**ANTIMICROBIAL RESISTANCE**

**PUBLIC MEETING**

**PRE-APPROVAL STUDIES AND PATHOGEN LOAD**

**BREAKOUT GROUP DISCUSSION - MONOGASTRICS**

**THURSDAY, FEBRUARY 24, 2000**

**8:30 A.M.**

**DOUBLETREE INN**

**1750 Rockville Pike**

**Rockville, Maryland**

**Gazebo**

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

**BREAKOUT GROUP DISCUSSION - MONOGASTRICS**

**February 24, 2000**

[PAGE]{.underline}:

**DISCUSSION/QUESTION/ANSWER** 3

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

**BREAKOUT GROUP DISCUSSION - MONOGASTRICS**

(2:00 p.m.)

**DISCUSSION/QUESTION/ANSWER**

CHAIRMAN MORRISON: Can we come back to this because I think this might
\-- you might want to have this discussion on tape, I\'m guessing. And
if we can come back to these points in just a moment. Okay. Is that all
right?

MR. SCHUSTER: I just wanted to comment \--

CHAIRMAN MORRISON: Well, let\'s hold off because I think it\'s valuable
discussion. So we\'re going to come \--

(Pause.)

CHAIRMAN MORRISON: Yes; we\'re taping now?

REPORTER: Yes, we\'re on.

CHAIRMAN MORRISON: Okay.

MR. SCHUSTER: Let me interrupt and give you some background because we
came up with these yesterday.

MR. ANDRES: Sure.

MR. SCHUSTER: Dale Schuster, Schering-Plough. I just want to comment on
Paula. When we came up with these yesterday, a lot of us, our feelings
were that there really weren\'t many pre-approval studies, perhaps none
that you can envision, that really were relevant.

And so, what we came up with was things that would be nice \-- baseline
information, background information, might support post-approval
studies, would not be too difficult to conduct and that interpretation
would be rather straightforward because they were rather standard things
to do.

For instance, the mutation rates of resistance in vitro, it\'s very
common to do that. It\'s standard procedures, maybe not an accepted,
validated method, but it wouldn\'t be that hard to get from there. So
these were some of the things that could be done that might be of some
use.

I think that \-- I personally fully agree with you that many of these
things, and perhaps all of them, have questionable relevance but our
view was that these could be done and it\'s not uncommon to do them and
maybe not that out of line to expect sponsors to try to generate that
sort of data as a background package going into a new chemical entity
type of thing.

DR. FEDORKA-CRAY: I think \--

CHAIRMAN MORRISON: Okay, Paula; could you use the microphone because \--

DR. FEDORKA-CRAY: Well, I mean, I think that \-- my point was is that I
think that as you\'re putting something forward that you would want to
\-- that you would want to just make clear that this could or this \--
this would or this would not be part of an approval package and it\'s
not \--

I mean, is it going to answer the question if there\'s a risk to human
health if you\'re not going to define, you know, in your objectives what
bugs you\'re looking at, because you could end up with a whole list of,
you know, aerobic and anaerobic commensals and other types of pathogens
and whatnot. And so, you know, to me, one of the questions that should
be posed would be exactly what are we doing here as far as looking at
\-- you know, what bacteria are you even willing to propose relative to
the drug because the drug is being proposed for a target pathogen and
that the drug may not have any relevance for some of these other
mechanistic type features.

And so, you know, I think that you just want to \-- you know, you want
to lay it out so that it\'s \-- they\'re achievable and that the
expectation is, is that you\'re not going to be reinventing the wheel,
you know.

Many of these tests \-- in fact, like I said, I think you already know
the mechanism of resistance when you\'re looking at the class of drugs,
but you may not have much of an idea of some of the effects that are
going to happen with other bugs or how that would even interact with
some other antimicrobials over time.

CHAIRMAN MORRISON: Paula, that\'s actually going to be a question that
we\'re going to be getting to in probably about an hour \-- what
pathogens and should we consider other organisms?

DR. FEDORKA-CRAY: So, I don\'t \-- I just don\'t see these as an
objective toward answering the questions, toward answering the \-- you
know, these are study considerations but not necessarily an objective of
the package.

CHAIRMAN MORRISON: Okay. So if I understand, your point would be that
perhaps points one, two and three are studies or types of studies that
would support the objective of characterizing the rate and development
of resistance. Not really objectives by themselves, but studies that
would support that objective. Perhaps point five is more of an
objective.

DR. FEDORKA-CRAY: I would say point five would be the objective.

CHAIRMAN MORRISON: Scott.

DR. McEWEN: Scott McEwen. But we heard from

CVM yesterday that they were going to do that before the

pre-approval studies, weren\'t they?

DR. FEDORKA-CRAY: Right.

DR. McEWEN: And we made the point that some of this information might be
used to, in a sense, validate that initial categorization or invite the
opportunity for reconsideration or something?

DR. FEDORKA-CRAY: I would change \-- I agree with Scott; I would change
the wording on categorizing. You\'re going to know the categorization
before, I think, you even submit the drug for approval.

CHAIRMAN MORRISON: Well, as long as we\'re \-- this was presented as a
slate of five. Now, as long as we\'re sort of modifying that, we
actually could delete the fifth one because we\'ve got our input earlier
where we said we hoped this information will influence or be able to
influence the categorization. Is that \--

DR. FEDORKA-CRAY: Don\'t you think that you\'re going to have \--
really, pre-approval studies \--

CHAIRMAN MORRISON: Oh, I\'m sorry. You should use the microphone again.

MR. ANDRES: Just bring the chair up here, Paula.

(Laughter.)

MR. ANDRES: You have to use the microphone, otherwise you don\'t get
recorded \--

DR. FEDORKA-CRAY: Paula Cray. I think that \-- I mean, I think the
categorization issue is even up \-- that it\'s not fully determined yet,
and so, how would that be an objective of a pre-approval study if that
already has to be sort of a priori information?

CHAIRMAN MORRISON: The thought was that \--

DR. FEDORKA-CRAY: And that, yes, I think that if you\'re going to design
a pre-approval study, you\'re going to look at probably just doing it
for a category one type drug because category two type drugs probably
aren\'t going to require anything. Category threes aren\'t going to
require anything, and if there in fact are categories such as one, two
and three.

So I\'m not \-- I mean, I don\'t know \-- designed to modulate how a
compound is ultimately categorized, you have to know that information
prior to going into the pre-approval study. So if you\'re setting up the
study, you just want to set up and say, okay, this is how we\'re going
to do it.

CHAIRMAN MORRISON: The thought was that let\'s say you have a compound
that comes in and it\'s going to be used in category three and then they
find out, holy smokes, while it\'s a great compound, it\'s really got
some implications for humans that we didn\'t expect; perhaps we should
put it into two or one at the end of the pre-approval studies or
opposite, comes in in one and you find out it\'s got zero risk for
people, even \-- and you know, so you might reevaluate the final use or
category.

DR. FEDORKA-CRAY: Well then, that brings up a question that I would say
is, do you need pre-approval studies at all? And that was discussed in
some of the other sections yesterday. I mean, do we really need a
pre-approval study at all because ultimately, drugs may be moved,
re-categorized at any period in time.

And so, if you\'re going outside of the box, then are you going to focus
most of your efforts on a post-approval type monitoring system where you
\-- you know, you\'re looking at the rate of resistance developing along
those lines.

I mean, that would be a question I would ask \-- what kind of support is
there for looking at these types of studies at all, you know, designed
as they are. And that\'s not to say that the companies don\'t come
forward and say, this is what we\'ve done, you know, much along the same
lines that they\'ve been doing now. But, jumping through other types of
studies, is it going to ultimately get you where you want to go?

CHAIRMAN MORRISON: So perhaps, Chuck, we could add a point in the
general area that if post-approval studies are going to be intensive and
vigilant, etcetera, there\'s a question of the value of pre-approval
studies. Is that your point?

DR. FEDORKA-CRAY: Yes.

CHAIRMAN MORRISON: Okay. And I want to clarify this one \-- if, in the
general considerations, if post-approval studies are going to be
in-depth and robust, etcetera, there\'s a question of the value of
pre-approval studies. Okay.

If there\'s going to be pre-approval studies, would you support or do
you think the idea of using the information that you generate in
pre-approval studies to influence the final categorization of drugs is a
valid point. Is that \-- not that you say or nay. Some people did.
That\'s the understanding on that point. That\'s the point of it.

DR. FEDORKA-CRAY: Again, I would say that that\'s more of a
consideration or a general point rather than objective. You won\'t know
that until the end of what you\'re doing anyhow. I mean, your objectives
are how do you assess the rate and extent \-- I mean, the impact on
human health, and that sort of falls out last.

CHAIRMAN MORRISON: Okay. Is there feeling from whoever that was \--

DR. BROWN: Right here.

CHAIRMAN MORRISON: Was it Scott or Robin?

MR. ANDRES: I think it was Scott.

CHAIRMAN MORRISON: Scott. Do you have a feeling on that, Scott?

DR. BROWN: Scott Brown, Pharmacia & Upjohn. Just for context, I think
what we were talking about yesterday was that the class and the proposed
usage of a compound would generally cause it to be put into a particular
category at the very beginning of the drug development process.

DR. FEDORKA-CRAY: That\'s right. So you don\'t need a categorization.

DR. BROWN: It\'s already done provisionally. Let\'s put it that way.
Then the data we\'re talking about would be used to \-- in this case,
what I\'ve used \-- I\'ve used the word modulate that categorization,
either upwards or downwards, depending upon whether the compound is
acting in expected manner for other compounds in that class or whether
that usage is now being shown through whatever data to be posing an
extraordinarily higher exposure to human zoonotic organisms and so forth
or less, and that ultimately there\'s going to be a transition from a
provisional categorization to a \"final\" categorization.

I use that word in quotes because you\'re right, Paula, it\'s going to
change over time depending upon the human drug usage and depending upon
the data that\'s captured post-approval.

But in essence, a final categorization that then drives perhaps the
threshold for the post-approval monitoring. Perhaps it drives the degree
of vigilance in the post-approval monitoring, and perhaps drives the
ways the compound might be used in the field.

That was the idea of this battery of tests and that throughout the
process, the sponsor would be able to discuss and reach concurrence with
the Agency about what decisions will be made from these kind of studies,
that we\'d have a clear decision criteria before we would embark on
these studies to know exactly what it is that the Agency is going to
decide based upon the outcomes. So that was \-- that\'s the context that
we had for yesterday.

Again, when we got the notion from the Agency that these studies are
pivotal, then the question was, well, if they\'re pivotal, that means
that the Agency is using them to make decisions, arguably, during the
FOI, and then you say, how do you write the FOI?

But, if they\'re being used for decision making, then the sponsor wants
to know how those decisions are being made, a priori, and that\'s I
think, the point where we\'d like to make sure that that\'s done, not of
the end game, because then all the money is sunk, but rather up front
where you know how you can adjust the battleship prior to its reaching
its port.

MR. ANDRES: Chuck Andres, CVM. And Scott, I think we put that under the
general comments point number three, standards for acceptance of
pre-approval studies would be set a priori?

DR. BROWN: Yes.

DR. BROWN: One more comment, and that is that

the comments that were made in a couple of the other groups that, well,
pre-approval studies really aren\'t necessary, and I think that was what
came out of the other \-- two of the other groups.

I guess we sort of didn\'t even consider, when we found out that these
studies were going to be pivotal, and so we didn\'t \-- I don\'t know
that we even considered whether they could be cast off as being
unnecessary.

We made the assumption \-- at least I made the assumption, personally,
that since the Agency said yes, they\'re pivotal, that they were going
to be required in some fashion or other and we\'re going to try to
figure out what to do to take care of that box checking.

(Pause.)

CHAIRMAN MORRISON: I\'ve just suggested to Chuck, on those three
\"objectives\" that we just sub those in under that major objective that
we have of characterizing the rate and extent of development, of
resistance development. Studies that might support this or studies that
might \-- could include one, two, three.

(Long pause.)

CHAIRMAN MORRISON: So we have three objectives now that we\'ve \--

MR. SCHUSTER: Dale Schuster, Schering-Plough. I mean, we\'re proposing
these as studies that could be included but I think there\'s very much
an awareness that these aren\'t really going to do a very good job of
characterizing the rate and extent of resistance development that you\'d
predict in the field.

I\'m not sure if we want to leave it exactly like this or mention that
that\'s a clear caveat of what studies we\'re proposing there.

DR. BYWATER: Robin Bywater, Pfizer. I think the problem with all this is
that we\'re going to be presented if, if we\'re not careful, with the
Agency setting criteria for acceptance or rejection of one of these
studies.

Calling it pivotal and hanging the compound on the basis of the fact
that you can transfer resistance and that resistance does develop \-- I
mean, the expectation is that these will be positive findings in a
sense.

It\'s a question of how you interpret them; and therefore, I think the
concern is very much that the pivotal nature of these studies implies
setting criteria. In fact, Scott said we need criteria; in one sense we
do.

But the awful danger is that those criteria will be so easily
incorporated into a negative decision that it\'ll come back to haunt us,
and maybe the complications of doing these programs in full, which is
what Paula was referring to \-- I mean, you can do these in a relatively
simplistic way and the way that I think we would normally expect to do,
at least something of these.

But if you want to do it fully and exhaustively, you\'re into a huge
amount of work, even in an in vitro context, and lots and lots more
questions.

CHAIRMAN MORRISON: So, are you questioning, Robin, the value of putting
these at all or cushioning the language

or \--

DR. BYWATER: I just think we should make it clear that this is
informational and we shouldn\'t be setting unreasonable criteria for
passing and failing at these stages. It ought to be part of the overall
evaluation which is the way we referred to it before we were given this
dreadful word pivotal to hang onto them.

And as part of the overall evaluation, it would help in the
categorization. It would help in the design of the post-approval
monitoring, which I think we all agree is the key.

CHAIRMAN MORRISON: Mike.

MR. ANDRES: If I could maybe allay a little bit of fears and
uncomfortableness, if we think of \-- I\'ve been trying to think of a
good analogy and I\'ll probably get kicked for this one but drug
residues \-- okay. The fact that a drug produces \"residue\" doesn\'t
render it unapprovable. Okay.

And risk assessments are made based on the residue present, amount, the
toxicology of the amount and its effect it could have on humans. And I
think as we go down this road on the resistance issues, the same type of
thought process will probably be used.

