**ANTIMICROBIAL RESISTANCE**

**PUBLIC MEETING**

**PRE-APPROVAL STUDIES AND PATHOGEN LOAD**

**BREAKOUT GROUP DISCUSSION - RUMINANTS**

**WEDNESDAY, FEBRUARY 23, 2000**

**2:00 P.M.**

**DOUBLETREE INN**

**1750 Rockville Pike**

**Rockville, Maryland**

**Regency Room**

[I]{.underline} [N]{.underline} [D]{.underline} [E]{.underline}
[X]{.underline}

**BREAKOUT GROUP DISCUSSION - RUMINANTS**

**February 23, 2000**

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**WELCOME AND INTRODUCTION**

by Jim Heslin 3

**INTRODUCTION**

by Dr. Gatz Riddel 4

**DISCUSSION/QUESTION/ANSWER** 6

Keynote: \"\-\--\" indicates inaudible in the transcript.

**BREAKOUT GROUP DISCUSSION - RUMINANTS**

(2:08 p.m.)

CO-CHAIRPERSON HESLIN: Okay. I think we will go ahead and get started,
it is a few minutes after two. What I would like to do is introduce
myself again, talk a little bit about this session, and then the others
will introduce themselves and what our respective roles will be in the
process.

There is sort of a technical problem, in that as the discussion is going
on, I would ask that you either speak loudly so that your voice can be
picked up so it can be recorded, or move to the microphone. I think we
are going to try to work this out so that if you are not being picked up
we will try to encourage you to go to the microphone.

My name is Jim Heslin. I am with the Food and Drug Administration,
Office of the Commissioner. I am the agency training officer and I have
been asked to be here today to help facilitate this discussion.

I am certainly not an a subject matter expert. My purview on the agency
is leadership training, but I will be here in the role of facilitator. I
would ask that we speak to the issue. There are five questions and
actually there is a sixth evolving question and address those questions.
Speak to the issue.

What I would like to propose is that since we have roughly six hours,
this afternoon and tomorrow morning, to get through this and also
recognizing that Dr. Riddel needs to be ready to give a presentation,
that maybe each of the questions \-- and I am putting this out for
consideration \-- that we put about 45 minutes to an hour for each of
the questions and that should allow us some time at the end.

We will try to work a break in here again this afternoon and again
tomorrow morning. And basically, that is the ground rules. Any questions
or comments so far?

(No response.)

CO-CHAIRPERSON HESLIN: All right. Susan, do you want to introduce
yourself.

MS. HARPER: Okay. My name is Susan Harper. I am with FDA Center for
Veterinary Medicine. I am a reviewer for new animal drugs in the
division of therapeutic drugs for food animals. Prior to coming to CVM I
was in large animal practice in Lancaster, Pennsylvania for eight years.

I went back to school, got a masters, was in academia for a while, went
to NIH, and now I am at FDA and very happy to be there.

My role this afternoon, I am going to try to concisely capture the key
comments and try not to demonstrate my ignorance of Powerpoint in the
process. So, if I would inaccurately capture anything, please bring it
to my attention.

DR. RIDDEL: Well, I am Gatz Riddel. And I got introduced yesterday and
you need to understand that I am in the position of volunteering for
something that I didn\'t really know what it was going to evolve into.

My background is the last 15 years I have primarily had a dairy emphasis
at Auburn University. So there may be some gaps in certain aspects of
ruminant medicine, from small ruminants to big feed lots that I need
some of you people to help educate me on.

Because I am supposed to represent the ideas and the concepts that come
out of your discussion here directed towards the five or six questions,
but also I think we are really supposed to be designing or inscripting
things that are going to impact food animal medicine, especially in the
area of ruminants from an industrial perspective, through the end-user,
to the human consumer. So I really think that we need to look at it as
an overall package.

I am sure we are not going to have any fist fights or anything. We need
to make sure that we do speak up as our facilitator has pointed out.

I guess I would like to throw the discussion open by maybe skipping all
five questions and if you all would help me out, what should the
objectives of pre-approval studies \-- understanding my background being
kind of negative in this \-- what are the objectives or what would be
the primary objective for pre-approval studies to bring an antimicrobial
drug to market?

Don\'t everybody jump up all at once!

Well then, I guess I am probably going to have to pinpoint specific
people and I know limited people in the room and you probably know who
you are, and so you probably need to get ready.

Tom Shryock, if you would would maybe give us some of your perspective.
Tell us from industry what you think. Because everybody\'s goal, to me,
and disagree if you do, should be from my perspective, to get products
to treat the animals that we are going to deal with, promote efficient
food production and safe food production, and have a product that the
consumer will be pleased with and will feel safe with.

Throw in one more. We have to always deal with the ever present
antimicrobial susceptibility issues.

DR. SHRYOCK: Thanks for picking on me Gatz. I will take that as a \--

DR. RIDDEL: It is a compliment.

DR. SHRYOCK: \-- compliment and we will throw out some strawman ideas
here just to get things rolling.

There are a lot of things. We want to have the safety, the efficacy, the
quality, all of those sorts of things, but also keep in mind public
health issues. But those are the big \"feel good\" kind of statements to
make.

I think what it really comes down to is we are charged with coming up
with specific study designs or objectives for specific studies, then
that is where the rubber meets the road and we have really got to get
down into some of the sub-objectives.

What do we need to prove in pre-approval situations? You know we have
heard a variety of things today with regard to in vitro studies. I think
Fred brought up a number of interesting points. Each one of those could
take six hours or more to discuss and a full literature review to
support that pro and con.

That may be worthwhile in part to do that sort of thing. Animal studies
with regard to pathogen load. I am not sure that those really have a
significant role, if any, in terms of the pre-approval contributions
that they make for public health issues.

We can do them, but the relevancy, the validity, and the predictiveness
are subject to question in my opinion. Resistance selection studies
might reinforce some of the in vitro studies, but again careful design
would have to be applied to those.

I guess the real bottom line is industry would be willing to do some
studies as long as they can be reviewed with the idea that there is
supportive information, not a pass/fail situation. Maybe we do need to
consider some of the post-approval scenarios with surveillance, etc. as
a more appropriate place to consider some intervention strategies.

I am just trying to throw out some ideas to get the discussion going. I
am not voicing these on behalf of AHI or Elanco. I am just trying to
throw out some ideas that I picked up and see what others think.

DR. RHODES: I will break the ice. I am Linda Rhodes from Merial. I am
also an ex-large animal veterinarian. I used to be in dairy practice for
many years out in Utah. I went back and got additional training at
Cornell and I have been in the industry for about 10 years.

I think what we need to start out with is first of all do we accept the
premise that pre-approval studies are necessary? I think we are starting
by saying okay, we need to do something, how are we going to design
those studies.

I think the first topic of discussion really ought to be based on the
presentations that we have seen up until now. Do we really think there
is enough information, enough background, enough science to do some type
of pre-approval studies?

I think clearly the question on the table is public health. I didn\'t
hear a lot of interest in developing resistance for bacteria because we
were concerned about tetracycline not working in cows. That is clearly
not on the table here. What is on the table is resistance and its impact
on human health.

So I think my question, initially from all I have heard, is I don\'t
think we are ready to design any sort of pre-approval studies. I think
the list of questions that Dr. Flynn presented and that numerous
speakers reiterated, about how could we possibly do this? Are they
predictive? Are they reproducible? What kind of statistics would we use?

What kind of bugs? What kind of load? What kind of duration? We have got
about 20-page D thesis to generate, I think, before we can even begin to
sensibly make some recommendations about pre-approval studies.

So, I would like to put on the table for discussion at the start, does
anyone feel that we realistically should be considering doing
pre-approval studies at this time?

CO-CHAIRPERSON HESLIN: Keep in mind that reactions to the questions and
so forth \-- this is not a consensus group. This is an opportunity for
people to give their points of view, as divergent as it may be.

MR. WATTS: Jeff Watts, P&U Animal Health. When we talk about
pre-approval studies, I am going speak to it more from a discovery
perspective. And that is, a lot of what we do and a lot of what I have
heard talked about is really things that we do early in discovery just
to understand the compounds.

Now, mutation frequency studies are fairly easy to do. Understanding the
spectrum of the compound in terms of just simple initial survey work,
just to understand microbiological activity. Is there resistance? Is it
in a class where there is no resistance mechanisms? How prevalent is
that resistance mechanism?

Some of those things are very basic and they are the first pass cuts
that we make, whether or not we even make the compound. And so those
things I think become, to me they are fairly obvious to do because we
are already doing them.

And so, I want to start back in discovery at that level because one of
the things that I think is useful for us in industry is can we make a
cut on compounds early? One of the things that is difficult to do when
we talk about pre-approval studies is to get out into Phase III trials
and then have a compound cut out.

We don\'t want to have six, seven, ten years investment in a compound.
We want to be able to drop that compound out quickly and move to another
compound.

DR. GOOTZ: Tom Gootz from Pfizer. Just to follow-up on that note. I
think that is totally correct, but there is another issue most larger
companies that discover and develop and sell antibiotics for animal
health also have similar antibiotics for human health.

Unfortunately, the amount that is taken in in terms of revenue is very
different for both of those. It is a much bigger industry in human
health. The last thing that a company would want to do who is in that
situation is throw out on to the animal health market a drug that is
going to very quickly induce or promote cross-resistance to something
else they are currently selling for human health or animal health. Or
something they may be selling down the line in either of those two.

So, upper management for pharmaceutical companies are the biggest
stakeholders of making sure that we make those right decisions and get
rid of a developmental compound quickly if it has an obvious fatal flaw.
Just like we do with tox studies.

They are not always successful, but we always try to do well-performed
and standardized tox studies on animal health or human health compounds
to make sure that that compound is not an outlier, that it doesn\'t have
a fatal flaw.

No one would knowingly want to put such a compound into animal health or
human health because you would have to pull it back. And that is the
worst thing that could happen.

So I think how this relates to pre-approval studies is that, as I said
before, I don\'t think you could reach consensus on the meaning or value
of a pre-approval study. If we have to do them, it might only help us
identify outliers.

I can\'t even imagine what the mechanism might be, but it might be a
compound, let\'s say it was brand new. There was no other compound like
it known to humans. And we put it into clinic, the field, for
development of an animal health product and for some odd reason that
scientists couldn\'t predict, on an auger plate in a laboratory it
selects resistance in animals for, who knows why?

A pre-approval study might be a way to try to identify an outlier. And
say wow, you don\'t want to review that compound, we don\'t want to
develop it. Not necessarily in that order. We don\'t want to develop it
period. And so it could be a way of identifying outliers.

But, I agree with the other speakers, I don\'t think \-- I just can\'t
see how pre-approval studies, no matter how they are set up, are going
to predict the success of an animal health compound, or a human health
compound for that matter, and how quickly resistance is going to develop
in the real world.

People said well, resistance will develop, that is a given. Of course it
will, to some degree. Penicillin resistance began to develop in South
Africa in strep-pneuma in I think, 1976 and today, if you go out into
the clinic, in the human health area, and you talk to physicians they
say well, I don\'t really care about penicillin resistance, I use a drug
that circumvents that.

So, I will just stop, I am just saying I don\'t see how some of these
pre-approval studies will really show us animal health with all of these
parameters we have been talking about. It is too complicated.

I guess I would just say that what we should do, is maybe we should put
the money towards better and more inclusive surveillance studies to get
a much broader view in our market-place of what the resistance really
is. Here I think I guess I am talking about mostly carcasses because
that is the last stop before it goes to some form of human consumption.

So, it is a difficult problem but I don\'t think we are going to solve
it by a real difficult model solution. I think there is some
pre-approval stuff, all of the micro that you guys mentioned, of course
you do that.

But, the threshold concept and having any one test in vivo have one
resistant isolate, I think that all of the speakers in two days have
shown all of the different ways that that could happen, but still not
really be an accurate reflection of how that drug will perform once it
gets into the marketplace and into the field.

So, I think it is very risky. The threshold concept, that is the part to
me that seems most frightening and non-valid scientifically.

DR. RIDDEL: Well, explain to me your understanding of a \"threshold\"
concept. Are you talking about in terms of pre- or post-approval?

DR. GOOTZ: I will just mention post-approval. Excuse me, pre-approval
because that is generally what the framework document is talking about
in terms we have to do.

Since it hasn\'t been defined I can\'t tell you what it means, but to me
it could mean if any of these tests either in the laboratory if you show
genetic transfer of resistance gene from a salmonella to an E. coli in
the laboratory or in a mouse; or somehow if you showed the transfer at
some low level in a food animal.

In theory, that could be a non-starter. One result in theory, in the
worst, most extreme example could say that we won\'t approve this drug.

DR. RIDDEL: Now, would you look at that to be something that CVM is
going to impose on you or do you think that would be something that the
industry would say we figured this out and even without CVM putting any
regulations in it, it is something that is not likely to make it to
market and stay in the market and therefore there\'d be the decision
made not to even pursue it. Like some of the others.

What I am trying to do is get an idea of what could be required to ease
the transition through approval into the post-approval phase which to me
is really where \"the rubber meets the road\". Ease that, answer any
questions CVM might have, but in the pre-approval area actually ask
questions that you wouldn\'t already have asked.

