CHAIRMAN WAGES: Low incidence and inconsistence of salmonella. We have
trouble finding positive salmonella chickens on the broiler side. The
other thing would be campy is multiple species.

DR. FEDORKA-CRAY: Serotype issues. For both of those.

CHAIRMAN WAGES: For both of them.

DR. FEDORKA-CRAY: For both.

MR. : Is there a serotype issue on the human side as well?

CHAIRMAN WAGES: That is what I was getting to with Copenhagen and
Hydleberg. That is what I thought were the primary isolates coming from
sick people. So that is what I was going by. It wasn\'t from chickens.

DR. FEDORKA-CRAY: And that is true for humans.

DR. GILBERT: Anything else?

DR. FEDORKA-CRAY: You can just put culture \-- isolation culture
methodologies; isolating problems.

DR. MEVIUS: Yes. That is important

CHAIRMAN WAGES: We need a PCR form.

DR. FEDORKA-CRAY: No. No.

CHAIRMAN WAGES: Excuse me. Retract that from the record.

DR. KOTARSKI: There was some discussion to \-- because of the low
incidence of salmonella, we discussed a salmonella challenge, and we
said if we had \-- we picked salmonella infected birds, but that
compromised our objective to address effective dose.

CHAIRMAN WAGES: Yes. By simulation, simulating the field and challenging
with a food-borne pathogen we could compromise that.

DR. KRUSHINSKIE: We also had very low levels of resistance factors.

MR. : Dennis, when we get through with this issue on the organisms, I
think there is another factor that we haven\'t looked at.

CHAIRMAN WAGES: Okay. Let\'s get through this and then we will \--

DR. GILBERT: What was that, Paula?

DR. FEDORKA-CRAY: Phage types.

(Pause.)

CHAIRMAN WAGES: Okay. So that captures the essence of me explaining the
potential problems.

DR. FEDORKA-CRAY: You could probably add one more and that would be
challenge dose. Now what do you challenge? How do you challenge the
house? Depending on how you challenge them, that would effect outcome.

DR. LUTHER: Let me ask a question. It just seems to me that the
traditional effectiveness studies should be independent of this study
that addresses the public health concern. Am I off base on that?

CHAIRMAN WAGES: Say that again.

MR. : That is what I was going to bring up. I mean, I am not sure for
resistance, but for efficacy we need to replicate, and that is important
because it makes your study a lot bigger and more labor intensive. And
again, I don\'t know how that impacts the resistance issue.

But certainly, if we are looking at efficacy here, we are going to have
to replicate each treatment regiment probably six to eight times in
order to generate \-- the pen is going to be the unit of measurement,
and so we have to have enough numbers to show a statistical result.

CHAIRMAN WAGES: Wouldn\'t you do the same thing with resistance?

MR. : I would think so. I would think you need replication for that as
well.

CHAIRMAN WAGES: Would that be important? We need to go up again and put
\-- and that is almost like validation. Right? Put number eight
somewhere in there. Put replication/validation. That is a good point.

DR. LUTHER: I think Susan was asking the question of whether the
efficacy part is compromised when you put cedar birds in and that sort
of thing, and I think the answer is yes. So I see these as separate
studies.

CHAIRMAN WAGES: You mean efficacy versus the resistance. I agree with
that. I think we agree with that. I think the efficacy issue came into
if we challenge, if we do this, does it effect our efficacy. No? What?

DR. CARNIVALE: What I was thinking is does one capture that?

CHAIRMAN WAGES: Maybe.

DR. KOTARSKI: Before you find the dose, do you look at a couple of
different doses and then evaluate resistance? Do you maximize resistance
first? Look at resistance and then do your \-- the efficacy study?

CHAIRMAN WAGES: To me you have to do your efficacy study and then
determine, after that, what impact your efficacy dose has on resistance.

DR. KOTARSKI: So this is going to be my efficacy. I haven\'t looked at
resistance. I said impact on resistance emergence in the past. I have
identified my efficacy. That is what I am going with. I am not going to
look at resistance. If I get resistance emergence, I have already done
the efficacy study. So I am not going to change. Or are you going to do
a couple of different doses with resistance emergence?

CHAIRMAN WAGES: That is up to the company. If I found the resistance
based on my dosage, then I may, as a sponsor, go back and say, well,
could I increase it, decrease it?

DR. KOTARSKI: It is scary because \--

CHAIRMAN WAGES: Don\'t get scared. Don\'t be scared. Trust me. I am a
doctor.