The fact that you show resistance may not be a trigger to say it\'s
unapprovable. It may lead us to, okay, what next question needs to be
answered before it satisfies our need to protect the public health?

So, I don\'t think it\'s, you know, okay, this box is checked, or it\'s
a defined decision tree. If the answer is yes, go home, take your drug
and go home. I don\'t think it\'s

\-- I know it\'s not that. So as we finalize writing any guidance
associated with this, certainly that will be taken into consideration.

DR. REDMAN: Sharon Redman, Novartis Animal Health. Just to Robin\'s
point, then, maybe \-- on that first objective with the studies, that
one of his points should be that \-- as far as, you know, studies could
include or you could have evaluations of studies would be a part of the
overall risk assessment, not pass/fail. Just to make sure that those
concerns are addressed when you deliver this message.

CHAIRMAN MORRISON: Okay.

DR. REDMAN: In other words, you have studies \-- could include \-- you
could have another thing that says evaluation of studies would be \--
or, you know, some \-- you know, it would be considered in the risk
assessment, and thus would not be pass/fail, because that is a major
concern.

You know, how can we set a pass/fail when we don\'t know, really, what
pass/fail is? We don\'t know the relevance. We don\'t know how these
will play out in predictability, so how can we have pass/fail at this
point? So, we need to continue to expand our database. We need to get to
that point where you could even do a mathematical model. We\'re not
there yet.

CHAIRMAN MORRISON: Okay.

DR. REDMAN: Really, that wasn\'t why I walked up here, though.

(Laughter.)

DR. REDMAN: So basically, on the point about the classifications, on the
next slide \-- yeah. Just maybe to, once again in our communications,
Scott, as far as design to modulate how a compound is ultimately
categorized, maybe we should use the word optimize because that way we
link that into \-- what we\'re trying to talk about is dose use rate,
those types of things.

In other words, we\'re not trying to squeeze it into one category or
another. What we\'re trying to do is scientifically say, okay, if I do
this, if I change the usage, if I change the dosage, whatever, I will
make a real difference on the human health hazard, just like we were
talking about optimization, the dose and that type of thing. So that was
just my suggestion, to change modulate to optimize. That\'s it.

CHAIRMAN MORRISON: Either to change modulate to optimize or design,
modulate how a compound is ultimately and optimally categorized?
Whichever?

DR. REDMAN: The less work the better.

DR. McEWEN: Scott McEwen. Just as a follow up to the analogy of the
residues, I mean, it could get to the point where it\'s almost lethal
for a drug, I guess. If we had, say, in the analogy of the residues,
it\'s a carcinogen. My sense is, if it is, that almost rules it out as a
food animal drug. Right? And in this situation, there might be something
that is of that sort of degree of severity.

MR. ANDRES: Can you speak up so we can \--

CHAIRMAN MORRISON: So that, just to kind of round out the analogy, I
guess, that yes, we do sort of weigh in the toxicity of the residues and
that gets factored into the MRLs and that sort of thing, but there is a
threshold which one reaches in that analogy where it kind of makes it
untenable for use in food animals and it\'s possible that that sort of
thing would exist in the resistance area as well, but I agree that the
industry would want to know that, up front, so that they can sort of
weigh that in.

CHAIRMAN MORRISON: Just a second, Paula. So did we \-- we didn\'t change
that word. Oh, you got \-- is ultimate

\-- oh no, you didn\'t. Okay. So is there \-- Paula.

DR. FEDORKA-CRAY: That would be my motion, to change modulate to
optimize.

CHAIRMAN MORRISON: Well again, we\'re not seeking consensus but if
there\'s general feeling that that\'s good, that would be great. Okay.
Chuck is saying that optimize is a strong objective and as long as
you\'re aware of that. Okay.

MR. SCHUSTER: Dale Schuster, Schering-Plough. I\'m not sure I\'m
comfortable with that change. I\'d prefer \-- what I heard being said
was that it would optimize the dose or the dosing regime or how the drug
is used.

That\'s a very different objective than affecting the category. I like
modulate the categorization and I think that should stand. But I also
like the optimize the dosing regime and I would add that as an
additional objective.

MR. ANDRES: Okay. So you\'re suggesting \--

MR. SCHUSTER: You made the point. Is that \-- are you comfortable with
that? That\'s what I understood you to say.

DR. REDMAN: Yeah; that was definitely the context of what I was saying.
It also goes back to Chuck\'s point, though, that that is a big
objective for us to have, so we\'ve already said that we\'re not sure
how we can optimize efficacy in the antimicrobial resistant safety
factors and everything all in the same one.

MR. FONDRIEST: Steven Fondriest, Union of Concerned Scientists. Just for
clarification, that was one of Fred\'s points. I\'m not sure \-- did we
take that out?

MR. ANDRES: Which?

CHAIRMAN MORRISON: I think we\'ve still got it bolded, questioning \--

MR. FONDRIEST: The optimizing \--

CHAIRMAN MORRISON: \-- whether we could do it.

MR. FONDRIEST: Is that the same \--

MR. ANDRES: This was a study, not an objective.

MR. FONDRIEST: Oh, okay.

MR. ANDRES: Chuck Andres, CVM. I guess when I heard the optimize, I
thought of this bullet and I\'m thinking, wait a minute, yesterday we
just heard that if we\'re going to be asked to \-- and I just want
clarification. I\'ll type whatever the group would want. I\'m just a
scribe.

But to me there\'s a disconnect between what we just typed and what\'s
up here in point four, which we discussed for a little bit yesterday.
And if it were up to me, optimizing \-- maximizing the effectiveness of
the drug while trying to minimize the resistance, we just said,
yesterday, may not be technologically possible. And you know, so
whatever you would like, we can modulate that answer.

(Laughter.)

MR. ANDRES: Scott.

DR. BROWN: I really don\'t want us to get bogged down in some of these
semantics because I think the idea is to get the concepts out.
Optimizing dose or regimes, to me has always been a bit of a tenuous
situation because I don\'t think there\'s one size that fits all. We
mentioned that earlier for a variety of things.

What I think you could do is to optimize the dosage regime with respect
to one or the other, either optimize it with respect to efficacy or
perhaps optimize it with respect to resistance development in the target
organisms.

I still don\'t think we have the wherewithal to optimize the dosage
regime with respect to the resistance development in zoonotics. That\'s
the part where I think we\'re most languishing and where I don\'t know
where the technology will lead us.

So, there are some subtle differences in the way those two things are
worded, and I understand the desire \-- we\'re actually trying to use
what we\'ve learned through these studies to better direct the usage of
the product. Maybe that\'s a better way to do it.

So maybe instead of optimizing dosage regime, just say, better direct
the usage of the product. Is that \-- would that work, Sharon? Would
that work, Dale? Better direct usage of the product.

CHAIRMAN MORRISON: Characterizing the rate of development and resistance
and some suggested studies that might address that. Then we\'ve got the
objective of the

post-approval process, the objective of modulating how a compound is
ultimately categorized and the objective of developing information that
will best direct the usage of the product. Anything else? What\'s next,
Chuck?

MR. ANDRES: This I think we have already, elsewhere.

CHAIRMAN MORRISON: Yes. Let\'s delete the last one. Why don\'t we just
stick that back in the general area? That\'s where things go. Okay.
Those are our objectives and our discussions of our objectives.

Then we went onto what data, what role could the various types of data
play, and this is where we talked a little bit about mathematical
modeling, in vitro studies, in vivo experiments. We didn\'t really get
into field studies, and we talked about the advantages and limitations
of those various kinds of data. Okay.

MR. ANDRES: Do some quick housecleaning.

CHAIRMAN MORRISON: While Chuck\'s doing that, maybe you just want to
refer to your overheads because we\'re on

the \--

MR. ANDRES: Ready.

CHAIRMAN MORRISON: Okay. One (a) is the next one, Chuck.

MR. ANDRES: Okay.

CHAIRMAN MORRISON: We said, all right, while we recognize that the
existing method, 558.15, is not adequate \-- we said that was \--

DR. McEWEN: Scott McEwen, University of Guelph. I think the first two
are more comments than what are the positive aspects of these concepts,
or possibly the first one could be, what are the limitations of the
concepts. Like that first one might be stated as a limitation of the
558.15.

CHAIRMAN MORRISON: Okay. Why don\'t we move that \--

DR. McEWEN: The second one, I think, is more of a comment.

CHAIRMAN MORRISON: Yes, that\'s definitely \-- and we\'ve got some view
that pathogen load studies should be considered, based \-- and remember,
we\'re saying, out of all that stuff that was presented yesterday and
the day before, what were the positive things we learned and then what
were the limitations that we learned, and there was a view that pathogen
load studies should be considered, and about three points later, there
was a view that pathogen load studies should be eliminated.

So we\'re passing these comments on again. We learned that mathematical
models enable us to test hypothetical scenarios; interventions could fit
into a risk assessment. In vitro studies can screen a larger number or a
large number of issues and greater controls.

Mathematical models, expertise available is limited. I think now we\'re
into limitations. A real concern of the predictability of these
pre-approval studies and how they might predict or not predict, what
actually might occur in the field.

DR. McEWEN: Scott McEwen, University of Guelph. Should we qualify the
limited predictability? Does that apply to all pre-approval studies or
just one study type because I think we\'re talking here about the
various concepts.

And while I\'m here, I\'d ask, with respect to the mathematical
modeling, to me, when I was up here talking yesterday and giving those
examples, I was thinking of population models, either deterministic of
the \-\-- type. We also have mathematical modeling for pharmacokinetics
and dynamics, I guess, that it might \-- and whether or not those
qualifiers relate to other types of modeling, that it could be at
different levels of organization, not population level. Maybe somebody
else wants to speak to you, but I was speaking here of the population
type modeling.

MR. ANDRES: Chuck Andres, CVM. Just so people from a editorial
standpoint, when Bob and I sit down to put all this together so that he
can present it this afternoon, if specific examples were given about
study types, I\'ll go ahead and put them in bold and that is, as I said
before, is the advantage or a limitation, positive or a limitation for
that particular individual study type.

If there\'s nothing bolded, it was essentially a generalized comment
about all of the studies. So when we talk about what\'s a limitation,
point number three under one (b), limited predictability of what
actually occurs in the field, I think the comment yesterday was, that
could be related to all of these studies because we \-- you know, still,
you\'re predicting. Until it\'s thrown out in the field, you\'re really
not going to know.

DR. McEWEN: Scott McEwen. As long as everybody remembers that, because
the way it\'s laid out here, that kind of could be interpreted to mean
\-- limited predictability could apply to mathematical models because
that\'s kind of bolded up top when it fact it \-- you know, as it\'s
written there, and what you just said, it applies to all of the study
types.

MR. ANDRES: Well, what we can do is, instead of getting bogged down in
kind of ordering, when we sit down to put all this together, we can
group all of those that are specifically study oriented comments and
those that are general comments about across all studies. Is that
satisfactory?

CHAIRMAN MORRISON: And when we do that, Scott, your point is
mathematical models for simulating populations. That\'s what you were
commenting about.

DR. McEWEN: I was. But I was just a little worried that we point out the
deficiencies of modeling, which we always do, but we tend not to point
out the comparable deficiencies in the other study types.

Like, when I said that it requires assumptions, well, we make the same
or even larger assumptions about experiments and in vitro studies, but
we usually don\'t state them explicitly so they don\'t get the same
attention.

And so, historically, there\'s been a lot of condemnation of modeling
for that reason, when you could make the same, in effect, condemnation
of other study types. So it\'s just the question of balance that we lay
out the advantages and disadvantages of all the study types and not sort
of pick on one.

CHAIRMAN MORRISON: Well, I most certainly heard point three as referring
to all these pre-approval \-- in vitro, mathematical models, a real
concern about the predictability. Point four, that these studies be as
robust as necessary to address the objectives.

(Pause.)

MR. SCHUSTER: Dale Schuster, Schering-Plough. I\'m not sure if we\'re
capturing it here or elsewhere, but one comment that I think merits
mentioning is that there\'s a need for validation of any pre-approval
studies.

If there were validated studies, robust studies, that existed, it might
make sense to apply them. It\'s a deficiency in technology, not a
deficiency in need for the studies, I see, and we can make that here or
elsewhere.

I had maybe just a clarification on what I feel about the pathogen load
studies. I guess my view is it\'s a bit going too far to say that they
should be eliminated for the current requirements. I\'m much more
comfortable in saying that for therapeutic drugs like we\'re talking
about primarily here.

It doesn\'t make sense to add a requirement. So my view, it\'s not
expanding pathogen load studies onto therapeutic drugs. I\'m not ready
to say whether it does or doesn\'t make sense to eliminate them for feed
additive studies.

MR. ANDRES: I guess when that point came up yesterday, there was a
feeling that \-- on the positive side that they should be considered,
which is what I\'m hearing you say now, for certain types of compounds,
certain types of uses. And a limitation we put down, some people voiced
the opinion they should be tossed; they shouldn\'t be considered at all.
And all I\'m trying to do is capture \-- again, we\'re not trying to
achieve consensus or agreement, other than people who have said what
they said. They feel like their voice is being captured here and we\'re
not, you know, skewing the presentation. So, those that felt that \--

MR. SCHUSTER: I guess \--

MR. ANDRES: Those that felt \--

MR. SCHUSTER: I can add \--

MR. ANDRES: \-- pathogen load studies should be eliminated, and I can\'t
remember who brought that point up yesterday. If that\'s something that,
you know, what you\'ve heard today changes your mind, hey, I\'m the
scribe.

MR. SCHUSTER: I would just like to clarify in my mind when we were
talking about it, and I don\'t know if it\'s true of anybody else, the
issue is, should it be eliminated from the Framework document which
requires it for all antimicrobials.

And I definitely agree with that. I\'m not sure that I would want to go
so far as to say it should be removed from 558.15 studies which are
applied solely to growth promotion products. Anybody else, I would be
interested in \--

CHAIRMAN MORRISON: You would suggest we add pathogen load studies should
be eliminated for therapeutic applications?

MR. SCHUSTER: Should be not \-- not applied to therapeutic
antimicrobials \-- or therapeutic applications uses of antimicrobials.

CHAIRMAN MORRISON: Okay.

DR. SILLEY: Peter Silley, Don Whitley Scientific. I just think on the
pathogen load issue, just carry it on from that. One of the reasons why
I believe we\'re saying that they perhaps ought to just be eliminated
completely is because how one interprets the data, the problems, the
variability, what the studies actually mean, those are issues and surely
they apply to whether we\'re looking at a therapeutic or something in
feed.