You said that already in the pre-approval and in the discovery phase you
are doing at least three of the objectives that Dr. Angulo mentioned
this morning, right?

DR. GOOTZ: I think the issue is that in vivo pre-approval studies models
which are not yet defined, but are asked of us by CVM could prevent even
in the therapeutic area. And obviously has prevented food additive
antibiotics that there are some no passes on those slides.

We don\'t know who they are, why they didn\'t pass, but evidently there
are compounds in those additives that didn\'t pass the 550815. Big
mystery, nobody seems to know other than the sponsor and you.

But, what we are concerned about is for therapeutic, new antimicrobials
that we might stake 10 years in or 20 years to discover from a
chemistry-driven program for another part of the country. Makes it up,
we have one in vivo test, pre-approval, that we have done and somebody
somewhere detects by a method, culture, PCR, it can go to any degree.

We are concerned that some positive result in there will via the agency
stop that drug from going forward. If it was, again an outlier of growth
change, we probably would see it before it got that far. I can\'t
guaranty that we would, but I bet we probably would.

But if the pre-approval stage was the first place we saw it and it was
dramatic, then yeah I think we would have an internal \-- I would think,
our project teams would have a real internal discussion.

We don\'t really care about you, we\'d be more concerned about
ourselves: resources and going to upper management explaining why it is
we are supposed to be experts in antimicrobial therapy and
pharmacokinetics and we wouldn\'t push a compound for five years. That
doesn\'t make sense.

Personally, I am actually more concerned about that than I am about your
group. But, nonetheless I think we are concerned that for the
non-obvious compounds, which I think based on history will be ball
compounds, antibiotics, we are concerned that just a positive test, a
positive result in some of these assays that have been talked about in
pre-approval will from your perspective stop the development of that
compound or, hold it up.

So we will do another test, another test, another test and pretty soon
we are six years into the patent life and it is not our compound anymore
anyway. If you know what I mean. It takes so long to recoup the
investment on antibiotics, particularly in animal health.

We just don\'t make a lot of money on them quite frankly. It may sound
like a lot to an individual, but it isn\'t a lot in terms of a company.
So, at least that, it is my understanding is the concern that we have
that CVM, some of these models just stopping or indefinitely prolonging
the progression of a new agent into development, into acceptance.

DR. SHRYOCK: Tom Shryock again. If I could just add to that. We also
have to keep in mind that this does not necessarily apply to
pre-approval studies in the sense that new chemical entities will be
coming forward. But that these studies could also be used for a
retrospective analysis of existing products.

And that can complicate a lot of sponsor\'s portfolios depending on how
things may be evaluated. So, if we did have a situation of a pass/fail,
this becomes a rate-limiting step. There is a whole cascade of
consequences that would have to be dealt with in that particular
situation.

MR. LADELY: Scott Ladely, USDA-ARS. One of the things on the first
question, can some monitoring of antimicrobials for resistance during
the efficacy studies in development of a drug, can that predict
resistance patterns in the future?

And I don\'t see any way it can. There are too many factors that enter
into the development of resistance. The amount the drug is used. Even if
they did other efficacy studies and never found a resistant isolate,
that doesn\'t mean that two months after the product is on the market
that somebody\'s going to find resistance. The more animals you put it
into the greater chance that is going to be.

So as far as the main goal of pre-approval for predicting resistances,
if the drug makes it on the market there is going to be resistance
developed. That is the bottom line of what is going to happen. But at
what levels there is no way to predict it that I can see.

And, as Tom stated the pass/fail deal, Dr. Mevius suggested that there
is an optimum level, a dose that corresponds to resistance development.
I think that is good information to have, but I think that that should
in no way have any value in deciding whether a drug can be used at a
level for therapeutic or sub-therapeutic.

It is good information for risk assessment, but it shouldn\'t have any
merit on approval.

DR. SINGER: Randy Singer, University of Illinois. I am also confused
about the idea of this pre-approval study. It seems that in some ways
that if the post-approval monitoring system were improved and maybe more
active in what it was doing, the pre-approval step might almost become
moot.

For instance, if we look through some of the articles, there have been
recent publications showing resistance trends. Clearly the flaws in
those studies are the time frame at which resistance was being assessed.
And the geographic scale at which resistance was being assessed.

There is a mismatch between isolates that may have been collected in
hospitals versus the monitoring that actually went on on the farm. So,
if we had a more dynamic monitoring system post-approval, one that not
only looked at antibiograms or susceptibility patterns, but actually was
looking at the prevalence of genetic mechanisms as they were in spatial
and temporal scales.

I think we could get a better understanding for where future drug design
might be most appropriate. You\'d have a better understanding of the
resistance mechanisms that are already out there and maybe a better idea
of how to circumvent the problem of immediate resistance development.

The other issue with this, I guess my confusion with pre-approval
studies, well, actually I am going to skip that point for now.

But, I am still not certain where we are heading with pre-approval
studies. It seems that in drug development and very active post-approval
monitoring is where we are going to get an idea of the rate and extent
of resistance development. I don\'t see being able to predict that
through a pre-approval study, at least to the point of saying that drug
may pose a risk.

We already know that there is going to be a risk of resistance
development. It is going to happen.

MR. FLYNN: Bill Flynn, CVM. Just to make a couple of points, maybe to
help the discussion on this objectives question. One, I guess really I
think the pre-approval studies may be just one piece of this whole, of
many different things that need to be done in terms of addressing
resistance.

A lot of people have mentioned post-approval monitoring as being an
important component, which is. So, I think one reason for us being here
is in what role can pre-approval studies \-- in other words, doing
things sort of upstream.

What can we do upstream to try to help this whole issue which is the
development of resistance. So, I don\'t think we necessarily have to,
when we are talking about objectives, be locked into the thinking that
it has to be a study that is making a prediction.

I mean an outcome of this may be well, we just don\'t have the science
to do this. But, if that is the case then what value is there to studies
done prior to approval that can help mitigate concerns about resistance.

I think a number of people have stated it already I think, in terms of
how can \-- can these studies be used in terms of optimizing how a
particular drug is used.

I think some of the concerns are when you use a particular class of drug
in a particular animal species, using a particular dosage form, at a
certain dose for a certain duration, that perhaps with the right
combination of all of those factors you may have a high likelihood that
you may have resistance developed.

Whereas, perhaps under some other different conditions it may not be as
likely. So, I think part \-- in that thinking we made what role can
these studies serve and it may be that it needs to be moved upstream
early in the development phase of antimicrobials in terms of when
companies are trying to determine what is the best use of this
antimicrobial that resistance is brought into the decision-making
process for developing that product.

So, I don\'t think we need to necessarily say that it has to be a study
to predict, that can predict when resistance is going to occur. I mean
it would be nice if you could do that, but it may be that it can\'t be
done. I don\'t know.

Then one other point about thresholds. I think in my talk yesterday I
tried, because I knew this was going to be a confusing point, if we
think that thresholds are directly linked. In other words, if we need to
have thresholds, if thresholds are what you make a decision on based on
if you run a pre-approval study and then you have to evaluate that study
relative to some threshold in order to make some decision about
approval.

Well, if we don\'t know what we are doing with thresholds it is going to
be pretty hard to design a pre-approval study. But I think what we said
yesterday, that they are not necessarily tied together, that yes in
certain circumstances it may be decided that it is necessary for
post-approval purposes that there be some threshold set for monitoring.

So that we know when actions need to be taken based on the results that
are coming out of monitoring studies or monitoring surveys that are
going on. But it is not necessarily linked to pre-approval studies.

MR. MUSER: I am Rainer Muser. I am a private consultant as my label
reads here. But I immediately have to say that my leanings are towards
the industry view because before I was put out to pasture I worked for
industry.

I would like to put in an element that probably was underlying quite a
few of the comments we have heard lately, but I think it needs to be put
out clearly. And that is there were several people who spoke up in the
last day or two about the essence of time.

One camp would say we don\'t need any more information we just know
there is a problem and those productions should come off the market. I
cannot share that view, obviously.

But there is another element too, industry needs those products to come
under market and not being delayed beyond reason. And it occurred to me
that one way of keeping products off the market would be to try to
design the ideal study or number of studies that would answer all of the
questions that were asked the last couple of days.

It is impossible. It cannot be done. So, then going from there, knowing
that we are not looking for agreement in this meeting just trying to
come up with points of view it should still be helpful to see the point
of view that came out from various camps and seemed to point in the same
direction.

So, let me try to avoid agreement, but say what I heard would possibly
be common ground of the scientists. One of them was for instances that
there maybe a better way of using resources than doing pathogen load
studies. So, I think it is worth pursuing that idea. Is it really
necessary to do those studies or can we do without them and come up with
an acceptable solution.

Another one was, I heard it in several different versions, that it may
not be possible to design one study that fits all antibiotics, whoever
they would be considered, so it might be better to say yes indeed some
studies have to be done but each product requires an individual design
for one study, packet of studies, whatever comes out. And it would have
to meet the characteristics of the products, if it is related or not
related, and so on.

And then the other element is even if we agree that we only want to
study a limited list of subjects in those studies, perhaps it is not
possible to come up with an ideal study right now. But, it may be
possible to come to a workable solution to tide these things over, that
FDA/CVM can make decisions until the final package is ready so they
don\'t have to wait five years before everything has gone through the
mills that has to be done. In the interest of making decisions.

Because, my concern is that indecision is a problem too. Not only making
wrong decisions, indecision is a problem and if it cannot help \-- and I
am sorry to say that \-- but I consider the people in CVM colleagues and
I would like to help them make decisions.

And, if we can do that with a workshop like this, wonderful. But
decisions have to be made. And this is my plea to everybody in the room:
let\'s try to help make decisions.

MR. BOETTNER: Alexander Boettner from Intervet International. I would
briefly like to come back to the reason why we are here and the reason
discussing these pre-approval studies as a basis, as a framework
document.

The framework document classifies antimicrobials and depending on their
classification, the sponsor has to provide data on pre-approval studies
or not. So that for us, from the industry point of view, tells me that
for certain types of drugs these data are required to estimate the rate
and extent of resistance development in view of human health.

So this is what I believe the objective of the FDA, why they are asking
sponsors to do these studies. From what I have heard over the last
couple of days from our discussions, I think that it would be very
difficult, if not impossible, to determine the rate and extent of
resistance development before a drug is actually licensed and used in
the field.

Of course I think what Mr. White pointed out, it would be very important
to address certain things in view of the characteristics of the drug. I
probably wouldn\'t call this pre-approval studies, but rather refer to
this as to evaluate pharmacodynamic properties of a drug during the
development process.

Which I think is fine, but not with a view to regulate drugs in terms of
resistance development and a possible ban of these drugs because there
could be a negative impact on the human health. So probably the wording
on pre-approval studies per se is not really appropriate.

And coming back to the comments made by Bill Flynn when he just said
that pre-approval studies are just one piece, or a little piece within
the entire assessment, we have to keep this in mind as well.

And here it would be important for industry to know more about the real
intentions of the regulator, how they would like to address these
issues. And again, I am emphasizing that this property can only be done
once a drug is licensed and by means of post-approval surveillance,
monitor the development of resistance and then make any assessments on
the possible impact this resistance development can or possibly have on
the human aspect, on the human medicine.

CO-CHAIRPERSON HESLIN: I had a question. You mentioned Bill\'s comment.
Do you see any application of the pre-market review process, you know it
is a total process. He was trying to identify what role could it play.
Do you see that it would have any role?

MR. BOETTNER: Oh yes, yes. I would see it as more from a
pharmacokinetic/pharmacodynamic point of view that these types of
studies or these types of data could probably give us some basic
information how to for this compound or for this class of compounds, how
this sort of \-- how to design post-approval surveillance. Or their
might be special things one should look for once a drug is marketed and
once post-approval surveillance is done.

It would be just one piece of information or basis and not necessarily
the result of a study where the regulatory authority would make a yes/no
decision on the approval of the drug.

DR. GOOTZ: I guess I have to say my name every time I get up, do I? Tom
Gootz, Pfizer. Looking at the printout that I brought of the proposed
framework document, I guess just updated in December of last year. I
highlighted, since I was very new to the area, I highlighted this whole
thing for things that I thought were deserving of attention.

And it is all highlighted. I have nothing that is not highlighted.

DR. SHRYOCK: \-\-- another marker.

DR. GOOTZ: Good idea. Getting down to the bottom line here, it would be
dangerous to our health as pharmaceutical company representatives if we
brought, I think

\-- not being facetious \-- but to our management anything almost other
than a Category III drug, as outlined in this document.

If they see this and you come up with a new quinolone or a new compound
they are going to, you know, do that (indicating). And you don\'t get
it. But, if you look in the Category I description, points one, two
three.

The last one says that if it is essential treatment for serious or
life-threatening diseases in humans, with no satisfactory alternative
therapy, important for treatment of food-borne diseases in humans.
Mechanisms of action or nature of resistance reduction is unique.

Last sentence: In addition, any antimicrobial that can induce or select
for cross-resistance to a Category I drug automatically becomes a
Category I drug.\" Okay? So, you are guilty by implication.

And also, from all the speakers this morning you have heard how we
don\'t even understand in bacteria how giving one drug all of a sudden
can somehow elevate resistance levels to unrelated drugs. That may be
due to inducible systems, afflux, who knows what.