DR. WEBER: I think someone suggested that some of these studies will be
going in parallel and you will have some indication of efficacy from
pilot work as you are going into the field, and some of these things can
begin then as well. Or you could bracket the anticipated doses. You
could have a second dose if you think \-- so you go on a parallel track
with perhaps bracketing some potential doses.

DR. KOTARSKI: I think I will do a pilot study.

CHAIRMAN WAGES: Go ahead.

MR. : Just to clarify one thing. So we are talking about changing our
entire philosophy on how we select our data? I just want to make sure we
are all aware of that, because right we look at efficacy and we have
always been told not to put anymore drug out there than the efficacious
dose.

And we are going to take that and we are look at the resistance and now
we may increase the dose based on \-- if you look at optimize for
resistance considerations, are you going to increase that dose based on
resistance considerations? And then, after you do that, are you going to
look at target animal safety where you had efficacy and your target
animal safety was fine, but if you increase the dose for resistance
considerations, your target animal safety falls out. I am just asking.

CHAIRMAN WAGES: That is the problem with this whole situation, but that
is the reality. I think Tom said what this is going to entangle is the
domino effect on the drug discovery process when you are looking at it
\-- because that is exactly what I think you would have to look at, is
we are going to dose it. Does it treat it? Yes. Okay. Does that dose
minimize resistance? Yes or no, maybe; whatever.

And then you are going to have to go make a decision. Do we increase
that dose and what effect does that have on withdraw safety, toxicity,
the whole \-- that is exactly what this does.

MR. : You are suggesting though that this (away from mike.) I think that
the increase in resistance, if it is observed, needs to be taken into
consideration \-\--

MS. : But how much increase in resistance and in what? If you use it, it
is going to increase resistance somewhere along the line. So what are
you going to say? Any increase?

CHAIRMAN WAGES: Well, we are talking about looking at resistance in
humans, not the animals.

DR. WEBER: I don\'t know to what extent you use it, but I think one
needs to consider the pharmacodynamic information that you would be
gathering as you go, the time above MIC. So you might effect the
resistance. And those are the sort of things you could be looking at
early on in terms of your micro-people, whether or not you are going to
hop on it five hours and just once a day as opposed to all day along
above the MIC, which might increase the potential for resistance.

Some of those early issues about resistance mechanisms and development,
I think your micro people are going to understand this a lot better than
waiting until we are down to try to decide what to take into the field.
They need to factor these things in in deciding the dose up front.

DR. KOTARSKI: And if you are talking about drug exposure \-\-- then
another aspect that doesn\'t come into the drug development process
right now, and I would challenge people to look in their \-- is the drug
concentration in people. Most chemists don\'t do that very often.

So, to do what you are talking about in terms of optimizing those ratios
of drug to bug, that is another \-- that is a mystery.

CHAIRMAN WAGES: Okay. We are getting down to the nitty-gritty. Dennis,
that problem, was that addressed with the efficacy?

DR. COPELAND: Yes. Mine was the replication.

CHAIRMAN WAGES: Okay. Is there any concerns with \-- we will probably
come in tomorrow and redo this, number eight. Think about it; sleep on
it. I will be studying it, and then we will start with another question
tomorrow.

The questions I think we have kind of got a handle on so far is what
pathogens should be focused on pre-approval studies and how much they be
selective, and I think we have covered that. And should surrogate
organisms be used, and we have talked about commensals, E. coli, gram
negatives, et cetera.

What factors should be considered when modeling resistance development
and pathogen load changes? We have done the pathogen load. We are now
talking about the considerations. The other ones we have left are what
role could the various types of data play in evaluating microbial
effects and what is that data that we want to collect.

I think we could probably then go down to number five. \"Are there other
alternative approaches or concepts that we ought to consider?\" And
then, what are the positive aspects of this model that we have basically
created.

CO-CHAIRMAN GRAU: And what are the limitations and can the approach
predict resistance development.

CHAIRMAN WAGES: Yes. And what are the limitations to what we have
proposed and can it predict resistance. So we have got \--

CO-CHAIRMAN GRAU: Or how could it.

CHAIRMAN WAGES: How could it? What are the mechanisms involved in it. So
we have got a couple of biggies left. I want to thank you all very much.

CO-CHAIRMAN GRAU: 8:30 tomorrow.

CHAIRMAN WAGES: At 8:30 we will be here to start. We are going to start
at 8:30 with or without you.

CO-CHAIRMAN GRAU: Hopefully with you.

(Whereupon, at 5:21 p.m., the meeting was recessed, to reconvene
February 24, 2000, at 8:30 a.m.)