It\'s not a rationale in terms of the study type. It\'s actually just
the nature of the data we\'re generating means it\'s almost irrelevant,
and therefore I would advocate that they should be removed completely.

CHAIRMAN MORRISON: So, we better not add that to that \-- put it as a
separate point? And it gets back to the suggestion earlier, maybe there
ought to be a whole discussion or a whole breakout or a whole meeting on
this whole pathogen load issue.

DR. BYWATER: Robin Bywater, Pfizer. Maybe we could just say pathogen
load studies are particularly pointless for therapeutic products. You
know, to at least make it quite clear that as far as therapeutic
products are concerned, they really don\'t make any great sense \--
short term, high dosage, you know.

Anything which is going to be long term, there\'s at least a
possibility, but as Peter says, there really isn\'t a decent way of
testing. The existing method is inhumane, inaccurate and probably
misleading.

DR. McEWEN: Scott McEwen. They\'re not limitations as written. Those are
comments. They\'re suggestions. I mean, if you\'re going to say that the
existing pathogen load studies are not predictive or are imprecise or
are invalid, then those are limitations. But as written, those are \--
it\'s not stated as limitations.

MR. ANDRES: Right. And I think, you know, we go back to the study
concepts that were discussed on, I guess now, what \-- we\'re talking
Tuesday. It\'s now Thursday. On Tuesday, what were the positive aspects
of those concepts and what were the limitations of those aspects that we
heard on Tuesday? And that\'s what we\'re trying to capture in answering
question \-- I guess I\'ve got them numbered as 1(a) and 1(b.)

DR. McEWEN: Well, as I said yesterday, I don\'t think that we were
presented information that would allow us to make a judgment about
whether they were effective or not. We were just presented with
information that said that there were some drugs denied approval, on the
basis of those, and some that weren\'t. But, you know, from an objective
sense, there were no data, that I saw, presented that would allow us to
make those judgments.

DR. FEDORKA-CRAY: Paula Cray. I would agree with Scott that there were
not study concepts. There were ideas. There were about 300 questions
that were presented. But there was nothing that was presented that could
be evaluated. And I would also agree on the pathogen load, should be a
separate issue apart from resistance because it\'s not \-- it\'s a
component of resistance but it\'s not resistance, per se.

You know, you\'re not looking at an MIC. You\'re not looking at whether
it\'s sensitive or intermediate. It\'s an effect of antimicrobial use
and that\'s a whole \-- that\'s an entirely separate issue.

CHAIRMAN MORRISON: So perhaps what we\'re hearing is that back in our
general, overall comments section we should have pathogen studies \--
pathogen load studies should be, sub (1) eliminated because some people
feel they should be eliminated. Sub (2) eliminated for therapeutics. Sub
(3) included for all, because we\'ve had all views so far.

DR. FEDORKA-CRAY: That was just making my comment that I think it should
be considered entirely as a separate area, separate from the resistance
issue because it\'s not determining whether the pathogens that you would
be affecting in a lone study are resistant or sensitive or \-- it has to
do with levels and that\'s entirely different than resistance.

CHAIRMAN MORRISON: Okay.

DR. FEDORKA-CRAY: It\'s two separate issues.

CHAIRMAN MORRISON: Okay.

DR. BYWATER: Robin Bywater. I think Paula\'s got a good point there.
Essentially, pathogen load studies are another aspect of the toxicology,
safety program for the drug and it certainly isn\'t a resistance issue,
exactly as she says. And then that is a further reason for eliminating
them altogether, from this consideration.

CHAIRMAN MORRISON: Okay.

DR. McEWEN: Scott McEwen. I think we need to write that comment down as
a suggestion or comment, the notion that they be considered separately
or in another form or something, because I think everybody seems to
agree with that.

CHAIRMAN MORRISON: You know, we\'re doing such a fine job here, you\'re
going to have trouble not just adopting this verbatim. Okay.

(Pause.)

CHAIRMAN MORRISON: All right. So continuing on our limitations; we\'re
almost done this. I believe, Scott, that\'s host/environment. A
limitation is that in these pre-approval studies, that you have limited
ability to evaluate the host/environment factors.

MR. ANDRES: This was on an in vivo study, wasn\'t it?

DR. McEWEN: Yeah, I think I was just yakking about different types of
studies and said that \-- I think it was the in vitro ones, so that \--
I think that comment, as I recall, referred to the in vitro.

CHAIRMAN MORRISON: In vitro studies?

DR. McEWEN: In in vitro studies we have \-- we\'re not as able to look
at host/environmental factors. I think that was \--

CHAIRMAN MORRISON: Does that the duplicate what you\'ve got below,
limited because of \--

DR. McEWEN: I guess so. I mean, I \--

CHAIRMAN MORRISON: Okay.

DR. McEWEN: I didn\'t have it written down.

CHAIRMAN MORRISON: Okay.

CO-CHAIRPERSON SINDELAR: I thought I heard you say it was the host, the
factors with the host as opposed \-- within the factors within the
environment and controlled environment as opposed to the variables
within a host.

DR. McEWEN: Yeah. I mean, yesterday was so long ago. I think we\'re
talking about \-- said that we need to consider agent/host/environment
issues within \-- or it would be ideal to look at those within the
context of pre-approval, and that the in vitro studies, sort of by
nature, tend to be more useful, I guess, for the agent related issues,
although we heard about in vitro modeling of gut ecology and that sort
of thing which brings in the \-- in some of the environmental issues.

That the animal studies, by nature, allow us to look at those host
factors and, in general terms, the field studies allow us to look at a
bit of more of the environmental \-- the contextual stuff, although we
can also consider agent and host issues in the field studies. I\'m not
sure how helpful it is to go down that road very far.

But I guess, in general terms, the in vitro studies, they suffer from
the generalizability (sic), I guess, or relevance to the real world, as
a general statement, and the closer you get to the field studies, the
more relevant it is to the real world but the harder it is to interpret
and the harder it is to undertake them and the more expensive it is.
There\'s a kind of a hierarchy in that sense, analogous to \-- I guess
to the sort of development phase where you kind of work up through
different species and into clinical trials.

CHAIRMAN MORRISON: Okay. So your suggestion is, there\'s three
considerations, the agent, the host and the environment, that in vitro
studies are particularly good and appropriate for studying the agent but
have their limitations because you can\'t \-- it\'s difficult to
predict, difficult to extrapolate. You\'ve got in vivo studies,
expensive, big pig numbers. And environmental studies lack \-- difficult
for lack of control, all the confounding variables.

DR. McEWEN: Yes. And I guess, also, if we\'re talking about field
studies with natural exposure, then there are statistical power issues
that are usually a major problem there. And so, they need to be large in
order to have much chance of telling us things and that \-- there are
major issues of cost and logistics.

CHAIRMAN MORRISON: Okay. Anymore comments on \-- I think, then, what
we\'ll see here in a couple of slides \-- is that it for where we got
yesterday other than general comments? Dave.

DR. WHITE: Dave White, CVM. I think I\'d like to also mention somewhere
in here, something that Dale brought up about validation,
standardization and reproducibility of these tests, if it\'s an in vivo
or in vitro. I mean, is this only going to be done in this one lab or
can I reproduce it in my lab, and if we can\'t \--

CHAIRMAN MORRISON: The need for standardization?

DR. WHITE: Yes; I would go with that.

CHAIRMAN MORRISON: Is that across all three studies, Dave, or \--

DR. WHITE: Yes.

CHAIRMAN MORRISON: So it\'s a general comment?

CO-CHAIRPERSON SINDELAR: A limitation?

DR. WHITE: I\'d like to \-- well, it\'s a limitation is what I\'m
saying. It\'s the lack of standardization.

CHAIRMAN MORRISON: Difficulty of \-- okay.

DR. WHITE: That\'s what I meant.

CHAIRMAN MORRISON: Okay. Okay. Good thinking.

DR. FEDORKA-CRAY: I think that you don\'t want to get caught in saying
that these have to be standardized for \--

DR. WHITE: No; I wasn\'t getting that \--

DR. FEDORKA-CRAY: Right; yeah, that the reproducibility is probably
going to be horrendous. If you go to a field and you try to reproduce a
field study, then what you\'re saying is, is that \-- for instance, when
we go in and we look at salmonella over time, and on a slide in
particular that I showed yesterday, it\'s rare that you\'re going to
find the same bacteria there all the time.

And each of the bacteria have different properties with respect to
resistance acquisition, acquisition of resistance attributes, and so, if
the demand is there for reproducibility over time in field studies,
that\'s going to be very, very difficult to achieve for some of the
zoonotics in particular.

CHAIRMAN MORRISON: Impossible.

DR. FEDORKA-CRAY: It would be impossible.

CHAIRMAN MORRISON: Yeah.

DR. FEDORKA-CRAY: Exactly. And I think that\'s what it comes down to.
And even doing controlled, challenge type studies, one of the things
that you would have to ask yourself in the field is, is how can you
mimic all of the variables, you know, even in \-- when you do lab type
studies and you\'re talking about reproducing that, it becomes very
difficult to include multiple bacteria.

You can really only do that on a singular issue. You know, you can\'t
\-- you don\'t have a very good idea what the interaction is when you
begin to add multiple bacteria to it. So then, how do you, in essence
then, design a study where all of that can be evaluated because that\'s
what\'s really happening in the real world.

And the problem with the real world is, you can\'t reproduce it all the
time. So you have general ideas but when you actually implement some
things, then it doesn\'t \-- it just doesn\'t hold up. And one of the
\-- and so, I\'ll leave it at that.

CHAIRMAN MORRISON: So the need for reproducible, repeatable studies
needs to be balanced against the breadth of possible study factors out
there and if you have a study that\'s always repeatable, then you\'re
not going to get very wide in terms of your study factors?

DR. FEDORKA-CRAY: You\'re going to be limited in the number of \-- I
don\'t want to say points because you\'re putting the bacteria in, but
the number of design factors that are going to be able to be included in
any one study is going to be limited.

CHAIRMAN MORRISON: Yeah.

DR. FEDORKA-CRAY: And this is both in vitro \-- I mean, in the lab and
in the field, too.

CHAIRMAN MORRISON: Did you get that?

MR. ANDRES: Yeah, I think I\'ve got all that down.

CHAIRMAN MORRISON: Okay.

MR. ANDRES: That\'s what I have. I mean, Paula, you give a suggestion
how you want to capture that as a limitation of the concepts that we
heard Tuesday?

DR. FEDORKA-CRAY: I think \--

MR. ANDRES: Or do you want it put under general \--

DR. FEDORKA-CRAY: Well, yeah. I think that you could put something \--
no, I think it should go here, but I think that you\'re going to have
\-- you would have to say something like design \-- you know, there will
be something about limitations in design. Yeah, I don\'t know that it\'s
lack of study and I\'m just looking at that now. Lack of study
validation as opposed to something along the reproducibility questions.
Because each study is validated in itself, but you don\'t \-- you know,
it\'s \--

DR. BROWN: Scott Brown, Pharmacia & Upjohn. The semantics I think we\'re
trying to get at are important here, in one respect that, what is
reproducibility? Can you get the same results, time after time after
time after time with the same study?

The second one, which I think a lot of used the word validation for, is,
do the results of this study infer correctly what will happen in the
field? The inference space for these studies is a tremendous issue and I
think that\'s the part that some of us who were talking about validation
were concerned about, is the real inference space, from a statistical
perspective of these studies.

So one is reproducibility. Can you do the study? Can you transport it to
another lab? Can they get the same result? And then the other one is the
\-- what can you infer from these studies and is that \-- has that been
validated?

CHAIRMAN MORRISON: Do we mean by that, Scott, the limited
predictability?

DR. BROWN: That\'s a big part of it, yeah, I think so.

CHAIRMAN MORRISON: I think we have that limited predictability. Maybe
what this point was trying to get at is the need for reproducible lab
protocols or the lack of \--

DR. McEWEN: How about, to follow along with what Paula was saying \--
Scott McEwen again. How about as the level of complexity of the
experiments and studies increase, the ability to reproduce them and
validate them decreases?

CHAIRMAN MORRISON: Thank you. Wonderful.

(Pause.)

CHAIRMAN MORRISON: As soon as Chuck \-- so I think that finishes, I
believe, our limitations that we listed. Is that right?

MR. ANDRES: Yes.

CHAIRMAN MORRISON: Okay. The next question that we\'re going to address
is modeling. As we think about in vitro, mathematical or perhaps in
vivo, if you were going to do a pig experiment in the pre-approval
session, what factors would you consider when modeling disease
resistance or antibiotic resistance?

And let\'s leave the pathogen load part out for now. So what factors in
your study design, as you listen to all of those \-- we\'re on question
three now.

(Pause.)

CHAIRMAN MORRISON: I think, actually, what we\'ve done is, a lot of
those limitations we were listing off as advantages and disadvantages of
different kinds of studies, roles of data.

On that question two, what role could the various types of data play in
evaluating microbial effects? Are there any additional comments?

(Pause.)

CHAIRMAN MORRISON: I think what\'s happened, Chuck, is that in
yesterday\'s discussion, we got to that question and, if I remember
correctly, what we\'ve done is in some of our points under limitations,
those are actually referring to different kinds of studies and the roles
of those data.

(Pause.)

CHAIRMAN MORRISON: Aleta is confirming for me that she feels we\'ve
answered a lot of two.

CO-CHAIRPERSON SINDELAR: It\'s just when we were looking at the
objectives of the pre-approval studies and we were making comments, many
of them, the purposes of the study and the utility in like
post-marketing surveillance, so I don\'t want to inhibit any further
discussion on number two.

I mean, if there are any other comments that you would like to say that
the role of the microbial effects would play, please come forward and
make that. We are really under time constraints and we want to move
forward on trying to provide an answer to all five questions and any
other issues. But, if there are any additional comments on the roles,
please step forward and make them.

(Pause.)

CO-CHAIRPERSON SINDELAR: Okay. So let\'s move onto question number
three.

CHAIRMAN MORRISON: Okay. All right. So, question three, there\'s really
two types \-- two subquestions. One is regarding modeling resistance
development and the other is pathogen load changes. And so, what I would
suggest is that we first talk about what factors should be considered
when modeling resistance development.