Then you finish by saying the following examples are types of drugs that
would be included in Category I: quinolones, vancomycin, sinerset or
things within those classes. And then the fourth one is third generation
cephalosporins.

That is most of the drugs that we work on in the pharmaceutical
business. I mean yeah we have macrolides and we have other things that
are used for animal health. We have ionophors, polymixins, and Category
III drugs, but that severely limits, I think, the structural motifs that
we can work on and submit if your labeled a Category I drug. Or can fall
under the skirt, if you will, of a Category I drug.

So, I think that we obviously want to help you and you want to help us
approve drugs. We want to do the right thing. We want to try to satisfy
to some degree the physicians \-- what are they \-- the concerned
physicians of science, whatever. They were here yesterday. Their issues.

But, you know, this sounds to us at least I think, very strict and
legalistic. I think this document. I know it is precise, because you
want to be precise for us, that is the way you work and that is good.
But, it does kind of take on the oneness of almost a legal document in
which we are sort of becoming almost liable or painted into a corner I
think of bringing forward a number of different types of antimicrobials
which could fall into this category.

So, anyway, I have here a note, \"not much left\". In terms of what we
could bring forward in terms of \-\--. So, that is what we responded and
so I think in some of this it is very confining.

And if you are going to uphold it by using pre-approval studies and
uphold these concepts to the letter, it would be very easy for you, I
think, under pressure even though it might not have been your initial
intent, to just stop the development of the drug. Or even worse take it
off the market once that first genetic experiment comes back and says
\"ah ha\".

\-\-- or whatever we would call it does see resistance in campylobacter.
Well, that gives you a lot of power to take drugs off. So I guess we are
just concerned about that.

CO-CHAIRPERSON HESLIN: Other comments or perspectives? You know even if
you are still in substantial agreement with the some of the things that
are said, I think we are trying to get a sense of the group position on
this.

Yes?

DR. RHODES: Linda Rhodes from Merial. Just to change gears a little bit,
I think it is very interesting that we have broke out by species groups.
And I think that one of the things that that suggests to me is that
there is a clear understanding that there is very different uses of
antibiotics in different species.

And since we are in ruminants, we might take a minute to think about how
differently antibiotics are usually used in the ruminant species. As
ex-practioners well know, we don\'t want to treat cows multiple times
with injections. And it is too expensive usually to treat cows with
therapeutic antibiotics in the feed or water, although occasionally that
is done.

And most of the antibiotics that are developed for the primary, the BRD
market, are injectable single, or at most two or three days worth of
dosing. So I think this really brings up a question which is should
there be different kinds of regulations involved with inducing
resistance for different ways that antibiotics are used?

And this is implied a bit in the framework document where they do talk
about dosage regiments, number of doses, times between the therapeutic
use and slaughter, the withdrawal time. This is mentioned as part of
that high, medium, and low risk area.

But I think one of the things we should be thinking about is do we feel
that its less likely that we will induce resistance with for example a
single dose of tilmicosin on one day that is not repeated and then the
cow goes on to have a withdrawal time of more than 28 days before
slaughter.

Versus a constant low-level exposure to a single antibiotic as I do with
my son when I treat him for an ear infection and I can\'t get that full
dose of medicine down his throat three times a day, every single day,
and so he gets exposed to a sub-therapeutic level whether I want him to
or not.

So, I think we are talking about ruminants. We need to think practically
about how these drugs are used in a field situation. And it may be that
that needs to be taken into consideration from a regulatory point of
view. In a more stringent way.

Because although there are varying amounts of data on that, I think the
general sense is it is less likely that we will induce resistance
problems with a high, single dose therapy then we will with a low-level
exposure. And there are many analogies to this: malaria and quinine
resistance and tuberculosis.

Many, many other disease situations in human health where this has been
fairly well worked out. So, perhaps we ought to be looking at this from
a very different perspective, depending on what species we are working
on.

DR. RIDDEL: I think without a doubt, the feed additives appear to be the
target for right now. They impact some aspects, not many of which I am
that familiar with as far as ruminant production, i.e. some feed lot
use.

But I think that we need to stay positive and rather than say there
doesn\'t need to be any pre-approval work, we need to maybe try to guide
it in a direction that would not be too onerous and would not
defacilitate the approval process too tremendously.

To the best of my understanding, that many of the people who talked
about modeling suggest that there is no one good model and it is going
to be very difficult to do. But, from an industry\'s perspective, when
you look at the overall process of getting a product to market, what
types of studies could be required that would be truly unacceptable?

What could be designed that would just make it to a point that you would
just have to give up? Another question is \-- I guess this is because of
my ignorance \-- if a drug today is considered a Category I drug, that
is defined by the current level of human medicine, correct? Can that
change?

Can a company \-- is there any way that a company can take a product and
make a case that it should be categorized at a lower level than what
would be most obvious when you first looked at it? I guess that would
have to come from the microbiologists in the group.

I would like to know what kind of things would be the worst-case
scenario or hurdles you would have to jump to get to the approval table?
Somewhere along the way I am also going to have to ask questions how can
we blend these pre-approval studies into a workable post-approval
monitoring program to facilitate things.

And then also look at \-- some of the people I have talked to say an
important step is categorizing the drugs, like it may not be a given.

DR. SHRYOCK: Tom Shryock. I will venture a worst-case scenario here.
Hopefully the Frankenstein situation will not appear. I think what that
could look like would be one of these pathogen load studies that becomes
a mass epidemiologic investigation.

Which is a multi-site location field trial late in a development stage
which requires that you have a bona fide test article that has been
characterized; final formulation. You have got to buy all of these
animals by taking them say to a slaughter situation. Doing all of your
microbiology and tracking for up to a year in say a feed lot situation.

You are investing maybe a million to two million dollars, I don\'t know.
And then having some sort of data analysis that you have failed because
you missed it by 10 percent of a prevalence type of situation.

To me that represents just chaos in something that none of the
colleagues in industry could stand to bear. And that is why we really
want to try to back that away from that kind of situation as early in
the pipeline as possible.

DR. RIDDEL: Tom, help me out just a second. Can we, for me, is it
inappropriate for me to try to separate the two issues: antimicrobial
susceptibility in the pre-approval arena from pathogen loads?

Because I am not familiar at all with pathogen loads and I have heard a
lot of people say that this may be irrelevant. We shouldn\'t use
relevancy to bog down the whole thing.

So, I guess I would like to \-- I asked my question wrong. I would like
to look at the antimicrobial susceptibility because that is the
headliner issue right now. There are so many other things impact the
pathogen load. Haslep from there on out. That sure was an unworkable
scenario that you laid out, but are there equally unworkable scenarios
for dealing with susceptibility issues?

DR. SHRYOCK: If you wanted to take it to that extreme and say that you
are going to look at salmonella or campylobacter or an E. coli 157 on
the basis of resistance, that could be the worst-case situation
compounded.

If it is just looking at susceptibility testing by going out and
collecting isolates, field isolates, that is to my way of thinking not
as onerous by any stretch.

DR. RIDDEL: Would it be inappropriate to suggest to CVM that the
pre-approval cannot in any way, shape, or form be as comprehensive or
all-inclusive as a post-approval monitoring program, right? Or should
not be?

DR. SHRYOCK: It depends on how you \-- there may be infrastructure
systems to go out and get those isolates. You may be able to draw NARMS
for example and get those 60,000 isolates from Paula\'s freezer bank in
the basement.

DR. RIDDEL: So you\'d be looking at pre-approval susceptibility where
hopefully that product \-- the organisms haven\'t been exposed to that
product to any great degree? They may have been exposed to related
products but you\'d be looking for kind of setting a time zero
susceptibility upon which you would base other thresholds for
development of resistance, right? And rate of resistance?

DR. SHRYOCK: I don\'t know if I would take it to the point of using that
to set a threshold because there are a lot of implications there. But I
think \-- we do a lot of baseline surveillance work in a very early
discovery phase. You get field isolates in, you see what is out there.
It is on a class-representative basis.

If you are going for another macrolide, erythromycin is a good
representative of that class for example. Although there can be
differences, as Paula pointed out, between tetracyclines. You can
explore that to a certain extent.

If you have these collections that are historically available, you
don\'t necessarily know their exposure history. But you kind of get a
feel for what is out there and that is as good as you can do in some of
these cases. Unless you are really going to make this a 50-state, mass
epidemiologic collection which is a very difficult thing to do.

So, you have got to maintain some of the practicalities in here and get
a sample that is reasonable to work with, that is fairly representative
and go with that and make your best guess decisions.

DR. RIDDEL: But it wouldn\'t be inappropriate to suggest that the
pre-approval studies dealing with that should just represent a sampling,
a random sampling of isolates out there as far as current susceptibility
and leave it at that?

Plus, other things that you might learn about predictability of the
onset or resistance from some of your very early studies?

DR. SHRYOCK: Well, you keep adding all of these extras on here Gatz. The
sample collection, I think pretty much everybody will do that to a
certain extent more or less. Or that could be done relatively
straightforward.

If you wanted to explore resistance frequency, rates or something that
gets into some other substudies: which bug, which drug concentration?
There is a lot of subissues along those lines that to varying degrees,
again sponsors do some to many of those kinds of studies.

It ultimately comes down to what are you going to do with that data in
terms of evaluation? To make pass/fail or is this ancillary information?
And at what stage? Is this internal within the company that never even
makes its way to Rockville or is it something we then need to consider
to build into a package if we take it forward because it is supporting
evidence then? So, some open questions perhaps.

DR. RIDDEL: Because I don\'t know and if it is proprietary information
tell me. What types of studies would a company normally \-- or, what
extent would a company with an antimicrobial normally investigate as to
giving themselves a feel for the potential for a rapid onset of
susceptibility?

How many, I would assume these would be field trials where the product
would actually be out and be in its appropriate use, or not?

DR. SHRYOCK: No, field trials really are the last step that you go to
because they are so doggone expensive.

DR. RIDDEL: How would you try to \-- if you were \-- I mean several
people \-- I understand the economic realities. If you were wanting to
protect yourself from the marketing people and from management, how
would you want to take a product you are trying to champion and give
yourself a comfortable feeling that you could take on, say this isn\'t
just going to blow up within six months after we put it out on the
market and be worthless?

DR. SHRYOCK: Things that are currently done, using existing classes as
the prototype, because I don\'t think we are going to have a whole lot
of new chemistry coming on board, go to literature. There is a wealth of
information there.

I will pick on macrolides because that is my basic experience here. You
have got all sorts of resistance mechanisms, mutation rates for a
variety of bugs. You can find that out and have a pretty warm, fuzzy
feeling of what is out there and what you can expect.

The second thing that you would do is go to a target population. One
that you want to get your claim on. And survey that. See what is out
there. Ask the diagnostic labs for their specimens. Go to some field
situations, get in some clinical isolates.

This whole issue, however, isn\'t on target pathogens. It is on food
safety pathogens. In that case we are going to have to go where the bugs
are. And that makes it a lot more difficult. If you want to go to those
particular farm animal situations, since this is a ruminant group we\'d
have to go to feed lots for example.

That is very difficult to get access to get ample sample numbers on your
own. So you\'d probably want to go say to the NARMS program and see if
they could provide some bovine isolates for example. There may be other
companies that do their own monitoring just as a component of their own
food safety programs. Get a random collection there and see what it
looks like.

You may be able to track some of the use history if you look and probe
hard enough. That to me is about as good as you can do. Mutation
frequency rates and all that stuff, yeah you can do that. I am not sure
what the value of all that really becomes at that very early stage, you
just want to know what is out there in the world, basically.

So that is pretty much what I would do. I would welcome comments from
others because certainly my experience doesn\'t represent everybody\'s
in this room.

DR. RIDDEL: Do you feel Tom, that \-- and I am sure you would, so this
is probably a loaded question \-- that looking at food safety, the
issue, the future of the animal health industry and animal agricultures,
do you think that those steps should be satisfactory to get a product to
where it can be put in use with an appropriate post-approval monitoring
program?

DR. SHRYOCK: I would say they go a long way towards that. There are
probably some other things that I can\'t think of here on the spur of
the moment that could be added on there. That would be a good start.
Ultimately the reviewers are the ones that are going to say thumbs up or
thumbs down.

Their careers are on the line for making a good decision/bad decision
which is kind of hard to predict the future and that is what you are
asking them to do. So our job is to provide them with enough information
to allow them to make a comfortable decision as well.

DR. RIDDEL: Then you all are going to have to help me because I came
into this thinking that this is supposed to be development of a whole
new paradigm, but if your telling me things \-\-- things that are
currently ongoing really should be answering all of the pre-approval
questions that can be answered logistically or feasibly?

DR. SHRYOCK: There is a lot that goes on that doesn\'t even get above
the water line of the iceberg here, that all of the companies more or
less do, that helps sort the wheat from the chaff early on.

And those things that we do bring forward are the ones that we tend to
discuss a little more fully. There are other studies that we could
consider doing as far as just setting up susceptibility test conditions
and some of the things that might support some of the prudent use or
even the NCCLS guideline kind of things.

But that is all factored into the mix in my opinion. Blended in with
some of the efficacy studies. You know, to set some of the dosage
situations with the assistance of PK/PD data, there is some real
attraction to doing that.