This is sort of \-- you know, you heard Paula and different speakers
yesterday say, here are all these issues that influence the study
outcome. And what I hear this question telling us is, well, how would
you rank these if you want, and if you\'re going to go and model
resistance development, what are the really important factors that you
would incorporate into your study design?

DR. BROWN: Scott Brown, Pharmacia & Upjohn. I\'m struggling a little
with knowing exactly what this question is trying to head toward but let
me take a stab at it and see if I\'m in the right direction.

If I understand risk assessments, and I had a lot of experiences with
mathematical modeling and pharmacokinetics, one of the things that those
two things together do is identify a lot of assumptions and they also
identify some of the uncertainty with those assumptions and you can
actually model what tweaking some of those uncertainty areas will do to
the predicted outcomes.

To me, one of the things that could be done with both of those, and I
think it\'s nice to have both of them together because they approach
from completely different methods, mathematically, and if you get the
same kinds of results, then you sort of have a lot greater comfort that
you\'re in the right direction.

I think what those two things could do, those two tools could do, is to
actually identify those factors that are important in resistance
development in swine and perhaps pathogen load changes.

They would then be more vigilantly identified and vigilantly monitored
in the post-approval process. I would strongly urge us not to say that
those will be the things that will impact on resistance development, but
I think it\'s important for us to say that those two tools might give us
a direction in which to look, ultimately, in the way that we modify
usage patterns and the way that we modify \-- the way that the
antibiotic or the way that the particular usage is being done in the
field. So, I don\'t know if that\'s the right direction that the
question was intended, but that\'s \--

CHAIRMAN MORRISON: And the two tools, one was mathematical modeling and?

DR. BROWN: The other was risk assessment.

CHAIRMAN MORRISON: Risk assessment.

DR. BROWN: The compartmental modeling is the one I\'m thinking about
that Dr. Lipsitch was talking about. They really approach things very
differently, both mathematically, but with very different mathematical
assumptions as part of the Framework.

DR. McEWEN: Scott McEwen. I agree entirely with what the other Scott
just said, and I\'d say that goes for all the types of mathematical
modeling, the pharmacokinetics, pharmacodynamic, the risk assessment and
the population dynamics type modeling of Mark Lipsitch\'s.

But I would add to what he said in the sense that these \-- where
possible these pre-approval studies and so on should assemble data that
could be used to fortify these types of modeling to fit the parameters,
too, and help us understand the structure of these models.

So in a sense, the data gathering that is part of this, these
pre-approval studies, where possible, should be designed with a view to
helping us do the modeling.

CHAIRMAN MORRISON: The other \-- we probably shouldn\'t limit ourselves
just to these mathematical analytical models because another model that
was presented I think was the pig gut model, in vitro pig, sort of in
vivo pig gut model.

DR. FEDORKA-CRAY: Paula Cray. I think, when I look at this question, and
it says what factors should be considered when modeling resistance
development and pathogen load, I guess what comes to mind is, is that
the complexity of design is going to limit the applicability in
answering how resistance will develop in multiple \-- in field
environments, in the real world, which is ultimately where you\'re
taking it.

CHAIRMAN MORRISON: The complexity of design is going to \--

DR. FEDORKA-CRAY: Is going to limit.

CHAIRMAN MORRISON: \-- limit it. Limit the \--

DR. FEDORKA-CRAY: It\'s going to limit the, you know, the applicability
for taking the information and translating it to the real world. I think
that should just be recognized, that all of those factors I talked about
yesterday and really

\-- and in talking about in developing animal models to look at
everything, and we just said \-- we just went \--

I mean, a lot of this I think we\'ve talked about in some of the other
sections, that I\'ve seen, that\'s already down on paper. And you know
what we\'re really addressing here is the complexity going to be a
limitation.

CHAIRMAN MORRISON: You\'re an expert and you\'ve done an enormous amount
of work in this, if you were to say, what are the top five factors that
you think will have the most effect on resistance development, what
might those be? Out of that complexity of nature out there and things
that you\'d love to be able to understand, if there was five factors
that you thought, these are really important?

DR. FEDORKA-CRAY: In ten seconds or less?

CHAIRMAN MORRISON: Yeah.

DR. FEDORKA-CRAY: I would really hesitate \-- I mean, you know, I would
hesitate to put down any factors. I mean, I think the complexity issue
is a factor itself, and I think that if you \-- you know, when you start
looking, if you want to say something very specific that you really
can\'t pick five because \-- or you can\'t pick two or you can\'t \--
because what ends up happening is, is that they\'re all intertwined, you
know, as you\'re going down.

I mean, in just designing an animal experiment and looking at age and
\-- I mean, this should be influenced by \-- to me, if you have an
indication for a particular drug, I mean, we all \-- I mean, I would
always go back to, you have a drug and you have a label indication.

The label indication is for a particular animal at a particular age for
a particular disease. Right? I mean, that\'s the whole premise of this
\-- drug, animal, disease, and it\'s going to be given for a certain
period of time.

And so, how does that influence, then, what you\'re going to essentially
put into the herd or the pen or the environment and predict what\'s
going to happen next. And I think that the complexity of that premise
limits, you know, the predictability.

CHAIRMAN MORRISON: Yeah. But let\'s say \-- you know, we saw a model
yesterday; we saw population size \-- you know, the size of the herd or
the, sort of the degree of intermingling within a herd is going to
influence it.

DR. FEDORKA-CRAY: Well, concurrent disease.

CHAIRMAN MORRISON: Age.

DR. FEDORKA-CRAY: Age, concurrent disease.

VOICE: Target pathogen.

DR. FEDORKA-CRAY: Target pathogen, stress.

VOICE: Disease background of the herd.

DR. FEDORKA-CRAY: Disease background of the herd.

VOICE: All 300 questions.

DR. FEDORKA-CRAY: All 300 \-- yeah. I mean, I think there was a list of
twenty points that I put up \-- genetics of the herd, you know. And if
you look at the farm design itself, access to other animals.

CHAIRMAN MORRISON: Waste management system.

DR. FEDORKA-CRAY: Waste management. Management in general.

DR. BROWN: \-\-- mention drugs, Paula.

DR. FEDORKA-CRAY: Drug.

(Laughter.)

CHAIRMAN MORRISON: The drug.

DR. FEDORKA-CRAY: I did mention drug earlier. That was acknowledged. I
mean, I think that sometimes, like when I see a question like this
that\'s so broad, I mean, to me, there\'s somewhat of a disconnect
between \-- here you\'re talking about drug, bug, animal, a particular
indication.

And now you want to throw in everything that happens from, you know,
time of farrowing through to the slaughter plant and the predictability
becomes really limited in that scenario.

MR. ANDRES: Chuck Andres. I think maybe to pull the scope in on the
question a little bit, and I\'ll try to use another analogy that maybe
fits \-- if you look at effectiveness studies, okay? We certainly don\'t
require that you test them under all potential conditions of use prior
to approval. It\'s essentially a grab sample, if you will, of the
environments that this product could be used in. And I think the similar
type logic here is that, yeah, we could probably sit and go through and
list 300 factors that should be considered, and at some point in time,
when CVM sits down with a drug sponsor, we\'re going to go through and
say, okay, what\'s really doable? What\'s really important when we start
talking about these factors? And that\'s where, from a guidance
standpoint CVM\'s trying to get your input as to \--

DR. FEDORKA-CRAY: Okay. But see, but then the frustration \-- I\'ll just
cut in right here then.

MR. ANDRES: Okay.

DR. FEDORKA-CRAY: Is that you\'re saying that this is a scenario that
you\'re going to operate under, and I would come back to you and I would
say that it would be totally dependent upon the application that was
being put forward.

MR. ANDRES: And I\'d say, okay, fine.

DR. FEDORKA-CRAY: And so, I think that\'s where it has to be recognized,
the complexity of the design. I think that these \-- to go through some
of these questions, they\'re broad in itself, and what you\'re asking
are for very specific suggestions for scenarios that may change every
time you walk through that door.

And I think that, you know, that the presentations yesterday certainly
gave you that grab bag to pick from, so in answering these types of
questions, that the focus would be more on the recognition that these
\-- that some of these types of issues that we\'re approaching or that
you\'re looking for answers for, there may not be an answer that could
be applicable either across the board or an answer that can be had at
all.

But one of the things that I would, you know, caution is, is just \-- is
trying to have an answer for everything when there can\'t be an answer
sometimes.

MR. ANDRES: But one of the exercises, I think, that the breakout groups
were trying to get \-- are there \-- what you heard on Tuesday, I guess
\-- was it Tuesday? Is there specie difference? We\'re talking \-- this
is the monogastric. We can call it swine because if it was poultry, you
would be over there.

Are there factors that we should consider when you\'re talking about
swine studies? Swine drugs for use in swine that we should consider,
that should be considered when we talk about modeling resistance
development? Or is it \--

DR. FEDORKA-CRAY: I think that those \--

MR. ANDRES: \-- universally, you know, the laundry list of 300 things
and it applies whether you\'re talking the ruminant down at the other
end, the avian or here or are there differences?

DR. FEDORKA-CRAY: Okay. But maybe \-- I mean, I\'m just \-- I\'m
capturing that and saying that the complexity of design mandates that
the situations be evaluated on an individual basis, and that when you
look down through that laundry list that that laundry list is going to
\-- you will \-- that you\'ll have to pick and choose as you\'re going
down through for particular applications.

The very obvious ones are the ones that were just listed. I mean, the
management, the stress, the age of the animal, the genetics, the
management, proximity to other animals, lagoon, waste management
features, herd health.

CHAIRMAN MORRISON: I think just by listing them we\'re answering this
question, so \-- because for all we know, the people who are \-- and it
wouldn\'t surprise me at all \-- the people who are looking at this and
evaluating this may not have been on many farms. And so, I think it has
value in just listing these, and the fact that it\'s very complex.
Scott.

DR. McEWEN: Scott McEwen. I\'ve been trying to think of something
specific to swine and I can\'t think of anything; maybe somebody else
can, that all those things seem to apply to all the food animal species.

And the second point is, I\'m not sure we captured the elements of Scott
Brown\'s comments about the modeling. And down below, mathematical
modeling, and I would put in brackets there, Pk, Pd, population
dynamics, risk assessment.

MR. ANDRES: Say it again.

DR. McEWEN: Population dynamics, risk assessment.

DR. BROWN: The point that I was trying to make earlier was that this
mathematical modeling can identify factors that we\'d have to be on
alert for, post-approval. Under the bullet point just above that, the
mathematical modeling can identify factors that may substantially affect
resistance development, post-approval.

And I think, then, Scott McEwen\'s comment was that the pre-approval
studies, he would like to see them generate data that would help feed
into those mathematical models.

MR. SCHUSTER: Yeah, I\'m finding this question confusing as well and I
think we\'re talking about two things and it might be helpful to break
them up. One would be animal study type of models, how would you design
a study in pigs? Certain factors would apply to that.

Other would be more of a theoretical prediction and that would be maybe
a mathematical model or a risk assessment type model or something. Maybe
if we break out the factors in both ways, it\'ll clarify that.

My own input is, if we\'re trying to predict a more theoretically, key
factors are class of drug. We know some are more readily induced
resistance than others. Another factor is spectrum of activity, if it
has activity against zoonotics or not, or against commensals or not.

And a third factor would be gut exposure of the drug, given its whatever
route of administration. An injectable may or may not give heavy
exposure to the gut.

CHAIRMAN MORRISON: So those would be three key elements that you would
want to understand to build your mathematical or risk assessment model?

MR. SCHUSTER: I think, theoretically, those three factors could give you
a sense of, is this a high, low or medium level of concern of drug? If
the drug didn\'t expose the gut flora significantly, you might argue
that there\'s no need to do \--

CHAIRMAN MORRISON: And those three factors, I\'m going to guess \-- if
we had another type of model being the pig gut model that we heard about
yesterday or the in vitro models, not mathematical models, those three
factors would influence those, too, wouldn\'t they? Those three factors
are pivotal to any kind of model \--

MR. SCHUSTER: Yes, but they\'ll come out. If you run the study, they\'ll
be built in as a matter of course. You wouldn\'t have to worry about
that in the design of the study. You\'re going to know your route of
administration and your dose and whatever that should be is going to
influence and you\'ll get a readout.

But from that standpoint, I think key factors are what species of
organism are you looking at or are you going to challenge it with, what
specific strain, because we know there\'s species and strain
differences. I mean, dramatic differences.

CHAIRMAN MORRISON: These are now pig model factors?

MR. SCHUSTER: These would be animal model factors.

CHAIRMAN MORRISON: Okay.

MR. SCHUSTER: Clearly, interactions or exposure to an outside
influences. If it\'s an isolated system or if it\'s free to interact
with all of the things, insects, birds, residues from a previous study.
I mean leftover manure or contaminants, human interactions. So I would
call that outside interactions are clearly going to be key.

If you\'re a completely isolated system, you\'re essentially doing
something like an in vitro study where this strain does or doesn\'t
mutate to develop resistance with this exposure, whereas if it\'s a more
open system, say on a commercial farm, you could be dealing with
hundreds of different strains and any one of them might be selected for
or not in the given study.

That\'s my short list of key factors and I might have others if I give
it more thought and I\'m sure other people might add some things, too.
But, I think the complete list is nothing short of 300 factors that we
heard the experts say, and I\'m not qualified to say which of those are
the most important.

CHAIRMAN MORRISON: So we\'ve got our \-- to put it into three big
categories, you\'ve got your farm/environment factors, a bizillion of
them.

MR. SCHUSTER: Right.

CHAIRMAN MORRISON: You\'ve got your drug factors, which were the class
of drug, the spectrum and the gut exposure.

MR. SCHUSTER: Right.

CHAIRMAN MORRISON: And then you\'ve got your strain or species of
organism factors.

MR. SCHUSTER: Yes.

CHAIRMAN MORRISON: The species of organism, the strain of the organism
and outside influences.

MR. SCHUSTER: And it\'s my view that certainly the drug factors, and
maybe if you\'re only interested in certain zoonotics because of
spectrum of activity or something, you might have some sense of whether
that needs to be investigated with a study put in practice or just
theoretically.

It\'s my view, if your drug doesn\'t expose the enteric microflora to a
significant extent, it\'s very unlikely to select for resistance among
the enteric zoonotics and it\'s very unlikely to affect pathogen load.