We have also got to keep in mind that we might be rate-limited or
bounded by top dose for a residue, efficacy. And then throwing in this
other one, on minimizing resistance, we may be at a point where we
can\'t change that does more than just a couple of migs per kilogram.
There may be no change. We may be just stuck and we are going to have to
live with whatever it is.

There are some issues along those lines too in terms of optimizing
doses. We can look at all of that, probably should if we are not. But
recognize that is not the panacea either.

I have probably talked way too much here. Will you help me out Bob?

DR. WALKER: I will help you out. Bob Walker, CVM. But I am a newbee at
CVM so I am really saying this as an ex-professor. We have listened to a
lot of dialogue over the last couple of days to a very, very complex
issue.

I guess from my perspective, and again this is my perspective and not
FDA\'s perspective or CVM\'s perspective, I think that what we need to
look at, first off we have to ask why do we want to introduce an
antimicrobial agent to the market?

I think there are three reasons. Two reasons. Number one, increase
profits for the company and \-- this is not necessarily in order. Number
two, is to try to address an infectious disease problem in the target
animal species.

Now in conjunction with this, the pharmaceutical companies have been
burdened with a third criteria. And that is the effect that that
anti-infective agent has on zoonotic pathogens.

So, if we look at those three things and try to address what we are
calling the pre-approval program, from my perspective, and I do this
having done a lot of experiments peripheral to this, and I will try to
bring you up-to-date on some of those things.

First off, if we take a fecal sample from a cow and streak it for
isolation on a McKonkel\'s plate to where we get 30 isolated colonies.
And we take each one of those colonies and subculture it. So where you
now have 30 individual colonies collected from the same animal at the
same time, and we do an MIC on each one of those whether it is against a
flouroquinolone, a beta-lactim, or a aminoglycoside.

What we will get is a variety of MICs. In other words, those 30 isolates
collected from the same animal at the same time will not have the same
susceptibility profile. And there may be as much as a five-fold
difference.

So, if we were to look at this as a pre-approval study and the first
time we picked an organism with an MIC of .5 and then we exposed them to
the drug and post-exposure we pick an organism that has an MIC of .03,
the drug has had a negative effect. Wow, let\'s go for it.

But if the reverse of that is true then we selected for a less
susceptible organism when in actual fact we really haven\'t done
anything. Because that was the population that was there to begin with.

So, another thing that we have done is we have looked at enteric
organisms that have been exposed to a flouroquinolone over a five-year
period. And we have found that with the E. coli that there was really no
change in MIC 50 or MIC 90 over this five-year period. The same thing
for Club C-pneumoniae.

But, we did find that with proteus, the MIC 90 jumped from .06 to .5.
Now that would suggest to me that that is a very sensitive organism in
terms of selecting for resistance or decreased susceptibility.

So, maybe that could be a sentinel organism. But maybe not necessarily
that organism. So, if I were looking at pre-approval studies, one of the
things I would want to do is I would want to take this new drug and I
would want to take an enteric population of organisms and find out what
is there.

And then I would want to take different species and expose them to
different concentrations of this drug and see which one could I change
the susceptibility profile on? Which one could I make less susceptible.

And then use that organism as a potential sentinel organism so that when
we got into other studies, instead of looking for salmonella which may
not be there or may not change at all, or E. coli and which E. coli are
we talking about? Are we talking about the one with the low MIC, the
high MIC, 01587 or the numerous other serotypes that have the attaching
effacing gene and the sugar toxin gene? I don\'t know.

So, look at this sentinel organism that we have demonstrated to be most
likely to develop decreased susceptibility to this particular drug.

Then I would look at my target pathogen and I would do a
concentration-dependent killing study on that target pathogen and also
on this sentinel organism. And I would look at what concentration of
drug I needed to maximize the killing effect of my target pathogen, but
I would also look at a concentration-dependent killing effect and see at
what concentration did I have the killing effect of the pathogen, what
did it do to the sentinel organism?

Did it kill off the sentinel organism? Or if you have done any
concentration-dependent killing studies, you know that a lot of times
you get regrowth of the organism. If I got regrowth of the organism was
it the same MIC as prior to exposure or did I select for a higher MIC?
This is data I would collect.

The next thing I would do is a pharmacokinetic study. A dose titration
pharmacokinetic study. And here I would want to know what is my drug
concentration at the site of the infection, in relation to my target
pathogen, and maybe using a radioactive labeled drug to see what my drug
concentration is throughout the gastro-intestinal track and see what
that is in relation to this sentinel organism.

I would also collect fecal samples from that animal or those animals
that I had done the kinetic studies in and look for this sentinel
organism and see if I had affected its MIC at all in relation to time.

And based on this information I would have a dosing regime that I could
look at for generating clinical efficacy, but I would also have an idea
as to how it may affect this sentinel organism.

And then any studies I did after that I would again be looking for this
sentinel organism and any zoonotic pathogens that we might happen to
come across, but we would already know that they are not as likely to
develop resistance as the sentinel organism. Because we have already
demonstrated that the sentinel organism is the most sensitive for this
occurrence to happen.

That is just some food for thought that I would do in terms of
pre-approval. Once it was approved then I would identify that sentinel
organism, again the zoonotic pathogens, and monitor the changes in
susceptibility profiles.

When you talk about resistance, the cat is already out of the bag. What
you want to do is design your monitoring program in such a way that you
can pick up slight changes in susceptibility.

And so if you have got pre-approval MICs of .03 and a year into the
approval of this drug your MICs are up to .12 or .25, you are still
susceptible, but you are losing it. And that is the point to initiate
mitigating factors to alter the course before you totally lose the drug
or before it adversely affects the human population. That is my
thoughts.

DR. RIDDEL: Dr. Walker, are there any pitfalls to picking a sentinel
organism that is not irrelevant to the target pathogen nor to food
safety?

DR. WALKER: There might be. But, you know \-- and this is just my
thoughts on it \-- but you know, describe to me a car. Well, what are
you talking about? Are you talking about a Yugo or a Mercedes? They both
have the same function, but there are different purposes.

And so what we are talking about here is a program for a specific
organism or a specific drug, or target animal species. We would have to
tweak it for different animal species or different drugs.

In this particular situation I think if we could demonstrate that the
sentinel organism was the most likely to have a change in
susceptibility. Far more so than enteric pathogens. Then that is just an
indicator organism. You are still looking for the zoonotic pathogens to
see what is happening with them, but chances are anything that happens
with them is going to be predicted a long time in advance by this
sentinel organism because it is much more likely to develop the
resistance.

And again it goes back to the proteus. The proteus that we looked at
changed dramatically, but the E. coli, the Klebsiella \-- I can\'t
remember the other organisms we looked at. Unfortunately, we didn\'t
have any salmonella. But, they really didn\'t change.

So, I think it is just an indicator organism of how things may happen.
And I think for every drug, animal species it may be a different
indicator organism, but I think it is something that could be
established very early on.

And again, these are just my thoughts of how if I were in a
pharmaceutical industry and I wanted to look at this, this is some of
the things that I would entertain.

DR. RIDDEL: I guess because I am not industry-oriented in microbiology,
from microbiologists, is there much of a risk of discarding potentially
valuable tools because of this approach?

DR. WALKER: What do you mean?

DR. RIDDEL: You can have a sentinel organism that may truly not be
relevant to anything other than the fact that it has the ability to
develop decreased susceptibility rapidly, but it is not relevant to any
zoonosis and it is not going to be a zoonosis.

It is not relevant to your target pathogen or disease process for your
label indication. Is there a possibility that somebody could, inside the
company, say we are not going to risk it because of this possibly
irrelevant organism?

DR. WALKER: I don\'t think \-- I think that all you are doing is
generating data with this organism. You are not basing the approval
process on this organism.

DR. RIDDEL: Well, I think decisions are going to be made at the industry
level based upon this that could affect a products that I might have to
treat animals with and a potentially valuable product could be \--

DR. WALKER: But you are also doing the monitoring. You are monitoring
that sentinel organism and you are also monitoring zoonotic pathogens to
see what it effects.

Do they use nalidixic acid in human medicine or in veterinary medicine
any more? No. And yet nalidix acid is used on the NARMS study. Why? A
sentinel drug. We are most likely to see decreased susceptibility in
nalidix acid long before we see it with cipro. It is just an indicator.

And that is all we are saying here. It is an indicator organism that may
give us an indication as to what effect this drug is having on the
microbial population as a whole, it is just this particular species of
organism has been shown to be more sensitive, more likely to change its
susceptibility profile.

CO-CHAIRPERSON HESLIN: Just a quick comment. You may want to look
periodically at the screen. Susan\'s trying to capture the essence of
what is being discussed, but she may need some help in doing that. So,
if what is conveyed up there is different than what you are hearing, let
us know.

DR. RIDDEL: While we don\'t, I think Dr. \-\-- said at the beginning
that this wasn\'t something that was going to arrive at a consensus. I
would really like to trust people in this room to keep me from sticking
my foot too far in my mouth and bringing something up like this.

If there are valid reasons to consider it a minority opinion or if there
is a valid reason not to mention it. Just out of my ignorance.

DR. SINGER: Randy Singer, University of Illinois. I just wanted to make
a quick comment on this indicator bug. In that I think it has a great
deal of importance, even if it is not the target pathogen. I think as we
learn more about the ecology of antibiotic resistance, we are going to
find many examples where some commensal or some organism doesn\'t seem
relevant that is carrying these resistance determinants, is actually the
mechanism by which these determinants make it into the human population.

You are not following a food-borne pathogen. What you are following is a
determinant, just some gene, that ends up inside of a human and is
transferred then to the normal flora inside of that human host and
becomes then a source of disease for that person.

I think there is examples of that with the, I believe with even
vancomycin. And so as we learn more about the ecology of resistance,
this indicator bug, I think, serves more than just as an indication of a
rising resistance. But does serve as some indicator of risk.

MR. LADELY: Scott Ladely, USDA. Again, on the indicator bugs. I think
that the target pathogen has to be monitored. As far as screening all
and finding the most sensitive bug to pick up resistance, you may be
shooting yourself in the foot if you have the product finally developed
and there is 65 percent resistance in that particular organism.

Fred\'s going to raise hell with you. As far as monitoring food-borne
pathogens, I think that should be left to Fred and Dr. Cray. Looking at
a couple of sentinel microbes plus your pathogen of interest, I think E.
coli and enterococci are just generic species would be a couple of, in
my mind, good ones to look at.

DR. GOOTZ: That was a good comment. I am glad you went before I did. I
guess the idea of a sentinel organism in human health, the best example
would be pseudomonas riginosa for all classes. Maybe staph \-\-- or
enterococcus, but pseudomonas always seems to be the one in human health
that the new drugs fall down first on.

That includes carbapenems, beta-lactams, certainly quinolones, and on
and on. While I agree, I tried to be positive and tried to reach
consensus, I agree that it could have some value. Pseudomonas
overpredicts in human health riginosa, the failure of fluoroquinolones
due to resistance.

It is a sentinel. It is the first one to become resistant and it is
certainly good to know that and to monitor it compared to the other
target pathogens like E. coli, klebsiella, etc.

And scientifically, I think it might be very interesting to look at
pseudomonas \--

DR. WALKER: You are going to \-\--

DR. GOOTZ: Oh, I know. No, I am just giving you an example. I am
agreeing with you from the human health perspective. Trying to give an
example, probably too long. But I agree with you that in the sense that
once you begin to generate that data, while a scientist would probably
feel comfortable with it, once it gets out there and is bantered about,
and not understood or put in perspective, I am just wondering how
negative people could make that information?

But getting back to animal health, sentinel organisms. Campylobacter
jejuni is a very good one for flouroquinolones. Which is probably why we
are all here. Back in 1991 or something people were trying to
characterize the mechanism of fluoroquinolone resistance in
campylobacter jejuni and our lab even isolated the gyrases out of that
organism.

I think we were the first lab to publish and show how you get single and
double step resistance mutations in DNA gyrases in campylobacter jejuni.
We isolated the proteins and did in vitro biochemistry. Later on people
did much more eloquent studies of actually sequencing the gyrase genes
in campylobacter jejuni to show the first step of resistance and the
second step.

It turns out that that is one of the least of course susceptible
organisms of human concern from the gut that we are discussing. It turns
out it has an odd gyrase. Even a wild type in the sense that it has a
\-\-- in place of serene in the active site of gyrase.

Now that sounds like who cares? That is not important. But it sets the
stage for why, when you expose it to fluoroquinolones that first step of
resistance took the MIC to .25 and the wild type to I think 8. So, as a
sentinel organism it has been very rough on animal health.

I think by giving fluoroquinolones for chickens, poultry, in water while
from a managerial point of view that is the only way to do it, but from
a selection or a resistance point of view or a sentinel organism point
of view.

It wasn\'t really good because the levels in the stool of quinolone
because you are giving the drug in water and the chickens are obviously
variable in how much they\'ll be taking and how much drug will get into
the fecal matter provided a nice selective condition, just like an auger
plate for that first step of resistance in gyrase it took raising the
MIC to 8.

Thus in Europe and places they were getting field isolates of
campylobacter from animal health sources that were resistant and saying
wow, what a horrible thing. This is the only way this could have
happened by the animal\'s health use of fluoroquinolone.