Scott wants to open a can of worms that I\'d rather not go in. He\'s
suggesting an environmental influence of the drug, which I would
consider that in an environmental safety stuff and if we build in
resistance there.

What we\'re focusing on in this conference is the resistance selection
and the target animal and that\'s what my comments are limited to. I
chose to limit it that way.

CHAIRMAN MORRISON: Good time for a coffee break, and we\'ll try and
catch up here.

(Brief recess.)

CHAIRMAN MORRISON: We\'ve been talking about factors that we would like
to incorporate or we would like to consider as we try to model
resistance development and we had some general comments with regards to
this topic, that the factors that affect the modeling may change from
product to product, that the complexity of the design, that these
designs are going to be incredibly complex, especially when you go to
the field and may limit the application, and that these mathematical
modeling can identify factors that may substantially affect
post-approval monitoring. Okay, Chuck; was there one more?

MR. ANDRES: Nope.

CHAIRMAN MORRISON: No? Okay. Then we said, well, there\'s really three
categories, or three if you lump these factors into three categories,
there\'s three categories. One was the drug factors; two was the
pathogen factors; and three was the environment field factors.

Within drug, we said there\'s the class of drug, the spectrum activity
and the degree of gut exposure. Within the pathogen, there was the
species and strain. And then, with environment, we just started listing
them off and recognizing we\'ll never get to all of them \-- herd size,
disease status, genetics, waste management, herd management, feed
source, stress, the age profile, etcetera. Scott.

DR. McEWEN: Scott McEwen. I guess, technically, if might be an advantage
to take out some of the host factors and make a host category because we
have an agent category, an environment category.

CHAIRMAN MORRISON: Oh yeah, that would be good.

DR. McEWEN: So there\'s like age and genetics and that sort of thing.

CHAIRMAN MORRISON: True epidemiologist. That would be great. So there\'s
a fourth category of factors. There\'s drug. There\'s the bacteria.
There\'s the host and there\'s the environment, and we\'ll pull out a
few of those environment ones and stick them into host like genetics,
age, stress.

MR. ANDRES: So here you want to put \--

CHAIRMAN MORRISON: So there\'s one more \-- environmental field factors,
another big bullet, host.

MR. ANDRES: I\'ve got this duplicated so what I\'m going to do is what
do we want to call \--

CHAIRMAN MORRISON: Oh, okay.

MR. ANDRES: The fourth \--

CHAIRMAN MORRISON: Host.

MR. ANDRES: Host; okay.

CHAIRMAN MORRISON: Delete herd size, delete disease status, delete waste
management, leave genetics, and make stress and age, two. Stress and
age. And I\'m sure there are others. Are there other big ones that occur
to you as you think about it as host?

VOICE: Immune status.

CHAIRMAN MORRISON: Immune status. Is that stress/immune status? That\'s
what really stress is, I think. Or no? We can put two; I don\'t care.
Stress, immune status. Pardon?

DR. MUDD: Concurrent \--

CHAIRMAN MORRISON: Concurrent infection? Health status?

MR. ANDRES: Would you want that on both environmental \-- we\'ve had \--

CHAIRMAN MORRISON: Yeah, it really is both. One is the health status of
our individual pig and \--

MR. ANDRES: Okay.

CHAIRMAN MORRISON: You can argue \-\-- Paula?

DR. FEDORKA-CRAY: I think there\'s another \-- if you\'re going to talk
about the target pathogen, a strain, again, going back to the impact on
human health, it\'s not the target pathogen that\'s going to influence
human health; it\'s the zoonotic commensals and you have a species that
strain complexities \-- your species is spelled wrong, too. It needs and
S. But you know, you have those factors, too, that you have to consider.

CHAIRMAN MORRISON: And so, is there \-- is the big bullet where we have
target pathogen is their agent and then two subs, the target and \--

DR. FEDORKA-CRAY: Right.

CHAIRMAN MORRISON: \-- other organisms?

DR. FEDORKA-CRAY: Right.

CHAIRMAN MORRISON: Okay. Its agent as your big one, and then you\'ve got
two subs of that, the target pathogen and the other one is the human
that you mentioned. Yes.

MR. ANDRES: I was just assuming we\'re talking about zoonotics.

DR. FEDORKA-CRAY: Yes. And I think if we don\'t put it up there, that\'s
not the assumption. The other thing is that I think that what factors
should be considered when modeling resistance development that I think
that there is \-- there are huge gaps in information that are available
and I think that should be acknowledged.

CHAIRMAN MORRISON: Up front in one the general comments?

DR. FEDORKA-CRAY: Up front, that there are huge gaps available \-- I
mean gaps and information.

MR. ANDRES: Okay.

CHAIRMAN MORRISON: Other comments, thoughts on this issue of factors
that we would consider as important in any modeling attempts to study
disease \-- or antibiotic resistance?

DR. FEDORKA-CRAY: And I would make one other comment \-- it would just
be a comment that I think that, especially something like this, would
beg for a small group interaction to ferret out study design.

(Pause.)

CHAIRMAN MORRISON: After a little bit of espionage, I find out we\'re in
the running for first place. We\'re doing very well.

VOICE: No surprise, is it?

CHAIRMAN MORRISON: What? Yeah. Among the other groups, we\'re apparently
doing well. It\'s very important that we win.

(Laughter.)

CHAIRMAN MORRISON: Okay. Paula had a point in here \-- huge gaps in
information. Huge gaps in information require specific studies to
address them.

DR. FEDORKA-CRAY: I don\'t think \-- I think part of the problem with a
lot of the models that are developed is that you have this information
gap and it leads to assumptions and so, a lack of information may
complicate \--

CHAIRMAN MORRISON: Interpretation?

DR. FEDORKA-CRAY: \-- interpretation \-- study design and
interpretation.

CHAIRMAN MORRISON: Dave.

DR. WHITE: Yeah; I was going to wait for the next slide.

CHAIRMAN MORRISON: Okay.

DR. WHITE: Or the \-- I guess it\'s this slide but there\'s another \--
the last bullet I wanted to mention. It\'s not up there yet, so \-- when
we were talking about what Paula mentioned before, the specific
pathogen, we\'ve also been, you know \-- also been talking about
potentially looking at commensal and I wouldn\'t call a commensal a
pathogen.

CHAIRMAN MORRISON: We are going to \-- in the next question we are going
to be talking a lot about what pathogens should we focus on, how should
the appropriate pathogen be selected and should surrogate organisms be
used?

DR. WHITE: Well, I was thinking, here, instead of target pathogen, if
you want to say target bacterium. I mean, I\'m not \--

CHAIRMAN MORRISON: Okay.

DR. WHITE: You know \-- because I\'m not sure what we\'re \--

DR. FEDORKA-CRAY: That\'s much better.

DR. WHITE: I\'m not sure what we\'re going to pick yet.

CHAIRMAN MORRISON: Target bacterium.

MR. ANDRES: Target zoonotic \-\--

DR. WHITE: Yeah. Parentheses, zoonotic or commensal or something like
that.

CHAIRMAN MORRISON: Okay. Target bacteria, and then in brackets, zoonotic
and commensal. No, up on the top line in brackets.

CO-CHAIRPERSON SINDELAR: No.

DR. FEDORKA-CRAY: No; just leave it like that and then go down to
zoonotics/ \--

CHAIRMAN MORRISON: Oh, okay. Or couldn\'t it just be target,
zoonotic/commensal?

DR. FEDORKA-CRAY: Uh-huh. It could be \-- you just have one.

MR. ANDRES: Commensal \--

CHAIRMAN MORRISON: Target \-- we\'re going to change it.

MR. ANDRES: Oh, we\'re going to change it?

CHAIRMAN MORRISON: Target, zoonotic, commensal and species, and then
just take \--

MR. ANDRES: Okay.

(Pause.)

MR. ANDRES: Is that better?

CHAIRMAN MORRISON: Okay. So we\'ve got drug factors, agent factors, host
factors, environment factors and we have some general comments. One of
the things that we talked about earlier, the other part of this question
is, what are the factors that you would consider when you were designing
your pathogen load studies?

And this group said \-- there were mixed feelings on the pathogen load
studies and one of the comments was, we really need or perhaps should
urge FDA/CVM to have a separate conference/session/something on pathogen
load.

So talking with Aleta earlier, she said, you know, if there are pressing
comments with regard to factors that one or more of you think we should
incorporate into study design, we can put them here or we can just say,
we think pathogen load is big enough and important enough a topic that
it should be addressed as a separate workshop; whichever you prefer.

MR. SCHUSTER: Dale Schuster, Schering-Plough. I think we\'ve talked
enough. Let\'s not schedule another workshop and put down our thoughts
now and see how it comes out.

CHAIRMAN MORRISON: Okay. And so, if pathogen load was to be incorporated
into pre-approval studies, what factors would you think are important?

DR. BYWATER: Robin Bywater, Pfizer. I think we said earlier that the
pathogen load studies don\'t make a lot of sense for short term
therapeutic product, at least not to my mind. I think we\'re talking
much more about long term feed medication or growth \--

CHAIRMAN MORRISON: So you would speak for not putting them in \-- not
spending time now?

DR. BYWATER: Well, no, it\'s just sort of making the point that the
pathogen load studies, perhaps, are not particularly relevant for short
term therapeutic type drugs.

DR. McEWEN: Scott McEwen. I think a lot of the previous factors would
relate to pathogen load as well. There\'s the drug factors, and Robin\'s
point is \-- relates to that and then there\'s the host
agent/environment issues as well. So, my sense is, all of the above
relate to pathogen load.

CHAIRMAN MORRISON: Okay.

MR. SCHUSTER: Dale Schuster again. Maybe under drug factors you can add
duration of treatment or dose regime. I would also add a withdrawal
period. I think that\'s especially relevant for pathogen load. If your
withdrawal period is extended, I think it becomes a nonissue very
easily.

CHAIRMAN MORRISON: So two to add under the drug.

MR. ANDRES: Oh, you want \--

CHAIRMAN MORRISON: No, you can just add them under the drug.

MR. ANDRES: Add them?

CHAIRMAN MORRISON: Yeah.

MR. ANDRES: Okay.

CHAIRMAN MORRISON: The duration.

MR. SCHUSTER: It would be treatment duration.

CHAIRMAN MORRISON: And the withdrawal period.

MR. SCHUSTER: The title of that section, resistance modeling, we can \--
just put key factors, whatever.

CHAIRMAN MORRISON: In modeling \--

MR. SCHUSTER: Because resistance and pathogen load modeling are just key
factors. Just above drug factors, the title, drug factors. I mean,
that\'s a given.

MR. ANDRES: What I could do is \-- what I thought, we\'re going to
separate them because there\'s so much comment on keeping the two,
resistance and pathogen load separate, but if you want \--

CHAIRMAN MORRISON: There was a comment that they overflow so much \--

MR. ANDRES: \-- just go back to the title and the question and I\'ll
remove \--

CHAIRMAN MORRISON: Is there a feeling that we should \-- is there some
feeling in here that we should not separate them? I\'m sorry \-- that we
should separate them? We\'ve heard the feeling that we should just lump
them. Okay. Let\'s just lump them.

MR. ANDRES: Great.

CHAIRMAN MORRISON: Dave, unless you were going to speak towards \--

MR. SCHUSTER: I had something else I wanted to add.

CHAIRMAN MORRISON: Okay.

MR. SCHUSTER: And that was, my view on this, like the drug factors, the
exposure to the gut, the withdrawal period, are all going to be known
and may preclude the need to do and in vivo study.

And all of these factors, that would be known up front, combined with
what we know about the categorization and the exposure might preclude
the need to do in vivo studies, and only a restricted few high
concerning situations would actually warrant doing an in vivo study if
any did, if we could even come up with a in vivo study that \--

CHAIRMAN MORRISON: If I understand your comment, and if I understand
this question, is if you were try to and design, whether it be a
mathematical or a pig gut model or whatever kind of experiment, what
would you incorporate into your design? You\'d look at these factors and
decide which ones of them are important?

MR. SCHUSTER: Yeah, and the first cutoff might be a risk assessment,
saying does this particular drug use scenario present enough concern
that we need to look into it further?

CHAIRMAN MORRISON: Okay.

DR. WHITE: Can we go back to the last slide, Chuck, real quick? Here
under agent factors, I wasn\'t sure if we wanted to think about, since
we\'re modeling resistance, resistance mechanisms. You know, known
resistance mechanisms or transfer. Do we want to add this under a
description under an agent factor or is this something we\'re already
thinking about, under an agent \-- you know what I mean?

CHAIRMAN MORRISON: So, it\'s propensity to \--

DR. WHITE: Well, I would say known resistance mechanisms or \--

CHAIRMAN MORRISON: Known resistance \--

DR. WHITE: Maybe just mechanism resistance, period, and then \--

CHAIRMAN MORRISON: Of this organism? Or of this \--

DR. WHITE: Of your \--

CHAIRMAN MORRISON: Of this agent?

DR. WHITE: Of the target or the commensals or zoonotic. You know, is
there literature out there, there have been studies done that have
described the mechanism and \-- I don\'t want to get too much into the
genetics of it, but you know, mechanisms and transfer.

CHAIRMAN MORRISON: Okay.

DR. WHITE: These are things we were trying to think about earlier.

CHAIRMAN MORRISON: Anything else on factors that you think would be
important to consider if you were to try and model disease resistance?
I\'m sorry \-- antimicrobial resistance or pathogen load studies? If
not, we go to the next question, what pathogens should be the focus of
pre-approval studies?

And then the second question, how should the appropriate pathogen be
selected? And the third question is, should surrogate organisms be used?
So what pathogens should be the focus of pre-approval studies? And I\'m
guessing this question refers to other than your target.

MR. ANDRES: (Inaudible comment.)

CHAIRMAN MORRISON: Well the target \-- and so I would say, the target,
and, what other pathogens? It begs the question \-- well, assuming \--
do you support the concept that there are other pathogens that should be
considered?

DR. McEWEN: Scott McEwen. I mean, to me, it\'s the zoonotic enterics
mainly, so, campylobacters, salmonella, possibly the list would then go
on from there in some cases, maybe \--

MR. ANDRES: Zoonotic enterics.

DR. McEWEN: Some E.coli. I mean, the question for me is where you draw
the line between calling something a zoonotic and then a commensal or a
surrogate or indicator. Like in some instances, E.coli could be both a
commensal and a zoonotic. For pigs, it\'s \-- to my mind, it\'s not a
zoonotic.