So, a sentinel bug can provide information, but it can be dangerous as
well. And it has been shown that you can get selection of resistance in
people with campylobacteriosis who take fluoroquinolones for therapy.
There are clinical failures.

We were on one of those studies years ago, too. It can happen, but it is
pretty rare. Therefore, the conclusion by everybody: regulatory
agencies, the CDC, the lay press, is that the use of fluoroquinolones in
poultry for animal health is really the only real mechanism by which
campylobacter becomes resistant to fluoroquinolones.

So, that is not a very positive thing. I am trying to reach a consensus
or reinforcement, but sentinel idea of a bug could be good, but it is a
double-edge sword. We have to make sure that we are able to as
scientists and clinicians get the upper hand in explaining the clinical
or field relevance of that type of data.

And while I think we could here, I don\'t have any concern about that, I
am really concerned more about the lay press and other groups getting a
hold of some of that sentinel data and making hay with it.

But the last quick comment, which hopefully is positive, I think some of
these pre-approval studies, susceptibility monitoring of use pathogens
is a good idea. We probably need to do more of it. And also I think in
Tom\'s block this morning he mentioned there are other ways of looking
at MICs, of field isolates, larger groups that just MIC 50 and 90.

And I think he mentioned cumulative percent plots. And that seems like a
minor, but it is a very, very important point in the sense that when you
plot your data out for MICs, let\'s say for 50 field isolates against a
given drug or individually for 100 drugs, it doesn\'t matter.

You begin to see subtle shifts in the MICs, of these individual isolates
that you can plot out on a curve, which you may miss at the MIC 50 or
90. And that costs nothing. We should always be doing that, we don\'t. I
tend to be very sloppy.

Sometimes you know to get things quickly for a meeting you just get the
MIC 50 and 90 and you know put it in the Powerpoint and away you go. But
some of these simple, straightforward things actually are pretty
important.

Where we can analyze subtle shifts in susceptibility of field isolates
pre-approval and also post-approval and then maybe take some of those
bugs that are shifting up, look at their genetics, ask on a very
individual basis what is the mutation? And is that mutation
characteristic of what happens in other organisms for that class of
compounds such as gyrase A for quinolones or you said for macrolides,
MLS type the resistance for deflux.

So, I think what I am saying is that some of the pre-approval studies
could be very useful. But they need not be so incredibly complex and
open-ended as at least has been mentioned, I know in good faith, at this
meeting so far.

Some of the things we are already doing could be pretty important.

CO-CHAIRPERSON HESLIN: We are coming up on 3:30 and we are scheduled to
have a break. Is this a good break point?

DR. RIDDEL: I think it is. Unless somebody else has a \--

DR. SINGER: Can I just make a quick comment?

DR. RIDDEL: Sure.

DR. SINGER: I just wanted to make a quick clarification on that sentinel
bug idea. When I brought up that issue as a potential predictor of risk,
I was thinking in terms of gene transfer. So clearly, as most of you
probably realize, fluoroquinolone doesn\'t really fit that bill.

We are talking point mutation in a chromosomal gene, unlike some plasmid
or conjugate of transposon which has this risk. So in picking a sentinel
bug, if we are thinking about a genetic mechanism that can be
transferred, that is where I was thinking of as a predictor of risk and
not in the case of like a fluoroquinolone.

DR. RIDDEL: Yes, I think when we come back I am probably going to get a
few comments directed towards pathogen load to help me out. Then we are
going to start looking at the inherent questions of what we were
assigned to do.

CO-CHAIRPERSON HESLIN: I think you can probably lead off since you
wanted to say something, but at 4:00 o\'clock we can reconvene. That is
about a half an hour.

(Break)

CO-CHAIRPERSON HESLIN: Okay. We will go ahead and get started. The
ending point for today is 5:30, so we have got about an hour and \--
almost an hour and one-half.

Let\'s start off this session with a comment.

MR. CONVEY: Ed Convey, Limerick Strategies. I have had a chance during
the break to talk to some people and I might be redundant on these
points, but I wanted to make them anyhow.

First, Tom isn\'t here, but the point that Tom made about upper
management making decisions against an uncertain regulatory background I
think is important. And presumably that is well recognized. That
presents a certain difficulty in terms of management decisions by
industry.

The other point I would make I think is also pretty obvious, but I am
going to make it anyhow. That, in my mind as a non-microbiologist, and I
want to make it clear that I am not an expert.

But, listening to the experts, it is pretty clear that the overwhelming
message was that the state-of-the-art is such that it is unlikely that
you are going to be able to do studies that are definitive in terms of
predicting resistance development and worse, making some determination
from those studies on impact on human health.

I think the Chair was on a reasonable tact though in asking the question
about what does industry do to get comfortable. And this is preliminary
to putting very sizable investments into a new antibiotic.

What would they do to get confident that the emergence of resistance
would not be quick? And that is a reasonable line of questioning.
Because these are the people who are going to commit hundreds of
millions of dollars into a new program.

And, if the specter is that resistance development is quick, and the
product then is a liability, then they are not going to make that
decision. So, within the expert community and industry, it seems like
the answer to those questions are worth ferreting out.

What would give you confidence as a pioneer drug developer that
resistance will not be an issue for an antibiotic? And I think the
experts that spoke to that acknowledged that that kind of background
studies are done in industry exactly for that purpose. To try to make a
decision about what is reasonable to take forward.

So, those are my comments.

DR. RIDDEL: Go ahead.

MR. WATTS: Jeff Watts. I want to speak a little bit to use patterns.
Besides also agreeing that one of the things that we should know and one
of the things that we do is know your compound well. Know the classes
that it is in and understand its various activities.

But I think it is also important to speak towards use patterns. And also
understand that there are patterns that contend to lend towards
resistance, but also use patterns and management practices that may help
moderate resistance.

We just completed a study. We looked at 811 staphorius strains for
mastitis. Ten different countries. We really went into this expecting to
be able to see differences in resistance patterns based upon the
products that were approved in the various countries.

One of the things that was remarkable was that the MIC 90 values, for
practically every antibiotic that we tested was flat. You could see no
differences from country to country.

Now, if you start thinking about how we handle staphorius cows, for 30
years we told dairy farmers, we told veterinarians there are no
syringeable solutions to your mastitis problems. It is a management
problem.

So, what do we do? With staphorius cows they get treated a couple of
times. If they don\'t respond they are called from the herd. And we
remove those animals, they are not treated for multiple times, and so
this moderates resistance.

Tom, we have used cloxacillin for 30 years to treat mastitis. And in
that particular study and in other studies that I have done, I have yet
to find a single \-\-- Most of our staphorius strains are actually still
susceptible to penicillin.

So these are practices that help to moderate resistance. We should
understand those use patterns. And, if we can understand those use
patterns that may moderate resistance, then as a sponsor we can respond
to that in a post-approval manner to help farmers manage resistance in
their herds.

DR. RIDDEL: While you are up there Jeff, as you are bringing a product
through R&D, is it feasible to be able to project what the use patterns
will be? Is it feasible to delineate use patterns which would select for
decreased susceptibility and maybe even project mitigation strategies
before approval as a part of your pre-approval study or document? Or
would that be inappropriate?

MR. WATTS: The simplest thing, I think there are some very general
things that you can do. And Tom, I will ask you to help me out here. The
simplest thing you can do is when you design your drug profile, the
first thing you do when you start looking for a compound say to treat
BRD, or to treat swine respiratory disease or whatever, the first thing
you are going to understand is how you are going to use that drug?

Are you going to use it as an injectable? Is it going to be an
intra-mammary for mastitis? Is it going to be a P additive. Those sorts
of things. And you know that certain types of those sort of applications
are going to have more of a tendency to give you more problems with
resistance because a sick animals don\'t eat well, they don\'t drink
water well versus an injectable.

So, there are some very general things that you can do.

DR. RIDDEL: What \-- of course I have been involved with DCPR and Anduka
who are fighting for extra label use. How is that going to impact or
complicate some of these things?

Right now, for fluoroquinolones, you can use it in beef cattle. You can
even use it in the relatively worthless dairy bull calf, but not the
valuable dairy heifer calf that is in the pen right next to it.

But that is legislative. Unless more regulations come along, a product
could come to market that wouldn\'t have that restriction. How would
extra label use by the profession impact some of these considerations?
Extra label but legal under DCPR and Anduka.

I guess I was asking you to predict potential use patterns.

MR. WATTS: It depends upon the use pattern. It depends upon the extra
label use. If you have a \-- let\'s say you are trying to treat a
pneumonia by an organism that is not on the label. Say you have got a
diagnosis, it is H-parasuis. And you know this compound has activity
against H-parasuis and you know that you still want to use the same
basic treatment pattern that you would use for treating any other \--
for treating the label bugs for SRD.

That to me is not a high risk situation in terms of extra label use. If
you are going to open that bottle and lavage animals to treat diarrhea,
that to me is a much higher risk in the extra label venue. So, it
depends \-- again, it would go to the use patterns. And how that
compound is being used.

DR. SHRYOCK: Tom Shryock. I guess, just to follow-up on some of those
points with the use. You know, it almost puts the practitioner in the
perspective how should I choose what drug to use? Should I base it on
efficacy and expected clinical outcome? Or, should I choose this drug on
implications based on implications to public health, which is a lot
further away from the immediate needs.

And that is a quandary I think that we may find ourselves in, in certain
cases. How does that all relate to pre-approval studies? I guess the
questions that we find that practitioner asking \"How do I choose my
drug?\" revolve back to what sort of studies should we or could we do to
enable that practitioner to make a worthy decision.

And I wonder if there is an opportunity to perhaps use some of these
pre-approval studies that are already being done, that we have already
mentioned: pharmacokinetics and some of the MIC studies, to maybe
embellish the label a bit more to perhaps consider some of the things
that were discussed several years ago in the flexible labeling workshop
for example.

The big old labels got a lot of information that would enable
practioners, who now have prudent use guidelines to subscribe to, to try
to really make their best clinical judgment on as much information as we
can give them to try to satisfy both goals.

That is certainly not addressing pathogen load or resistance selection
studies necessarily, but I am just wondering if maybe that is one of
those out-of-the-box kind of exceptions that you have got a Powerpoint
slide in reserve for.

I don\'t know. It is just something to think about.

MR. BOETTNER: Alexander Boettner from Intervet International. I would
like to come back to a question you asked before we had the break. You
said well, what would be the worst possible scenario for pre-approval
study? Let me make a rather provocative statement to this regard.

I would say not a study design could give us this scenario, the worst
scenario probably is the process we are dealing with at the moment. And
what I am mean by this is that for pre-approval studies and all of these
issues, for the last two years no new antibiotics has been licensed.

Every single compound in the regulatory process is more or less stuck.
Where at the same time, with the use of existing compounds we may
continue to contribute to resistance development and to put things into
perspective.

Wouldn\'t it be important to look at resistance development of all
compounds being used and not only concentrating now very, very much on
the new compounds which are in the licensing process.

DR. RIDDEL: So, you are not asking for CVM to begin to require
post-approval modeling on this that have been approved for years, are
you?

MR. BOETTNER: Say that again?

DR. RIDDEL: You are not asking for somebody to require monitoring
programs for a product that has been approved for years, are you?

MR. BOETTNER: Yes. Well, I think we have to sort of \-- if we are
looking at resistance development and the potential impact on human
health, we should not limit this to new approvals. We have to sort of
assess these risks with existing compounds as well.

And we may be looking at the use pattern of existing compounds and
looking at potential development of existing compounds would be \-- I
put it \-- English is not my native tongue, but \-- maybe a more useful
exercise than just sort of now discussing in length how processes how
new animal drugs approvals could be regulated while looking at \-- the
studies of pre-approval studies where there are still a lot of question
marks.

And, in the mean time none of these drugs do get approved and it gives a
sign to industry that they probably, because this process becomes very
unpredictable, that they seize with their research programs or \-\--
programs to develop new drugs for animal health.

DR. RIDDEL: So I guess for my edification. Do not some of the ongoing
monitoring programs evaluate this information? And if an antibiotic was
approved, became an obvious contributor to reduce susceptibility in a
zoonotic pathogen, wouldn\'t there be a likelihood that CVM or some
other regulatory agency could force some type of mitigation of that?

Right now, aren\'t they collecting data on susceptibility to antibiotics
that are currently on the market? It is not formalized. I mean, it is
formalized, but it is not within any mitigation goal.

MR. BOETTNER: Not that I know of. I know that there is NARMS, there is
monetary. But whether there are any mitigations from the results
provided by NARMS, I don\'t think so.

DR. RIDDEL: Again, out of my ignorance, have there been \-- I know the
studies have not been performed uniformly, there has been a change of
protocol through the four years that NARMS has been in effect, right? So
you may be comparing apples to oranges.

But, there hasn\'t been any currently labeled antimicrobial that has
been pinpointed as being a hot point or being a serious problem, right
or wrong?

MS. : That is right.

DR. WALKER: \-\-- we just went back and looked at staph and \-\--
isolates from 1987 to 1999 against four fluoroquinolones that were
commonly used in \-\-- veterinary medicine.

We found that the MIC 50 and MIC 90 over that 11-year period or 12-year
period really didn\'t change at all for any of the fluoroquinolones. The
MIC 100 changed, beginning about 1986. We started picking up some
resistant organisms.