It would be a commensal or indicator. Enterococci, you could argue that
in some instances it could be a zoonotic. Probably others would argue
that it\'s not; it\'s really a commensal. So, I think the main ones I
would put down would be campy and salmonella and then see what other
people about other zoonotics.

DR. FEDORKA-CRAY: I think we\'re going to run into a problem here,
though, where if you say zoonotic enterics and you say campy, you mean
campy coli or you mean campy jejuni? Because campy coli is, you know,
more prevalent in swine than in other species.

Campy coli is not supposed to be implicated in human health, so do you
want to look at that? Do you have to look, then, for herds that have an
effect on \-- you know, or have jejuni in that, how do you screen those?
The same thing comes down with salmonella, which strain do you use?

Which strain are you looking for? Which phage type are you looking for
in all of this? And I think that this was \-- this is sort of like the
crux of the whole initial workup in there is that what are you actually
going to pick? And then, there\'s some discussion about the \-- when you
look at the commensal bacteria, or you look at not necessarily commensal
but you look at the enteric, or the surrogates. Are surrogates
predictive of a human health hazard and how do you assess that?

And where do you come up with that information ahead of time? So, I
would \-- I mean, I would have another comment in there that qualifies
that the selection of a pathogen and/or commensal may be problematic in
that there are multiple strain and species within each category or
genre.

CHAIRMAN MORRISON: Given that, would you go beyond the target? Are you
speaking for \-- maybe we ought to just stop at the target.

DR. FEDORKA-CRAY: Well, I mean, I think this goes back to whole
question, again, of what are you trying to \-- you know, what pathogens
should be the focus of a pre-approval study and I\'m not sure there
should be a pathogen that we need to look at for a pre-approval study
because all you\'re looking at is the bug that you\'re putting forth for
the application. Now if you\'re looking at a risk to human health, then
what do you target? And yes, you would target the zoonotics and yes, you
might target some of the commensals. Then I would say that the
difficulty occurs that within, say swine, you know, is campy coli
relevant?

And are you going to get enough information to know that campy jejuni is
a \-- I mean, do you need to do all of the studies for campy jejuni,
knowing that the likelihood of campy jejuni showing up in swine is very,
very small. I mean, you know, what percent is relevant? And then again,
with salmonella, is what strain are you selecting, you know?

CHAIRMAN MORRISON: So are you speaking \-- would you say \-- you would
suggest, do you have the opinion that we should do the target and only
the target?

DR. FEDORKA-CRAY: I would suggest that the target should be listed and
that the statement, the selection of pathogen or commensal may be
problematic, given the different strains, serotypes, phage types,
etcetera. Yeah, that may \--

CHAIRMAN MORRISON: Preclude going beyond the target?

DR. FEDORKA-CRAY: That may preclude \-- right. That may preclude going
beyond the target in that relevant information may not be possible.

CHAIRMAN MORRISON: So there\'s no evidence that we know of that
indicates that there\'s an indicator zoonotic pathogen?

DR. FEDORKA-CRAY: I wouldn\'t want to \-- you know, the most important
pathogen for swine is colarsuis and colarsuis is very \-- has a very,
very low prevalence in the human population. You say titanarium, which
is, you know, in both, but you know, we have more and more evidence that
phage types are playing a big role.

Do you take titanarium? Do you take titanarium copenhagen? And we know
that all titanariums aren\'t equal either. I mean, which one are you
going to select? And I just think that we need to, up front, say that
this is \-- the selection is excruciatingly difficult.

DR. McEWEN: Scott McEwen. I like the excruciating part.

(Laughter.)

DR. McEWEN: I think we need \-- I think we could acknowledge something
that was mentioned in the risk assessment document, is that there\'s a
\-- I think CVM has given consideration to a sentinel organism, maybe
one that\'s either \-- one or two that either are \-- most of the

food-borne diseases attributed to it and/or resistance, there\'s a
propensity for developing resistance and the \--

Acknowledging the inability to look at all combinations of organisms and
serotypes and that sort of thing, that I think there were thoughts given
to using this sentinel as kind of one that in a sense errs on the side
of safety, but you can imagine industry\'s concern that that might set
inappropriately high standard.

So I think there is that possibility as a way of getting around this
issue that Paula has raised of \-- an enormous number of different
strains and so on; how do you \-- where do you start?

MR. WHITE: If I go back to what I reiterated before, maybe instead of
what pathogen in the title, it should just be what bacteria should be
the focus of pre-approval studies?

And also, in terms of \-- the question like Paula was mentioning, with
coli as relevant to human health, I think that\'s a good question
because it may not play a role in terms of disease but what if it\'s a
reservoir of resistance genes for jejuni? I mean, these are things I
just think we need to take into account. That\'s all.

CHAIRMAN MORRISON: What was the second point, Dave? I\'m sorry. About
the reservoir?

DR. WHITE: Yeah. I mean, when we\'re talking about other organisms, that
may not be the particular pathogen \-\-- some of these animal analogs or
the animal equivalent. Are they potential reservoirs of resistance genes
that could be transferred to the pathogen we\'re interested in in the

pre-approval study or whatever we\'re going to do post-approval
monitoring on? So I don\'t know if that confuses it or \--

CHAIRMAN MORRISON: Is that reservoir a point that refers back to our
agent in the last section or is it here, or both?

MR. ANDRES: It\'s here.

CHAIRMAN MORRISON: Here.

DR. WHITE: Yeah, I guess.

CHAIRMAN MORRISON: Here. Okay.

DR. WHITE: I guess I\'d like to hear from the group, I guess, on this
one. I just \-- I didn\'t mean to open a can of worms. I just wanted to
\-- there\'s other things to think about relevance in terms of just
overt disease, that we also could think about possibly as this reservoir
of resistance now.

DR. BROWN: Scott Brown, Pharmacia & Upjohn. I guess one of the things
I\'m struggling with is knowing which

pre-approval studies we\'re talking about that these pathogens ought to
be looked at because, in one instance, we\'re looking at sort of a rate
and extent of the development of resistance.

And if that\'s the case, it\'s, at least in my feeble mind, possible to
identify a \-- sort of a strain type that would be a \-- almost like a
QC organism that you know what it\'s likely mutation frequency is and
that sort of thing and could have some positive/negative controls that
you understand that organism well enough that you can test your
particular compound and see whether your compound is a rapid producer of
resistance or not.

It might or might not have any relevance in terms

of whether it produces disease. On the other side of it, the
pre-approval studies, if they\'re designed to establish baseline
resistance in sort of the field \-- I use the word field very reservedly
\-- in the sort of all the population, I think that\'s a different issue
and then you do have to kind of wonder, which one\'s are you looking
for?

But I wonder if it\'s not possible to look at sort of an ATCC
well-defined strain of something or other that would be genetically
similar and really characterize it well and then use that one as the
organism that you would look at in terms of the mutation frequency onset
and rate of resistance and that sort of thing.

DR. FEDORKA-CRAY: This is Paula Cray again. I see where you\'re coming
from, Scott, but I just would \-- can you find that strain? I mean, that
would be \-- and is an ATCC strain \-- I mean, one of the problems with
ATCC strains that we have is that they tend to be attenuated.

They tend to be \-- you know, they don\'t mimic anything that is going
to translate in the real world situation. I mean, they\'re often used as
QC because of their stability type issues, not because they\'re
reflective of anything that might be happening in a real world type
situation.

So I would just \-- I mean, I would just question who\'s going to do all
the studies to find that strain and, you know, what strain do you select
and \-- I mean, you know, all of those types of issues.

DR. BROWN: That\'s why you get paid the big bucks, Paula.

(Laughter.)

DR. FEDORKA-CRAY: Oh yeah, big bucks.

CHAIRMAN MORRISON: So did I get that right, Dave? I substituted bacteria
and then we\'re going to have a target and then selection of others
depends upon which pre-approval study is being considered?

DR. WHITE: Yes.

CHAIRMAN MORRISON: Okay. And then, if you\'re going to select one, the
selection of other pathogens may be problematic, a given? So there\'s an
if statement \-- if you\'re going to do it, okay, now it\'s difficult
and then you get into a slippery slope, down which you have to figure
out, okay, where are we going to stop? Okay.

DR. McEWEN: Scott McEwen. Well, I wonder about including a bullet or
line, just saying we discussed the strengths and limitations of a
sentinel in quotation marks or prototype or model organism or organisms.

DR. BYWATER: Robin Bywater, Pfizer. I mean, I think the archetypical
sense in all of this is E.coli. It\'s the one you can find everywhere,
leaving entirely aside whether it\'s anything to do with source of
resistance or whether it\'s a pathogen in a pig, it\'s still a very
convenient sentinel organism and if you\'re really wanting just to see
what was happening in terms of resistance selection and the enteric
flora, why go any further? And it\'s there in every animal for you to
look at.

DR. WHITE: Dave White. One thing, that would be, of course \-- this may
fit into the choice of an organism might depend, of course, on the
spectrum of the activity of the antimicrobial. I mean, if it\'s gram
positive, we\'re not going to look at campylobacter, salmonella or we
shouldn\'t. I mean, if it\'s a macroli, we shouldn\'t look at
salmonella; we probably should look at campy. And if it\'s gram
positive, maybe we need to pick it \-- look at enterococci or
staphylococci.

CHAIRMAN MORRISON: Sorry. The next question being, how \-- no, no. Yeah,
that\'s the one we\'re on now, what pathogens. I\'m sorry. Were you
referring to go onto \--

MR. SCHUSTER: His answer fits in the next question.

CHAIRMAN MORRISON: Number five?

MR. SCHUSTER: No. How should appropriate pathogens \-\--

CHAIRMAN MORRISON: Okay.

MR. SCHUSTER: Is there a \-\--

CHAIRMAN MORRISON: Sure. With my dual purpose, I missed your statement.

DR. WHITE: Me?

CHAIRMAN MORRISON: Yeah.

DR. WHITE: Is, we should just take into consideration what the spectrum
of activity of the antimicrobial to be assayed or analyzed or tested or
what. Gram positive versus gram negative would influence what organisms
we would choose. I think that was a problem with the old 558.15 studies,
obviously.

MR. ANDRES: Consider the spectrum of activity of the antimicrobial. What
would be a better way to describe that?

CHAIRMAN MORRISON: Other comments on really any question within here?
What pathogen should be considered? What we\'re talking about now is how
should the pathogen. If you were going to select something else, how
would it be considered? And maybe we could put in the four (c) now,
should surrogate organisms be considered? Again, we sort of bounced
around this issue. Are there specific comments on that?

DR. McEWEN: Scott McEwen. It\'s not entirely clear to me what\'s meant
by surrogate. I guess \--

CHAIRMAN MORRISON: I guess non-pathogens.

DR. McEWEN: Well, one interpretation of surrogate could mean what we
were talking about before about having a model strain or one that\'s
well understood and that we\'re going to make the assumption that
that\'s representative of the spectrum of pathogens. That could be seen
to be a surrogate organism. Another interpretation could be, a surrogate
could be as an indicator organism.

The presence of this resistance in say E.coli could be used as an
indicator of what would likely happen in pathogens which is hard \-\--
as a commensal as a possible donor of determinants, that sort of thing.
So, I think we need some clarification about that or else give
alternative explanations there.

CHAIRMAN MORRISON: Scott, you mentioned \--

DR. McEWEN: The sentinel \--

CHAIRMAN MORRISON: Yeah, the sentinel indicator bacteria, that we just
move that.

DR. McEWEN: Well, I guess all I\'m saying is, is there one sort of
definition/interpretation of surrogate organism or do we have different
possible interpretations and I\'m just saying that, in my mind, it\'s
not a specific term for one.

It could be either \-- a surrogate organism could be what\'s called a
sentinel organism, I think, and in a campy risk assessment, that\'s one
that either is most of the food-borne disease or a large proportion of
food-borne disease is attributable to it, or it\'s one that has a
propensity for resistance development and so we\'ll use that as our \--
I hate to use the word \-- the phrase worst case scenario, but one that
errs on the public health side of things.

That\'s a possible use of a surrogate. Another one is as Scott Brown
suggested, ATCC type strain, well characterized, would allow us to do
reproducible studies and ones that could be interpreted across
laboratories. That would be a possible surrogate.

And a third type of surrogate could be, as I think Robin was suggesting,
that is an organism like E.coli which is \-- its presence is widespread.
It\'s easily cultured. Its resistance in that organism could be
interpreted to be an indicator of what might happen in enteropathogens
or it could be interpreted to be just an alternative species.

I\'m not quite sure. So I\'d see those three different, at this point,
three different possible types of surrogate organisms.

MR. SCHUSTER: Let\'s not worry about the definition. Which would you
want to use?

DR. McEWEN: So the question is, which would we want to use and I guess,
you know, not speaking as an advocate, necessarily, of public health
here, but one I think defendable use of a surrogate would be to, as is
identified in the campy risk assessment, that first definition I gave,
an organism that is \-- to which a lot of food-borne disease is
attributed and/or \-- and it could be the same organism.

There\'s a propensity for resistance development. And I invite other
people to say that that\'s not appropriate or we should have \-- we
prefer another type of surrogate.

CHAIRMAN MORRISON: Chuck has asked the question, do we \-- this question
says, should organisms be \-- should surrogate organisms be used? Yes or
no? And \--

MR. SCHUSTER: That\'s \-- I mean, if we don\'t know just how to define
it, that\'s why I thought we \--

MR. ANDRES: Okay. If yes, then these three considerations? I mean, I\'m
just trying to \-- how best to present.

MR. SCHUSTER: Yeah; Dale Schuster. I thought, since we\'re not sure
what\'s the definition of surrogate we would put in, what would be
appropriate alternatives to a real world pathogen or, you know \--
including a laboratory strain of a real world pathogen.

CHAIRMAN MORRISON: And so, that \--

MR. SCHUSTER: This would \-- where we would define what would be an
acceptable surrogate and \--

CHAIRMAN MORRISON: Okay.

MR. SCHUSTER: \-- if that\'s not a surrogate in your mind, then we
don\'t support it; we support this. And I agree with Dr. McEwen; I think
that appropriate strain and species of a zoonotic pathogen with a known
understanding of its ability to resistance development, I guess I would
lean for one not that\'s not particularly high or low but middle of the
road, but definitely a zoonotic species, not something that doesn\'t
cause disease.

MR. ANDRES: Right.

DR. BROWN: Scott Brown, Pharmacia & Upjohn. I would agree with both what
Dale and what Scott McEwen have said. I think the other \-- the only
caveat I would have is that if \-- unless we have something that we have
identified and is something that is \-- I use the word standardized
again, then five years from now it\'ll be a different strain and then
the criteria for what is appropriate or inappropriate changes, and then
we\'re left with a continuing changing set of criteria.

So I would propose that yes, it be a zoonotic organism; that yes,
there\'s a known capacity for it to develop resistance and we can argue
whether it\'s high, medium or low, but at least it\'s defined and then
it\'s a strain that becomes very well characterized and is the same
strain used, regardless of whether it\'s compound X or compound Y, or
maybe there\'s a particular categorization of compounds that use that
particular strain.

DR. BYWATER: Robin Bywater, Pfizer. Well I can see the attraction in a
very general way. I have a problem envisaging the actual experiment that
would be done. I\'m talking about challenging a group of animals with
this organism, getting it established and then exposing it to the drug?
Possible but not easy, as Paula described yesterday.

I actually quite like the idea of a sentinel organism, sentinel species,
because it\'s there and you don\'t have to put it there; and therefore,
I would be very wary about setting up a requirement of the kind of
studies that would be practically very difficult to achieve, but I may
be missing the point.

DR. McEWEN: Scott McEwen. I think it\'s fair to present as certainly a
reasonable alternative. I mean, somebody\'s going to have to decide
which way to go and there\'s \-- both of those are rational and I\'m
sure there are three or four others that are rational.

CHAIRMAN MORRISON: Has Chuck captured these three correctly? That if a
surrogate is one of these three, then you can see logic behind it. That
if it was an indicator with propensity for resistance or if it could be
ATCC, well characterized, well understood bacterium or you could argue
it could be \-- it should be an E.coli, ubiquitous present resident.
Those are the three that we\'ve said, if that\'s what a surrogate is, we
can see the logic behind it.

DR. McEWEN: Scott McEwen. One further thing \-- E.coli, I guess I\'d ask
the question if that would be appropriate for say gram positive drugs?
So, E.coli or enterococci, but the general idea of a ubiquitous
commensal organism.

CHAIRMAN MORRISON: Equally gram negative or \-- just so you remember.
Other comments on this whole topic of should pathogens be the focus \--
what pathogens should be the focus of pre-approval? How should the
appropriate pathogens be selected and should we have surrogate
organisms? That\'s what we\'re talking about.

DR. McEWEN: Scott McEwen. Did we answer the middle question?

CHAIRMAN MORRISON: We had one suggestion from Dave White, I believe, one
slide up.

DR. McEWEN: I guess I would suggesting adding importance to human
health.

CHAIRMAN MORRISON: Is there logic within this question of the prevalence
or how common this pathogen is out there in the industry? Does that
impact whether you would include it or not?

DR. McEWEN: Well, to me, it\'s implicit in the importance part of it.
Important implies that it\'s virulence and \--

CHAIRMAN MORRISON: Oh, okay.

DR. McEWEN: \-- the spectrum of disease in people but also it\'s
frequency and degree of transfer and amount of exposure that people are
faced with.

MR. SCHUSTER: I would just add that importance and importance being
relative to swine being a source. I mean, if it was important but it
comes from chickens \--

CHAIRMAN MORRISON: Yeah. Under importance,

there\'s \--

MR. SCHUSTER: So just add that caveat as source from swine or something
like that.

MR. ANDRES: Okay.

CHAIRMAN MORRISON: Yeah.

MR. ANDRES: Swine or monogastrics?

CHAIRMAN MORRISON: Swine.

DR. WHITE: Dave White. I guess to expand on what Dale was saying, are
you trying to get like association with a particular animal species of
the pathogen? So maybe pathogen association with historically or \-- I
mean, one question luckily we don\'t have to deal with is aquaculture. I
don\'t know what you would pick for surrogate or pathogens if you looked
at aquaculture products.

MR. ANDRES: That\'s in another \--

DR. WHITE: I know. I\'m saying, luckily it\'s not us, but \--

(Laughter.)

VOICE: That\'s in another room.

(Laughter.)

DR. WHITE: I\'ll sit down.

CHAIRMAN MORRISON: Chuck, let\'s go back to the beginning of four.

MR. ANDRES: Okay. Number four.

CHAIRMAN MORRISON: So to review question four, then, what pathogens
should be the focus of the pre-approval studies? We said \-- we changed
pathogen to bacteria and we said, well obviously the target organism.
And then, the selection of other bacteria really depends upon which
pre-approval study was being considered.

One might consider a sentinel or indicator bacteria and if you were to
select other pathogens, we talked about this almost being a slippery
slope about how far are you going to go? How are you going to select \--
a very difficult, complex question. Let\'s go to the next one, Chuck.

How should the appropriate bacteria be selected, the spectrum of
activity and the importance to human health. And the last one, should
surrogate organisms be used? We were unclear on the definition of
surrogate.

We would support it or there was support in the

room, in general, if it included either an indicator with a propensity
for resistance, either a well-characterized ATCC bacteria, or something
that was ubiquitous and well understood. Other comments on question
four?

The last question is, alternative approaches, concepts that we have not
talked about. Now, we\'ve thrown a few of these ideas, probably into
general, so we may have had some things come up but just in sort of a
brainstorming way. Are there things that we\'ve missed that have
occurred to you? Alternative approaches, concepts that have not been
considered, presumably for pre-approval.

DR. VAUGHN: Michael Vaughn with Bayer Animal Health. What we\'ve gone
through the last couple of days really highlights the complexity of all
this pre-approval discussions and what ought to be done, and I guess the
next challenge for CVM is to sort through all this and to see if
pre-approval studies are going to be pivotable, are going to be
information gathering and what role they might play in assessing the
approval of new antimicrobials and the impact they have on resistance in
zoonotic and human health and so forth.

So it\'s going to be a tremendous challenge for them. And they may
conclude that it isn\'t \-- the pre-approval studies may not contribute
anymore into their decision making process as to whether they will
approve an antimicrobial and they may focus more on the post-approval
process.

And as the body of information is gathered post-approval, then they
could maybe better assess the impact it\'s going to have. And we also
can\'t forget the risk assessment model that we discussed in December,
and as that risk assessment model matures, based on the comments that
were gathered last week, or I guess today \-- today is the final day for
the comment.

And as that risk assessment model matures, then it may be a real
positive tool to be in this whole process, too, and we may focus less on
these pre-approval studies.

CHAIRMAN MORRISON: So Michael, your comment is that over the last day or
so, you\'ve wondered about that FDA/CVM might consider all of these
discussions in light of the role of pre-approval as opposed to
post-approval and risk assessment?

DR. VAUGHN: Correct. And you know, the final decision may hinge on the
complexity of all these and we may never be able to come to a conclusion
that pre-approval studies ought to be used in the approval process, the
final approval process of an antimicrobial, you know.

We may ask for further information that can be plugged into a risk
assessment model or like was brought out yesterday, some of the
information that we\'re going to gather in these pre-approval studies
may help direct us just to where we need to go on our post-approval
monitoring process.

You asked for any additional things, I think we need to not forget that
we have a risk assessment model that is in the developmental phase and
that we are probably going to reconsider the role that these
post-approval monitoring programs are going to have in the decision
making process, and ultimately, that may be what we need to focus on.

CHAIRMAN MORRISON: So maybe what you\'re saying is it might be a shame
to cast our pre-approval process in stone before we work through these
other parts of it.

DR. WHITE: And I think that as CVM assesses what went on in all these
groups, and it was necessary, you know, and I think \-- and I really
appreciate Paula being here today. She really brought home the
complexity of all this.

You know, there aren\'t really simple answers maybe to all these
questions that we want to answer as to \-- and as CVM assesses it \--
and I\'m glad they have that job and not me, this is a very complex
issue.

And as they assess that, we may focus more on the risk assessment in the
post-approval as a process to monitor and evaluate resistance in human
health issues.

CHAIRMAN MORRISON: Okay.

MR. FONDRIEST: Steven Fondriest, Union of Concerned Scientists. While I
haven\'t been working in this issue very long, it has been going \--
from what I\'ve seen, it\'s been going on for \-- this process, now,
over a year?

An alternative that would work, it is simple, would be simply \-- is to
categorize antibiotics, would be to ban the ones that are being used in
human medicines that are very important for human medicine that are also
being used subtherapeutically in livestock.

It\'s an issue that has not really been discussed at all at this meeting
over the past three days and I think you should consider it.
Post-approval studies, pre-approval studies, risk assessment, this all
has been going on for quite a long time and it\'s likely to continue for
a long time.

Dealing with resistance development is going to \-- resistance
development is going to occur in antibiotics that are used in livestock
and it\'s going to adversely affect humans.

We could ban certain antibiotics now, ban the use of them as
subtherapeutics and we could solve \-- begin to solve this problem and I
would urge CVM to do that now, not wait another year to categorize
antibiotics and how they\'re being used, the risk to humans, and ones
where risk is unacceptable, ban them. It\'s simple in practice.

CHAIRMAN MORRISON: So you would expedite this whole process by simply
banning subtherapeutic use of drugs that are used in humans?

MR. FONDRIEST: Where there\'s significant risk to human health, we could
ban them now and we could solve that problem.

MR. ANDRES: Define significant \--

CHAIRMAN MORRISON: Chuck is asking if you would define the significant
risk to humans.

MR. FONDRIEST: I think the risk assessment addresses it as significant,
or the Framework discusses significant impact to humans and I would
think that would be something that the Food and Drug Administration
could define and then \--

CHAIRMAN MORRISON: Okay.

MR. FONDRIEST: \-- we could criticize that later.

MR. ANDRES: Okay.

MR. FONDRIEST: But, define it first for us and we\'ll give you an answer
on what we think, if it\'s a realistic definition of significant.

CHAIRMAN MORRISON: Okay.

MR. SCHUSTER: You have subtherapeutic \--

MR. FONDRIEST: Initially, yeah, I am addressing \-- yeah, that\'s
subtherapeutic use, for now.

DR. BYWATER: Robin Bywater, Pfizer. I mean, this suggestion does beg a
whole lot of questions. We\'re here to decide on a process for
regulatory approval of new compounds, not what to do about the old ones,
specifically.

And also, the question about what is the significance of the risk to
human health is certainly one which is a matter still of debate rather
than established fact.

DR. McEWEN: Scott McEwen. I would agree that this statement should
probably go on the comment section. I mean, I don\'t see \-- I guess
maybe we could ask Steven to defend whether he thinks it\'s an
alternative approach for pre-approval or it\'s a comment. I guess the
one thing that I would suggest is \--

CHAIRMAN MORRISON: If you can stop right there, just for a second.
Let\'s finish that thought because your point, I think, is an important
one, that the comment \-- or this process is about new, pre-approval
process for new drugs.

MR. FONDRIEST: Yeah, you\'re right, but I would say yes.

CHAIRMAN MORRISON: So we\'re looking at alternative approaches for
pre-approval of new drugs. That\'s what this is about.

MR. FONDRIEST: Right. Well I think, first of all \-- thanks for bringing
that up, Robin. Yes, pre-approval, and this is a comment dealing with
the pre-approval approach and it should be extended.

It should also deal with the drugs that are already registered because
we\'re basically \-- the barn door is open, the cow is out of the barn
and we\'re not going to be able to put him back in unless we do
something now and that would require addressing the antibiotics that are
presently in use. And I don\'t think this is just a comment; this is an
alternative. I mean, yes, it is a comment but this is an alternative to
dealing with the pre-approval program is we could nip it in the bud now
and just ban, outright, certain antibiotics used in subtherapeutic
applications.

CHAIRMAN MORRISON: If I can \-- under this point, I think what you\'re
getting at is to now allow new subtherapeutics that pose a significant
risk. Now you may have a general comment for existing that perhaps can
go perhaps in the general comment but if you want \--

MR. FONDRIEST: Okay. That would \--

CHAIRMAN MORRISON: Okay.

MR. ANDRES: Is what I have \-- I\'ve made one word change up here to
make it appropriate for this discussion as far as pre-approval,
categorize new antibiotics and their use in humans and would be prohibit
and not approve the subtherapeutic use?

CHAIRMAN MORRISON: Yeah, not approved.

MR. FONDRIEST: Right, not approved.

MR. ANDRES: Because you\'re not banning it; you\'re prohibiting it.

DR. McEWEN: Scott McEwen. I just have on that we could consider as an
alternative approach and it may be implicit in some of the previous
things but I kind of like the idea of testing a bank of organisms,
presumably enteropathogens, zoonotics, that have been collected as part
of the NARMS and other surveillance systems, and screening them for the
genetic determinants of resistance to a drug under application to
establish the sort of baseline of resistance or lack of it out there.

Now that may already be part of what\'s proposed elsewhere, but I find
that sort of an appealing \-- it came out yesterday, to some extent
\-\-- approach.

CHAIRMAN MORRISON: To test a bank of organisms for resistance to the
drug being applied for or \--

DR. McEWEN: Right. Presumably, during the development process, the
genetic mechanisms of resistance would be determined and we\'d have a
test developed for identifying those determinants and that it shouldn\'t
be too onerous to screen a bank of organisms that we\'ve collected as
part of

the human and animal, food animal surveillance from NARMS

and establish a baseline that would then help with the

post-approval monitoring, foreseeing if there has been an increase, and
help to establish this temporal business that\'s been so much at issue
with fluoroquinolones. But it would \-- you know, applies to all the
drugs really.

MR. ANDRES: Is that accurate?

CHAIRMAN MORRISON: Well, and maybe the last part is to establish a
baseline \--

MR. ANDRES: Okay.

CHAIRMAN MORRISON: \-- for post-approval surveillance.

MR. SCHUSTER: If I could add a comment to Scott\'s as well as \-- I know
there are some companies that are \-- think about hiring people to kind
of reverse resistance. I mean, make it in the laboratory first before
you observe it out in the field so that you would have the mechanism
identified first and it\'s like engineer resistance or something. You
know what I mean? Actually, when I interviewed at Pfizer, that was going
to be what I was going to do \--

(Laughter.)