So, for the most part it is a small sample of organisms, but the bottom
line is that for the most part we are not seeing a lot of change with
that particular organism.

MS. : I hesitate to actually whether I should actually say anything,
because I am just supposed to be listening.

But, in terms of your comment on the existing products versus new
approvals, that is always been kind of a point of confusion with what we
put out on the framework document.

We have always intended that the overall approach in terms of the
framework once that is finalized, would be applicable to products that
are already on the market. But realistically, we would need to
prioritize which products we looked at because of limitations and
resources.

And so, we would most likely use whatever categorization system that is
finally agreed on to help us focus on the products that are of most
concern.

So, in terms of whether \-- the NARMS data I think is definitely
something that would be very helpful in identifying where products may
pose a public health concern. And I think we would potentially use that
in the future, but we have not at this point in time made any decisions
to take any particular action or work with any companies on mitigation,
specifically in relation to the NARMS data at this point in time.

So, I think we are going to address that. We are getting there. But, all
of this is not finalized yet. But we feel that for the new products we
also need to look at the issue in terms of microbial safety and we feel
that the pre-approval studies are an important component of that.

DR. PETRICK: My name is Dave Petrick and I work with Schering-Plough
Animal Health. My background isn\'t in microbiology. My job now is in
regulatory affairs.

I just wanted to put some of the comments and some of the thoughts I
have had over the last couple of days in that environment. I think,
listening to the presentations, it just strikes me that every time
someone draws a straight line and says here\'s a good path, there is
seven more divergent paths that follow.

Whether it is looking at Oh, yeah. This is what we need to do
pre-approval, it is important to have this information. Then we come up
to but what is the context in which we collect it? Should it be in an in
vitro study? Should it be with a live animal? Should it be from the
field? Should it be here? Should it be there?

Then we go well, what is the environment that it needs to be tested in?
Should it be like the rumin, the secum? It just strikes me that there
are a lot of things that we don\'t know and there is a lot of things
that we are very unsure of.

I guess what causes me to have a great deal of concern over just the
concept of pre-approval studies, is if we generate data, we can\'t lose
sight of the fact that it won\'t just be here with us. I think one of
the other speakers had that remark that they are not concerned if it is
within this scientific community because we can understand it, we can
put it into context.

Well, that may be true, but CVM doesn\'t work within the scientific
community and neither do I as a regulatory person. We have to work
within the confines of is the product safe and effective and if it is,
therefore should it be approved or not?

And I guess the fear I have is with data being generated, there is a
requirement that all pertinent data from the regulations are submitted.
So that means that CVM then has to deal with that data in some way,
shape or form. And I just have a fear we are walking ourselves down a
road where we will spend money, we will collect information, data will
be submitted, data will be reviewed.

And, at the end of the day we are not going to be any further along at
being able to predict rate and extent of existence or extent of
resistance development for any product, whether it is new or whether it
is old.

Part of the reason this issue has hung on for as long as it has, from
the Swan Report forward, is we can\'t put a finger or we can\'t put our
thumb directly on the problem. We can\'t define it precisely.

And I think we are kidding ourselves if we think we can walk away from
here with a definitive study design that is going to give us those
answers. If we can find a means of putting it in a context of baseline
information or information that will start a process, then I think that
is wonderful.

And putting my management hat on at the company that I work for, if I
could run a study I wouldn\'t care if it cost \$100,000. I wouldn\'t
care if it cost a million dollars. If it would give me the guidance to
say that I know my products going to be good for 10 years, that is money
in the bank.

But, from what I am getting unless someone can tell me I am wrong, I
don\'t think were at that point now. I just worry about trying to either
codify or put into guidelines or put as a requirement for approval, a
study or studies that generate data that no one is really clear what its
meaning is.

I guess that is where I come from a regulatory standpoint.

MR. HALLBERG: John Hallberg from Pharmacia & Upjohn Animal Health. I am
going to work on a working-delusion here. I have been sitting here
listening to all of the comments and I have come up with several, I
don\'t know if you\'d call them revelations, or not.

But I think we could probably say that for a pre-approval study or any
study, one-size will not fit all. There are too many compounds, too many
different classes, too many different metabolisisms to say that this is
the study that will get us these results.

But I would propose that in the process of approving an drug, and I
basically come from clinical development and recently made the
transmission to regulatory. So I am new at regulatory and a little more
experienced there.

But if in the process of the submission of an NADA, you are using a
phased-reviewed submission scenario where you go in and request an IDD
first time in. In theory you should be able to go into the government at
that point and for your compound give a brief identification of
mechanism action: how does this think work?

From the laboratory you should be able to generate what are potential
resistance mechanisms? So if I take a bacteria and force it with this
drug a bunch of times, what are the different types of resistance that
we could generate and bank those. That is a piece of information for the
future.

I should be able from the literature, potentially if this is a family
issue, I should say what is the potential of cross-resistance? Put that
up there. Typically, before I go to the government with an I80D I need
to have some preliminary idea of metabolism. What happens when I put
this compound in a cup? Or put it in a paper or put it in whatever? How
active are the metabolites versus the parent, okay?

Then what I should be able to do from that is I need to get an I80D
approval to go out into the field and do studies. Now, at that point I
am probably also going to go in and talk to Steve\'s group, or Cindy, or
Sue, and put a developmental plan forward on how to get this product
approved: efficacy studies, human food safety, target animal safety.

I am going to submit those protocols to get that work done. Now, as Marc
Papich told us, in the design of the efficacy studies we should use our
PK/PD information to identify a good effective dose and potentially not
a minimumly effective dose. But something that is going to give us good
efficacy in the field when we are treating our disease.

In the process of doing that, that gets us into our clinical efficacy
studies. From those studies we gather a whole bunch of pathogens
typically on pre-treatment sampling that we can use to establish a
baseline of what are the MICs for these pathogens early in the game.

Because in theory, these drugs, this is the first time this drug has
been in the field for this indication. If you are doing I80D studies.
Then, that should be submitted to the agency as here\'s something else
we put on the shelf.

Then, as part of the approval we should consider establishing \"what is
susceptible\". Okay? We have this problem right now, of well is it
macro-susceptible, is it this base susceptible? What is susceptible? And
a lot of compounds we don\'t know that.

Then, when you get all this database done and you submit your NADA as
potentially part of the last discussions with the agency for approval,
is how to you set up the post-approval surveillance? What are we going
to monitor? Where are we going to monitor?

I would suggest to the group that this monitoring be on target pathogens
and that we should let the NARMS folks worry about the zoonotics. That
our compound would be added to the NARMS observation at that point, on
approval.

Then, for the next few years take that as the database to start that.
Resistance is going to happen. When it is going to happen nobody really
knows, but until we set up something to get us in the ball game with new
compounds, we won\'t know how that is going.

That is my working delusion, and I don\'t know if that helps or not.

CO-CHAIRPERSON HESLIN: Anyone want to respond to his delusions?

DR. VAUGHN: That is the best idea I have heard yet. I am Steven Vaughn
with CVM. I just want to throw out a few other ideas just to consider,
not that I have any answers.

First of all, I am looking at it from the perspective that we are a
public health agency. So what is our job? Our job is basically to
prevent human pathogens that have resistance factors to important
therapeutic compounds in human medicine from reaching humans and causing
disease.

From that standpoint, if we work backwards we have to be able to approve
drugs that are safe by some standard. We don\'t know what that standard
is, for sure. Some folks are using reasonable certainty of no harm as a
standard that is pulled over from the pesticide part of the Food, Drug
and Cosmetic Act.

Some people are saying we should use a food standard which is not
deleterious or injurious to people. What preponderance or amount of
evidence do we need to be able to say a product is safe?

The other part of that is it is also safe in the context in the
conditions of use. And I think that gives us a tremendous amount of
flexibility to be able to say that we have a pre- and post-approval
strategy or construction under which we can take certain information
pre-approval and utilize it in a post-approval mode to ultimately
accomplish our mission. And that is to prevent those pathogens that are
resistant to important therapeutic compounds from causing disease in
people.

I am concerned a little bit about \-- and this is where Steve Vaughn\'s
personal opinion, I will take off my CVM hat \-- I am a little concerned
about the framework document in that regard. I am not so sure that the
framework document is a pre-approval document.

I think really the logic behind the framework document is that the
categories are really categories of priorities for mitigation. And
whether that occurs in a pre-approval or post-approval mode, I am not
sure at this point in time, myself.

I would think if we saw an increase in resistance occurring, or a loss
of susceptibility that our priority for mitigation would be based on the
categories. I am not so sure that we can make a blanket statement in a
pre-approval mode that if it is a Category I drug it should never be put
on the market.

I am still inclined to think that regardless of whether it is a
therapeutic drug or a therapeutic antimicrobial or a production
antimicrobial, it might be valid to approve those products. I am
concerned from the standpoint that when we do something, everything we
do has the ripple effect.

What is going to happen when we remove production uses? One of the
proposed mechanisms by which production drugs work is they lower disease
incidence in cattle. I think we need to keep that in mind. We know we
have dealt with that in the residue arena, where we have had a big
effort to push a particular drug from being used because of a residue
concern.

And then the next drug of choice that became popular was worse than the
drug that we had in the first place. We need to think about what we are
doing and the impact of what we are doing when we look at making
categorical statements.

So that is one point to consider. Another thing that I am thinking about
is that we need to be able to identify when a product that we have
approved actually is the cause of the loss of susceptibility. And I am
not quite sure how to do it.

I was trying to think of a good word to say and I am not a
microbiologist. Maybe Tom can get up to the mic here, or Jeff, and tell
me, but if there is some way to be able to fingerprint for a trace back
post-approval system to be able to identify that a product was
implicated or not implicated.

I am concerned we are dealing with resistance that is a global issue. We
heard several speakers speak to that. I don\'t know in a feed lot
situation if I get isolates from a feed lot, what the source of that
particular resistance might be if I started to see it in feed lot
samples.

We have four million feed lot cattle coming from Mexico every year into
U.S. feed lots. I don\'t know what prior treatment exposure they had in
Mexican ecosystems and what problems that may have caused and been
introduced into a U.S. feed lot. I have no way of knowing that unless I
have some trace back capability.

So, that is one of the things we may want to think about in terms of
pre-approval. Can we develop information that allows us to either say it
was caused by a particular product or not caused by a particular
product? Some of that may be defensive research on the part of the
pharmaceutical companies.

We also, most importantly, need to know how to mitigate. If we do see
the development of resistance, what are the tools we have available to
mitigate? I am concerned about what we can do with the on-label
indications and I am concerned about what we can do with the off-label
indications. The regulatory tools that we have available are somewhat
limited.

We can modify labels. We can take enforcement actions against certain
extra label uses, prohibit extra label uses or withdraw products. But,
there is a very finite arena of things that we can do.

I think, about situations that Jeff talked about, we have done a real
good job of educating dairy farmers about staph mastitis. But, as soon
as they walk out the exit door of the parlor they walk through an
oxytetracycline footpath. And I wonder if we are doing the right kind of
things in those kinds of situations?

I do think we need to have some pre-approval screening to have some kind
of baseline information, but I don\'t think we need to tweak it down
where we have to say this is the number. This is the dose, the optimum
dose at which we cause the minimal amount of resistance. I don\'t think
that is a real number.

I can certainly speak to effectiveness trials and we look at dose
titration. That is why we abandoned dose titration, we don\'t think that
it has the inferential value to a population to be able to say that is
the optimum dose for all clinical situations for a particular
indication.

That is why we are more inclined to think of dose ranges where we modify
dose intervals and duration, and routes of administration for varying
clinical situations.

So, I think if we talk about trying to optimize this I think we need to
talk about in terms of ranges rather than trying to pinpoint single fix
doses. That is it.

DR. RIDDEL: Any comments from other people in industry on the working
delusion?

(No response.)

DR. RIDDEL: Okay. Well, I think those were all really good ideas. I
think they may begin to form some grounds for our response tomorrow. If
there are no other comments, let me force you to get back to helping me
out just a little bit.

I had a mole slip around through a couple of other rooms to see what
comments were going in those directions. And there were similar negative
comments relative to pathogen load. And while I think I am going to hold
you to not throwing everything out saying we don\'t need these things,
we are going to have to do something.

But I think, and again this is my area of lack of expertise, I need
somebody to help me to come up with some well-founded comments on if
pathogen load studies are irrelevant, especially for some of our use
patterns then.

Or, if some of the studies that have been described in some of these
models, such as knowing the metabolism and knowing some activity that
metabolites, if those that have informational impact that could at least
secondarily address pathogen loads. I need some information along those
lines.

I have not heard anything except negatives about pathogen load studies.
And while I think we are going to have to approach CVM from a ruminants
standpoint with some type of pre-approval format, I think maybe there is
segmented parts that we can say this really isn\'t relevant to what we
are dealing with.

But, I need some help on understanding pathogen loads because that is
one area where I have no basis in at all.

DR. SHRYOCK: That is consensus. Look at Tom and you want him to talk and
be the strawman.

With pathogen load, I guess some of the positive aspects? I can lay out
a few of those. And a few of the limitations, the list might be a little
bit longer.

I think probably you could really excerpt a lot of these questions or
comments from the talk that Kathy gave, the talk that Paula gave. There
is a lot of considerations.

And if you were to ask me to design a study that I had a lot of
confidence in that I could take to my management and say: If we did
this, we would have this thing aced. We would have a bona fide
predictable study.

Given all of these variables in here with regard to animals, the dosing,
the duration, is it challenge? is it seeder? type of situations. When in
the process would you want to sample for your zoonotic pathogens? Which
pathogens do you want to sample?

All of these kinds of things are posed as questions and you can design
these studies and do them and get information, but it is only as
relevant as that one study under the conditions of use in that
particular experiment. There is no guaranty that you will have data
generated that is predictive in a total, national type of situation.

There is no measure of validity relative to perhaps other drugs, at
least the 55815 studies you are only testing a medicated, non-medicated,
and environmental-type control. The extrapolation from all of this based
on some arbitrary measures for pass/fail, how does that really relate to
human health? I have some difficulties trying to get to that endpoint.

I guess I really spent a lot more time on the limitations than on the
positive aspects. Those positive aspects would be that you actually do
have an animal model of some sort. So you have this black box of gut
ecology factors in place. It is not just an in vitro setting where you
have optimal growth conditions for a bug or two.

The studies can be controlled, very much so. You can pen your animals
individually, control their environment, diet, dose, everything. It is
easy to control those.

There is is some precedence for doing some of these kinds of studies. We
could design based on what has been done in the past. So there might be
some history that one could follow, is a positive aspect of at least a
pathogen load study.

I think I will just stop at that point and see if there is anybody else
that would like to chip in, but those are a few thoughts that I have off
the top of my head.

MR. LADELY: Scott Ladely, USDA-ARS. I don\'t think they are relevant, I
am sorry. If you are looking at salmonella, it depends on what serotype
you isolate that has more to do with resistance pattern than anything
else.

If you tried to save some money, bought a bunch of Holstein calves, you
are really screwed because the prevalence of salmonella\'s going to be
higher. It doesn\'t have much to do with what you are treating the cows
with.

Resistance patterns for salmonella it just seems like some serotypes are
more prone to resistance than others.

DR. PETRICK: Dave Petrick again and I will just hitchhike right on that
to go back to my comment that I think relevance is incredibly important
in a regulatory environment. And we want to make scientific-based
decisions, but if we are going to make a regulatory decision based on
science, the science has to have a good foundation as well.

Because, if we don\'t have a good foundation in the science, the
regulation can\'t be sound, and I don\'t think that is where we want to
go either.

So I think one of the really important things is to make sure whatever
studies we are doing, they are always relevant to the question at hand.

DR. RHODES: Linda Rhodes from Merial. I think the slide that really put
this in perspective for me was Paula\'s slide where she showed all the
different types of salmonella sampled in the same population over time
and how incredibly variable those isolates were, depending on the age of
the animals.

I mean this is very impressive data. I think what it shows is that you
can imagine a large number of variables that are going to effect your
pathogen load isolate data that have no relationship to the treatment of
the drug.

And so when you have so much variability in the endpoint that you are
measuring, you know it may be a good thing because it will just mask any
drug effect you have and then you can say well there was no effect and
everybody will be happy and you did something.

But, it goes back to that whole point of relevance. What are we really
asking? I think because the mechanisms are so unclear, what causes this
variability in shedding over time in the same animal and in animals that
are growing? How does the way you collect the sample impact your data?

I think until we can show some test system in an academic setting or in
a government lab-sponsored setting, where we can do the same experiment
with the same drug over and over again in different populations of
animals in different laboratories and get the same endpoints. I don\'t
think anybody is going to have a lot of confidence in whatever data we
generate.

It is kind of like doing the confirmatory method, you know you have to
take it around to several different labs and they all have to be able to
perform that method reproducibly and get the same data from the same
types of tissues before the government has confidence that we have got a
good confirmatory method.

In a way, I would like to see those kinds of data. I would like to see
the same drug in the same population of animals performed at six
different academic labs or government labs, showing a similar effect on
pathogen load and then maybe we\'d have some confidence that these data,
these studies that we are planning to do would mean anything.

I think that is what is lacking, is an ability of consistently and
reproducibly being able to show a similar effect in any kind of defined
test system.

And then beyond that, if you were able to come up with that, which I
think would be very difficult to do, then it comes back to Dave\'s
question of what is the relevance of those data? Is it really predictive
of what is going to happen in the slaughter house and how much
contamination are we going to get on a carcass that is then going to
have a human health implication?

But I don\'t even see the beginning of reproducibility of data here. I
mean maybe people who are much more experienced than I am in this area
can comment on can you reproduce these types of data in a consistent way
across labs and have any confidence in the predictive result of these
types of experiments?

DR. RIDDEL: I will take that to be a no.

MR. MUSER: Rainer Muser, representing myself. Maybe it helps to add some
other argument to what you are asking for. Dr. Angulo brought up the
idea of that there is a limited number, he didn\'t say limited number of
resources, but he did say we might be able to use our resources better
in another area that pathogen load because it doesn\'t really mean that
much.

And what it means to me is that when we put an antibiotic on the market,
the resistance situations are an exception to the rule. It is a small
number of things that are happening. The pathogen load are a subsector
of that again. So we are beginning to chase the infinitesimal with doing
that type of study.

The question is really then how meaningful it is, particularly
considering that a true role of pathogens in food derived from animals
could probably be controlled better by other means than trying to figure
out how an antibiotic down the road might cause it.

It might be better by hygiene in the slaughter plant or whatever, you
name it. There are good measures to take care of pathogens in food
derived from animals.

CO-CHAIRPERSON HESLIN: Well, before everybody runs out. We still have a
blank number three up here that needs to be filled in.

DR. RIDDEL: To look at a couple of specific questions that Dr. Quinn has
asked us to look at, I think some of these we have covered.

The pathogens which should be the focus of pre-approval studies.
Consensus to me seems to say that target pathogens, known zoonotic
pathogens, and now we have the concept of the sentinel organism. Are
those all things that we could or should agree to? Things that we should
present coming from ruminants?

DR. EWERT: Kathy Ewert, Bayer Animal Health. I just want to \-- I
wasn\'t in the room for that discussion, but I just want to clarify what
I, in industry, understand the framework document to address and that is
public health or food safety issues.

Target pathogens, those pathogens being the organisms targeted for the
drugs we are using, for example nuflura, bactril, or micatil. We target
pasteurella and hemophilus and those sorts of bugs.

Those target pathogens really have no implication at all in food safety.
And those are the responsibility of the sponsor of the industry to
monitor and most companies do monitor that in some way or another.

So I would see what the rest of the group thinks. I would not suggest
that as a pathogen to be monitored in pre-approval studies. That is done
as part of our efficacy work. If our drug is inefficacious against a
target pathogen then we don\'t have a product and there is no reason to
move ahead.

As far as sentinel organisms go, I mentioned yesterday in my
presentation that I can find nothing relevant in the literature to
indicate that monitoring the sentinel organisms gives us any kind of
indication of what is going on in the food-borne pathogens.

So I think that discussion took place earlier, but I just wanted to go
on record as saying that.

DR. RIDDEL: Okay. And you understand, I think Dr. Walker presented the
thought that you would culture all of the enteric organisms out of an
animal, a group of animals, and check them all for susceptibility
changes.

The one which shows the greatest change would become the sentinel
organism and use that as a predictor of a worst case scenario, more or
less. Am I paraphrasing what Dr. Walker said correctly?

DR. EWERT: But how would that then correlate to the true food-borne
pathogen with changes in susceptibility in the food-borne pathogen?
Unless we know that that particular organism has the capability of
transferring a resistance component to the food-borne pathogen.

I mean we can do that now. We can do that now, but I just question what
the relevance is of that to looking at issues with food safety.

MR. BIENHOFF: Steve Bienhoff with Intervet and I would like to reiterate
some points about this sentinel organism.

I think that it opens up more questions than what you are going to get
on answers in that. If you are looking at sentinel organisms and you can
increase in a resistance, what does this mean as far as your pathogens
are concerned? What point do you intervene on your drug?

When you go to an agency you are proposing an organism as a sentinel
organism, which one do you pick? You look at a number of them and there
is going to be various ones that will show resistance. And you take the
one with the most resistance, the one that is maybe further down the
line, maybe more predictive.

But which one do you pick? So you have those questions to answer and
then once the drug is on the market then you have to come back, you get
this resistance showing up out in the field. Again, what does that mean
for your zoonotic pathogens?

Is it really that predictive of what is happening? And at what point do
you intervene? So you get all of these questions there that you haven\'t
answered. What do you do now?

So you are collecting data, and data is nice, but a lot of time data
produces more questions than answers.

I think what we are trying to get to is the point where we are coming up
with some answers on how to approach it, but going in that direction
opens up a whole other area.

MR. SCHMID: Peter Schmid, Intervet. In my opinion, during the early drug
development we get a lot of information on the susceptibility of
different bacteria against the new compound.

Not only the target bacteria but also gut flora. And if you take the
most susceptible population from the gut, for example E. coli and look
into the MIC distribution, we can do together with our first
pharmacokinetic studies, we can test the influence of the intended use
of the compound on the MIC distribution of the gut flora.

I think this is a more sensible and more sensitive measurement of the
possible influence of the intended use of the product on resistance
development or resistance selection.

MR. LADELY: Scott Ladely, USDA, again. For sentinel organisms, it is a
tough deal. I don\'t know what the best ones to pick will be.

But, what they\'ll probably do, this is my hunch, in the future is
they\'ll be looking at stuff like the NARMS data and CDC\'s data, human
and animal isolates. And as resistance levels come up they are going to
take some action.

If they are looking at salmonella, campylobacter, those organisms, maybe
that should be our sentinel organisms. I don\'t know.

That is why we need to follow resistance. Because at some point in time
they are going to say, and from looking at that data, government data,
the human and the animal isolates, they are going to say this is getting
out of hand and they are going to want to pull some drugs from some
uses.

So maybe we should just go with the particular species that they are
monitoring, the government\'s monitoring.

DR. EWERT: Kathy Ewert from Bayer Animal Health. That just brings up an
interesting question here. We might have different definitions of what
sentinel here.

What you are talking about that they are monitoring for NARMS is already
a salmonella and campylobacter, those are potential food-borne
pathogens. Potential being the key word.

However, what the agency is talked to us as a company about, a sentinel
organisms that are not particularly pathogens, for example E. coli. The
whole population of E. coli.

MR. LADELY: Right. But how good does that tell you about the food-borne
pathogens \--

DR. EWERT: Well, exactly. That is the question that we are asking. But I
mean there are thousands and thousands of strains of E. coli.

MR. LADELY: We will be checking E. coli. We will be looking at the
generic ones. That should give us a better idea with salmonella because
looking at salmonella depending on the serotype resistance is just all
over the \--

DR. EWERT: We have got quite a bit of information generated with our
post-approval monitoring program and with pre-approval studies that we
did. Looking at E. coli as a sentinel organism compared with salmonella
as a food-borne pathogens, and found that there is no correlation.

MR. LADELY: Right.

DR. EWERT: There is no correlation. And based on studies that we did, we
had salmonella with higher MICs and E. coli that we got out of the same
sample with very low MICs. Conversely, we saw E. coli with high MICs and
salmonella with very low MICs.

So we found no correlation in baseline work that we did. This is in
cattle. And with our post-approval monitoring, while we saw a transient
rise in a few E. coli isolates, we never saw a single isolate elevate
with its MIC for salmonella, never.

So that makes me wonder what relevance do those E. coli isolates have to
the overall food-borne illness picture.

DR. RIDDEL: For my information, being concerned about antimicrobial
susceptibility and some of the invasive salmonella and campylobacters
having very important therapeutic tools in human medicine, can the same
be said for E. coli? For example 0157? Antibiotics are they a mainstay
of treatment for that disease in people? If not, then they probably
should be specifically excluded because of lack of relevance to the
issue, right?

DR. EWERT: That is correct. And that is what we did, at least in our
post-approval monitoring. We specifically said that we would not look
for anaerotoxigenic E. coli of any sort. They would just be the generic
coliforms.

But, there are other people that can speak to this better than I can.
But it is my opinion that 015787 is not an organism for which
antimicrobial therapy is indicated in humans. That is correct?

DR. SHRYOCK: (Nods yes.)

DR. EWERT: Okay.

DR. RIDDEL: Thanks.

DR. WALKER: Bob Walker, CVM. When I was talking about the sentinel
organism, say we have a new drug, miraclemycin. We don\'t know where
miraclemycin is going to fall in this scheme and so one of the things
that we want to do is to do some preliminary tests.

So we are concerned about the potential of selecting for resistant
organisms that may be human pathogens or could transfer resistant genes
to human pathogens.

And so we take this drug and we take a number of enteric organisms from
the target animals\' feces of the animal species that we are going to go
for approval with, and we test this miraclemycin against all of these
different bacterial species to get a baseline MIC and then we look at
what happens with repeated exposures at various concentrations.

Now we know with staphorius, it has been shown in the literature that if
staphorius is exposed to ciprofloxin in concentrations at two times the
MIC, resistance occurs every 10^-7^. If it occurs at four times the MIC,
it occurs every

10^-10^. And both of those are relatively common.