DR. WHITE: It seemed like a good idea at the time. Here\'s a new
antimicrobial coming through the pipeline. Let\'s see if I can make it
resistant in the lab. Then we characterized the mechanism and we know
maybe that\'s what\'s going to happen out in real life, so I don\'t \--
I don\'t know the \-- I wasn\'t looking for \-- what\'s that?

VOICE: (Inaudible comment.)

DR. WHITE: It depends upon \-- well, no. If you have a bank of isolates,
maybe it will. So I mean \-- I don\'t mean one strain, an ATCC strain,
you know what I mean?

CHAIRMAN MORRISON: So it was to cause or initiate or simulate or to
something resistance and then to the proposed compound and then study
the mechanism. Is that right, Dave?

DR. WHITE: Yes.

CHAIRMAN MORRISON: And study the mechanism by which it \-- to the
proposed product and then study the mechanism.

MR. SCHUSTER: I wanted to make a comment here at the end, not so much as
an alternative approach, although we might put it in there, but more to
get the sense of what are the important things that our group feels?

We have twenty-one slides. We present these, our key factors are going
to get lost in the details. In my own mind, and I think I\'m supported
by at least a few of my colleagues \-- the key point of this is that
based on the discussions we\'ve had on Tuesday and yesterday and our own
internal thoughts, is that pre-approval studies are not in any way going
to be able to predict the rate or extent of resistance development.

I want that made very emphatic. There is no evidence that we can do any
pre-approval study that will accurately predict the rate and extent of
resistance development. Therefore, public health cannot be based on
using pre-approval studies as a safeguard.

It doesn\'t really make sense for them to be pivotal if they aren\'t
telling us a whole lot. The appropriate approach that I see, and you
might call it an alternative approach, is to use the surveillance,
post-approval surveillance, the NARMS program to protect public health.

Pre-approval studies should consist of the information gathering type of
studies that we outlined, the in vitro studies, and only the extremely
few studies that look particularly concerning might be subjected to more
detailed investigation to provide some assurance that it\'s not going to
be a disaster after it\'s approved.

I think it\'s very important to get this message across. Which pathogens
we use and whether we use surrogates and all such things as that, we\'re
all going to come to a consensus on that and not argue to significant
extent.

But clearly, the \-\-- of pre-approval studies is a very contentious
issue and I don\'t think they can be designed in a way to truly protect
public health alone.

MR. ANDRES: Is that emphatic enough?

MR. SCHUSTER: That looks very encouraging. Thank you.

(Laughter.)

MR. ANDRES: Is that accurate, that first one?

MR. SCHUSTER: Tony Mudd is proposing that we make that as a concluding
remark. That\'s fine. My concern is that the point is made very clearly.
I would be inclined to do it up front, to put the rest into context and
to avoid the very likely possibility that we don\'t get around to it
because we get hung up on the details that are presented to us.

DR. BYWATER: What about \-\--

CHAIRMAN MORRISON: Is there anybody in the group that doesn\'t share
that opinion?

DR. McEWEN: Scott McEwen. I agree, it\'s the statement that the studies
probably can\'t be used to accurately predict the rate and extent. I
wouldn\'t go so far as to say that they\'re useless because I don\'t
think we know that.

CHAIRMAN MORRISON: I didn\'t hear that.

DR. McEWEN: And that wasn\'t said; I know that. So I wouldn\'t \-- I
mean, I wouldn\'t buy into the notion that because of this we reject a
notion of doing pre-approval studies, and again, that wasn\'t said, but
I wouldn\'t want that to appear, from my perspective.

DR. WHITE: Dave White. Could I add a comment that maybe you want to say
pre-approval studies cannot, at this time?

MR. ANDRES: That\'s fine.

DR. WAGNER: Dave Wagner, CVM. I\'m just wondering if you want to modify
this a little bit to also include an alternative, then, to pre-approval
studies?

CHAIRMAN MORRISON: I heard the alternative which we haven\'t got written
yet. Was that \-- or that these studies could be used, as we\'ve said
\-- as a few in vitro studies to identify major warnings, etcetera, and
to guide the \-- what you would regard as the important or more
important portion of the drug approval process being the surveillance
post-approval NARMS type surveillance project.

MR. SCHUSTER: Yes. Essentially the objective would be to do the baseline
information that will support that because that is the public heath
safeguard.

CHAIRMAN MORRISON: Is it fair to say that these studies could be used to
identify major or somehow to identify the major \-- you want to screen
out, if they haven\'t already been screened, products that, holy smokes,
there\'s a huge red flag here, or \-- and/or, more importantly, to
develop the necessary information for the post-approval surveillance. Is
there two parts to that? Is it \--

MR. SCHUSTER: I\'ll defer on the first one. The second one, I think, is
absolutely \-\-- but the main objective is to support \--

CHAIRMAN MORRISON: Develop the information required/useful for
post-approval surveillance.

DR. McEWEN: Scott McEwen. I\'d like to capture that first statement of
yours, Bob. Probably in a sense that, you know, CVM should seek to
identify \-- I\'m looking for a word other than red flag but I think
that\'s maybe a good one to use. Just red flags in brackets \-- in
quotation \-- in inverted commas, for drugs where there\'s \-- I guess
the sense is that there\'s a propensity for resistance and a public
health threat that\'s of such magnitude that it \--

CHAIRMAN MORRISON: That\'s the essence of that.

DR. McEWEN: I\'m grappling for the words, obviously.

MR. SCHUSTER: I would prefer that the support for pre-approval is made
as a strong bullet. The red flag, I\'m not convinced yet from the data
that we have, that we can even do that and that would be like a possible
objective if we can envision the right scenario.

My concern is if we did mutation studies and transmission studies, we
can\'t ignore those that show \-- mutations to resistance is extremely
common and it can spread across any pathogen imaginable. I mean, that
would be the case, but \--

CHAIRMAN MORRISON: Yeah. Does that capture it? To require/useful for
post-approval surveillance and possibly identify major red flags?

MR. SCHUSTER: Yes.

CHAIRMAN MORRISON: Okay.

MR. SCHUSTER: That looks good.

DR. SUNDBERG: Paul Sundberg. And I\'m going to suggest that that may be
a step back from where we \-- we\'re stepping back to say, well,
possible major red flags, then \--

I thought we were at the point where it wasn\'t going to be

a pass/fail, that it was a vector, vectoring situation for post-approval
surveillance rather than a pass/fail.

CHAIRMAN MORRISON: You\'re worried that if we have a red flag, then red
flag is a matter of judgment, whose red flag it is?

DR. SUNDBERG: Yeah. And it just seems that that\'s a step back from what
we\'ve been trying to do.

DR. McEWEN: Scott McEwen again. I\'m not sure that it\'s implied that
that\'s necessarily a pass/fail, and maybe some more words are required
but I would \-- I mean, I could envisage a process where some major
concerns are identified and then maybe there\'s an \-\-- approach taken
with the industry to further substantiate those concerns.

But as a screening exercise, presumably what you\'d like to have is a
mechanism that has high sensitivity, in quantitative terms, not in human
concerns \-- in terms \-- high sensitivity for identifying possible
major public health threats.

And then that doesn\'t imply that that the screening test is pass/fail,
but then it\'s \-- I would imagine that there\'s a working with the
industry to sort of reconcile those concerns.

DR. BYWATER: Robin Bywater, Pfizer. I wonder whether the red flag could
be defined as having identified

a major red flag that could lead to the need for further

pre-approval studies to be carried out so that the red flag wouldn\'t
necessarily say you\'re out the door but it might well say you\'ve got
some indications here that really need to be further investigated before
\-- in the pre-approval process before you go onto \--

CHAIRMAN MORRISON: So just to add that it might require further studies?

DR. BYWATER: Further studies in the pre-approval process or further
pre-approval studies.

CHAIRMAN MORRISON: Okay.

DR. BYWATER: I mean, I think that goes \-- it shows us there\'s a
reaction to these initial results without necessarily bringing back this
pass/fail criterion that we thought perhaps wasn\'t appropriate earlier
on.

MR. ANDRES: Remove the word major?

DR. BYWATER: Yes.

CHAIRMAN MORRISON: Oh, okay. Removed the word major and added that could
lead to additional pre-approval studies. Paul. We\'re wearing people
down.

(Laughter.)

CHAIRMAN MORRISON: Other thoughts? So we\'ve had these major sort of
overarching conclusions. I agree with you wholeheartedly, we\'ll get
lost in the minutiae and you want to take away two or three points and
the rest of it\'s all here. Are there other major overarching points
that people share or alternatives, to go back to our question five?

MR. ANDRES: We\'ve got four things. Do you want to review what we have
for five right now?

CHAIRMAN MORRISON: These are alternative approaches/concepts that have
not been considered, one; that in light of everything we\'ve done, we
would like to make sure that the role of these pre-approval studies is
considered in light of the post-approval and risk assessment. I think
there was two, not just post-approval, risk assessment, but if I
remember correctly, it was post-approval, surveillance and risk
assessment.

MR. ANDRES: Well, pre and post versus \--

CHAIRMAN MORRISON: It\'s the role of the pre-approval study process
needs to be considered in light of the

post-approval process and risk assessment.

VOICE: The post-approval monitoring.

CHAIRMAN MORRISON: Monitoring.

VOICE: The risk assessment \--

CHAIRMAN MORRISON: Studies.

MR. ANDRES: Studies. Post-approval, monitoring and risk assessment.

CHAIRMAN MORRISON: Secondly, that something we hadn\'t talked about was
that a bank of organisms might be tested for resistance to provide a
baseline for post-approval surveillance.

Thirdly, that this process could be expedited if new antibiotics that
were going to be used in humans were simply prohibited for
subtherapeutic use. Fourthly, if we could engineer resistance in the lab
to the proposed product and study the mechanism, that might be
revealing.

DR. WHITE: Actually I wanted to make a comment on that \-- if we could
maybe add a caveat and say this may not be possible for all
antimicrobials?

MR. ANDRES: Okay.

DR. WHITE: Under that one.

CHAIRMAN MORRISON: If possible, engineer the resistance?

MR. WHITE: If possible.

CHAIRMAN MORRISON: Other thoughts, alternative approaches that we\'ve
not considered?

MR. SCHUSTER: Can we just go over the first three slides?

MR. ANDRES: All right. That\'s the first slide.

CHAIRMAN MORRISON: You\'ve got me worried. Oh, this first slide. I see
it. Okay.

MR. SCHUSTER: When this is presented, I\'d make sure the yes is what we
were told by FDA and not what \--

CHAIRMAN MORRISON: Oh, yeah. That\'s good. We were told yes. Okay.

MR. SCHUSTER: And maybe the second point could be our view \-\--

DR. McEWEN: Could we say some in the group? I\'m not sure that there\'s
unanimity on that.

DR. SUNDBERG: I was going to say, speak to the same thing, that perhaps,
Bob, when you present this, we don\'t need to put it in there, but our
protocols may be a little bit different than other groups, whereas we
have included statements from individuals.

We\'ve included statements that we \-- everybody\'s kind of nodded their
head at, but at some point, it\'s not a consensus, to point out that we
didn\'t reach consensus on all these and then, so the some in the group
type of thing.

CHAIRMAN MORRISON: Okay. You\'re thinking, Dale, everybody will doze off
after about this point?

(Laughter.)

MR. SCHUSTER: These aren\'t really what \--

CHAIRMAN MORRISON: Biggies; yeah.

MR. SCHUSTER: \-- the messages are and I want to be sure that they\'re
clear and that we review them and agree that \-\-- represents our
consensus and our \-\--

CHAIRMAN MORRISON: Chuck, could you go to the general slides? I\'m
wondering if some of those general slides shouldn\'t be up front,
perhaps right behind our immediate \-- our biggie.

DR. McEWEN: Well, you know, I\'m not so confident that, Bob, you won\'t
be able to emphatically present all of our deliberations here. I think
you will be able to, so \-- I mean, I agree that having a couple up
front is good to underscore them but I \-- we don\'t have so much
information that you will be overwhelming folks, I don\'t think.

CHAIRMAN MORRISON: Okay.

MR. WHITE: There\'s actually an hour and a half scheduled for that.

CHAIRMAN MORRISON: And I\'m assuming you all are going to be there to
\--

MR. SCHUSTER: That\'s twenty minutes a group.

MR. ANDRES: Yes. Well, you\'ve got a minute a slide.

MR. SCHUSTER: I guess I\'m not sure what the first bullet there is. I
thought that\'s what we\'re \-\--

MR. ANDRES: Who made that comment?

CHAIRMAN MORRISON: Was that Steven?

MR. ANDRES: Wanted to have specific workshops on \--

DR. SUNDBERG: Actually what it was was an attempt to get us off the
\-\-- on pathogen load and say if we can\'t reach something, then let\'s
have a workshop on it.

CO-CHAIRPERSON SINDELAR: On pathogen \--

CHAIRMAN MORRISON: Oh, on pathogen load?

MR. SCHUSTER: That was pathogen load. And there was the \-- we should do
it; we shouldn\'t do it; we can do it; we can\'t do it. If we can\'t
decide or we don\'t have the information, then let\'s get the mechanism
by which we can get an informational system to make a decision.

CHAIRMAN MORRISON: Is there a feeling on whether these general slides
should be up front or at the back or do you care? Don\'t care. Okay.
I\'m going to turn the floor back to you.

DR. BYWATER: I think we should also \-\-- above the discretion of
dropping some of these bits and pieces that don\'t fit into the flow of
your presentation. I don\'t think you should necessarily feel you\'ve
got to give every little bit that we\'ve gone through.

CHAIRMAN MORRISON: I\'ll work \-- I\'m guessing Chuck and I are going to
sit \-- and Aleta are going to sit and go through this. Any changes that
look, you know, important at all, we won\'t make. If something just
doesn\'t flow, we\'ll try and make a few word changes, if you\'ll give
us that \--

MR. SCHUSTER: I would like to thank you. I\'ve heard other groups have
not been as smooth. I thought that this was a very good way of bringing
things up and you\'ve got \-\-- I thank you very much.

(Applause.)

CO-CHAIRPERSON SINDELAR: Thank you. We actually have until 12:30. If
there are any other comments, please make them now. Otherwise, we will
go to the task of summarizing this for preparation of \-- you know, at
2:00.

MR. ANDRES: At 2:00, yep.

CO-CHAIRPERSON SINDELAR: And we\'ll all be back in the Regency Room at
2:00. Thank you.

(Meeting was recessed, to reconvene for group presentations, Regency
Room, 2:00 p.m.)