If it is 10 times the MIC, resistance doesn\'t occur. So we would expose
these different intestinal organisms from this target animal species to
varying concentrations of this test drug or new drug, over a period of
time. And we are not going to see a change of MICs in all of these
organisms. It is just not going to happen.

Strep-piogenese has been exposed to penicillin for 50 years and the MIC
hasn\'t changed. It is still the same. I talked to you about what we saw
with the staph-intermedius. It has been exposed to anaerofloxin for 12
years and we are really not seeing a change in the MIC 50s, MIC 90s.

But, one of those organisms may, as the proteus did, show an increase in
MICs. Look at that organism, see why this occurred. Is there a resistant
gene associated with it? Identify that. Identify the factors that
contributed to this increase in MIC and then look at that as your
potential sentinel organism.

Because any time that organism or that species of organism is exposed to
this drug, under clinical conditions, it may have a decrease in
susceptibility. And that is what you want to look for. Not waiting for
it to get resistant or to become resistant, but to look for a change in
susceptibility.

Like I indicated before, if you started out at a .06 and it jumps up to
.25 or .5, it may still be susceptible but it has changed. And then you
can become, start looking at mitigating factors or factors that could
have contributed to this.

In the mean time, because this was the most sensitive organism in terms
of this potential change of all the ones you tested, you can kind of
rest assured that while it has gone from .06 to .25, the pathogen in
this environment probably is still back at .06 or .12 or whatever it
started out because it is not as sensitive to change.

DR. RIDDEL: Dr. Walker, let me ask a question before you leave. That is
understandable and that is a good educational concept for me. But, the
information you described as far as sentinel organisms, should it be
information which is the property of the company upon which they would
base decisions for further development for going through the process?

Or, should it be information that if it goes to CVM then it is going to
become a part of the regulations and requirements. And if it is not
relevant to the point at hand, which is human food safety, then should
that even be offered up as a potential comment in this process?

Things need to be safe and they need to be appropriate, but you don\'t
want to throw out things that are not as relevant as they could be that
may make the process more difficult.

DR. WALKER: And I think that is a very good question, a very good point.
I think that we are in a field or a time of discovery right now and I
would like to think that this is something that can be worked out with
CVM.

That this organism, say it is a proteus, is not a human pathogen. Say we
are talking about a fluoroquinolone resistance. This new miraclemycin is
a fluoroquinolone and we know that fluoroquinolone is not plasma
transferrable. At least at this stage of the game.

So, the chances of transferring resistance to a human pathogen are slim
and none. So, what we would propose then, if I were in the drug
companies\' shoes, what I would propose to CVM is that we are looking at
this as a sentinel organism, recognizing that it is not a human
pathogen, but also recognizing that it is most likely of all of the
enteric organisms from this animal species to change in susceptibility
profile.

And having CVM then recognize that maybe that is a good sentinel
organism to use. I don\'t know where it goes from there. I am too new on
the scene to make any further judgments then that.

DR. RIDDEL: Well, from what I understand what Dr. Ewert was saying,
susceptibility for this \"sentinel organism\" could climb sky high and
the pathogens with which we have to concern ourselves with being totally
not linked to that.

So, yeah, we know we have a pathogen that can develop resistance very
readily, but where does that factor in to decisions by the company,
decisions by the agency, or the overall approval process?

DR. WALKER: Yeah, I think that is another very good point and we may
have to look at that. If this is a sentinel organism, but it is totally
unrealistic, and we go back to staphorius. We know with staphorius it is
a problem with penicillin. Strep-piogenes is not a problem with
penicillin.

So if staphorius were the sentinel organism for penicillin resistance,
it was a poor indicator of strep-piogenes and maybe that is a very good
point.

But I think this is an indicator organism that we could at least watch
and monitor and if it has no relevance down the road then within the
discovery period or the development period, maybe that data will come
out that we are not seeing any change in the susceptibilities of
salmonella.

If we go back and look at the salmonella that they are getting in the
NARMS study. What is the MIC 50 or the MIC 90 in the salmonella that
they collected last year? Did it change any from the year before? Or how
close is it to say for ciprofloxusin? How close is it to the susceptible
breakpoint?

We don\'t have the answers to those. But we do for the proteus and we
know that it is moved. And so that is all I am saying that it may just
be an organism that we can look at mechanisms of resistance, we can look
at changes in susceptibility due to exposure to the drug.

It is an organism that most animals would carry if this were the
sentinel organism so it would be readily detectable in the fecal samples
from most animal species, or at least the target animal species.

So, do you see what I am saying? It is just an indicator organism.

DR. RIDDEL: Yes. And then I think I guess the last question, and I
can\'t remember who made the comment, but everybody always uses the
phrase perception is reality. And what if 60 minutes gets a hold of this
information about this sentinel organism that is going through the roof.

To me, having been involved in some lawsuits, the scariest phrase I ever
hear is \"I will be judged by a jury of my peers.\" There are people out
there I don\'t want judging me because they are not smart enough to
integrate the facts. And this is a very complex situation.

And that is something. I know you can\'t be scared of the press, but
that is important \--

DR. WALKER: But the other part of this was, is once you have identified
this you have a monitoring system that allows you to detect minor
changes in MICs. And this is a very stat system.

If your dilution scheme is appropriate and you can detect these minor
changes in MICs, you can determine when you are losing it with this
organism long before \-- unless it is like an aminoglycoside which is a
day and night thing like Dave White talked about.

But you could get an indication that you need to initiate mitigating
factors because this organism is changing in its susceptibilities and if
you continue down this path it may become resistant.

But then you go back to the press and you say well, this is a
non-pathogen and is incapable, again for the fluoroquinolones, incapable
of transferring resistant genes to human, so it is not really of
concern.

Granted, there is always going to be some people that are concerned, but
from my perspective I think we would get a lot further in pre-approval
studies looking at that type of situation than the tremendous
variabilities there are in E. coli or other organisms that may colonize
in the intestinal tract.

Just like it was brought up today, do we do E. coli and if so which one?
And what is the MIC? Or do we look at anaerobes? You know, that is just
a plethora of organisms and I am not sure that any drug company could
ever afford to get involved in.

DR. RIDDEL: I appreciate the comments and I don\'t want to live my life
scared of the press, all I remember is in 1989 the Wall Street Journal
had headlines about finding 64 percent of samples of milk on the grocery
store shelves having levels of sulfamethazine in them as defined by the
Charm II test.

Now, that was a headline, one-inch letters. If it ever showed up in the
classified that those parts were three to ten parts per billion, when at
that time CVM considered 50 parts per billion a level of safety. And so,
the perception and the ill-effect on our industry\'s consumer was there,
the reparations were never made known.

DR. WALKER: That is why you use them as an indicator organisms and you
look at changes in the degrees of susceptibility, you don\'t look at
resistance, long before resistance occurs.

DR. SHRYOCK: I guess I will have to disagree with you on this one, Bob.
To choose a bug like a proteus or something to me is adding more
complexity than we have already got which is considerable.

To me the relevant public health organisms, we have already discussed
salmonella, campylobacter, enterococci. E. coli is of questionable value
to me. If we were going to invest a lot of resources in other organisms,
that requires a whole other mindset in order to do that.

And then try to make that relevant to perhaps a zoonotic pathogen which
is there is already some question as to what that is relevant to.

So, we are only getting ourselves deeper and deeper into a quagmire by
going off on sentinel organisms that are, from my perspective, not very
valuable to look at. We can do these decrease susceptibility shifts with
salmonella, with campylobacter for certain drugs.

Others, as David White indicated, once you get a resistance gene or
plasmid in there, you go from zero to 60 right away. It is an all or
none type phenomenon. You don\'t get this MIC shift. That is only with
certain classes of antimicrobics.

So, from my perspective I would just rather go with something that we
have already got a handle on. There is some data in the literature and
see where we can go with that.

DR. PETRICK: Just very quickly. To go on with what Dr. Walker was
saying, if indeed you can detect subtle shifts in monitoring
post-approval by doing your dilutions correctly. Then I would propose to
the group that don\'t worry about it pre-approval, that the time to do
it is post-approval when you can monitor something carefully.

When you\'ll increase your field to test from and you can, it sounds to
me from what Dr. Walker was saying, you would be able to catch it at an
early enough stage if you have enough power built-in and enough
resources built-in to the post-approval studies.

So, I think that is something to keep in mind as well.

DR. SINGER: Randy Singer. I guess at the risk of shooting my just
budding research program right here and now, the idea of cultivating a
sentinel organism for monitoring may be moot because there are
techniques that people are working on, for instance for genes that can
be transferred.

Or if you can identify very specific primer sets you can do direct PCR
directly into \-- take your fecal sample and you are looking for genes
in that fecal sample and you are not worried about cultivation any more.
You are just looking for whether or not that gene exists.

You don\'t care about what bug its in any more, you just want to know
whether or not a resistance mechanism is present. So you begin to be
able to monitor many more animals over many more time periods over much
broader spatial scales without the worry of picking your target bug.

Now of course you get back to well, what is the risk? But if you are
thinking away from fluoroquinolones and are just worried about gene
transfer, it again, and what I hope to be doing is looking at it as an
indicator of risk. So, the idea of picking a single bug as an indicator
may be hopefully moot in the future.

DR. RIDDEL: Randy, would use of that information, if that testing
methodology becomes available where you could look at a fecal sample
from the target animal species and say with confidence, yes or no, there
are or are not genes with resistance in here anywhere, would that be
something that you think should be implemented by the pharmaceuticals as
the develop the product? Or would that be something that should be in a
\-- and therefore be in their pre-approval strategy? Or should it be in
the regulatory process?

I guess, I am assuming, again operating from a high level of ignorance,
that when we talk about these pre-approval studies we are talking about
something that is going to become a regulatory document that you are
going to have to deal with, right?

DR. SINGER: Right. The only way you can do an assay like this is if you
know precisely the sequence of the gene you are targeting and that it is
a specific primer set. So it is not cross-reacting with other resistance
mechanisms, genetic mechanisms.

I don\'t see its place in pre-approval studies because you won\'t yet
know which genes are possibly conferring resistance. Unless you are
using closely related antibiotic genetic mechanisms as indicators of
what you might expect, once this product is used.

This I see as more of a post-approval monitoring system. I mean, and it
is not going to be \-- well, I can\'t foresee where molecular techniques
are going to head, but it is not going to be something that is so easily
implemented. Because again, you are going to have to be very certain
that what you are probing is again very specific for the, you know, this
specific gene for a specific antibiotic.

Because you won\'t have the organism to then go back later and look for
an MIC. All you have got is DNA and you don\'t know from which organism
it came. So, it is more post-approval unless you want to use related
antibiotics pre-approval as a screening.

CO-CHAIRPERSON HESLIN: Just a quick time check. According to the clock
on the podium here it is 5:25. According to that it is 5:12. Either way
we are down to our last five or ten minutes or so.

MR. SCHMID: Peter Schmid, Intervet. I think the gene assay is not very
sensible and not very meaningful. The presence of a gene itself doesn\'t
tell you anything. It is a question of expression of the genes and what
happens to the genes under the selective pressure of an antibiotic?

MR. LADELY: Could you repeat? I didn\'t catch the first time of that
question.

DR. RIDDEL: Would you repeat that please?

MR. SCHMID: I think the presence of a gene itself doesn\'t tell you
anything. It is a question of the expression of the gene. And the second
question is what happens to the gene under the presence of an antibiotic
which puts selective pressure on it?

DR. RHODES: I actually think what you are proposing is really probably
going to be the way of the future. I agree that just having the DNA
doesn\'t mean that the protein is expressed, it doesn\'t mean it is
doing anything in the cell.

But, there are now some really eloquent studies that are being done to
look at the cassettes of vancomycin resistance for example. And to
really very carefully characterize the genetic drift involved.

I think if you go for DNA versus MICs, what you have done is you have
made an end run around that whole list of questions that Paula put up
about how big your sample is and what your culture conditions are and
how often you sample and from what tissue you sample?

You really are getting right to the heart of the question, is the
pressure, the selective pressure of your treatment in a larger
population creating a larger number of resistant organisms at the DNA
level?

And really that is the basic question. Because the fear is that the DNA
is then going to transfer into a zoonotic pathogen at a higher rate
which is then going to lead to a higher incidence of disease.

But, I think we are probably about 10 years away from being able to
really have the resistance genes fully characterized. Their variation,
in an epidemiological sense in the population fully characterized, and
the PCR methodology reproducibly available to be used in a field
situation.

So, I think it is really going to be a good direction to go in for the
future, but it is probably at least a decade away from being some type
of test off of which we could regulate.

DR. RIDDEL: Well, I think we have come to a \-- if there is a good place
to split and maybe allow me to get introduction role a little bit better
and have a strategy with my professional facilitator over here.

I would like to ask you all to come back tomorrow morning and maybe we
will have a set of comments that may at least be the framework for what
we will talk about in our workshop review that you can supplement or
delete.

Something a little bit more that we can work from. And it may not be
just a set of answers to the questions. But these are comments we would
like to make from a ruminant perspective as far as pre-approval studies.

Okay? I appreciate it.

(Breakout Discussion Concluded at 5:20 p.m. to Reconvene at 8:30 a.m. on
Thursday, February 24, 2000)