**ANTIMICROBIAL RESISTANCE**

**PUBLIC MEETING**

**PRE-APPROVAL STUDIES AND PATHOGEN LOAD**

**BREAKOUT GROUP DISCUSSION - RUMINANTS**

**THURSDAY, FEBRUARY 24, 2000**

**8:30 A.M.**

**DOUBLETREE INN**

**1750 Rockville Pike**

**Rockville, Maryland**

**Regency Room**

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

**BREAKOUT GROUP DISCUSSION - RUMINANTS**

**February 24, 2000**

[Page]{.underline}

**INTRODUCTION**

by Dr. Gatz Riddel 3

**DISCUSSION/QUESTION/ANSWER** 5

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

**BREAKOUT GROUP DISCUSSION - RUMINANTS**

(8:40 a.m.)

DR. RIDDEL: Okay. I guess we should get started. I appreciate
everybody\'s help and your indulgences yesterday trying to get me up to
speed.

I think what I need today is \-- I really don\'t foresee my role going
down a list of question and answering them one-by-one in my presentation
this afternoon. I look at this as trying to put, from the ruminant
aspect, our best foot forward as to coming up with a workable solution.

Something that will satisfy public health concerns, CVM\'s concerns, and
the industry\'s concerns as well the target animal species\' concerns
for helping derive a pre-approval set of studies.

And so I have got a couple of questions that I need to ask \-- that will
again, to educate me like several I asked yesterday \-- but I think I
would like to hold those until the end.

I am going to need input from people today, just to make sure we cover
all the bases. Right now, in as short a period of time as we can, but as
long a period of time as it takes, to go down through that set of
questions that we have.

And I think that while \-- you know I am new to this and I have always
heard people talking about CDC said this and a CDC proponent\'s saying
this, and our industry\'s being very reactive to that. Last night at a
dinner I was cautioned about using the F word as being not appropriate.
That would be Fred.

But, I think that there are some things that were thrown on the table
that we need to maybe not respond to, but we need to make sure that we
have our ducks in a row as far as answering concerns that if we don\'t
answer them they are going to come back and bite us.

So, I don\'t know if you have your list of questions there, but we will
do \-- I was talking to a couple of the other species groups and they
did proceed down through the questions and I may have gotten us off the
track and not kept us as focused yesterday as I ought to.

And I thought I had some questions answered and in reviewing, I found
out that ignorance is bliss and I was a lot happier before the few
things I learned yesterday afternoon.

I guess the very first thing is, and again this to me from the outset
has been a confusing question. It may be that it doesn\'t require much
of anything, but what are the positive aspects of study concepts
presented?

I assume that everything that we have heard up until just after noon
yesterday, those would be study concepts. What kinds of things can we
take from materials presented that could be positively used to help
construct not a proscriptive, but at least guidelines for information
needed for products before they come to the approval process?

You all can\'t be slow starters again today. I used all the tricks I had
yesterday. We just can\'t do this again. Okay.

DR. GOOTZ: Tom Gootz, Pfizer. It is a good suggestion you have made of
going down the list, but it seems to me to some degree to be reiterating
the discussions that we got into yesterday.

I am wondering, this is an alternative suggestion, to try to get as many
positive and consensus things out of this as we can. Which I think is
your goal as presenting our thoughts as a group.

Can we just \-- I think you have 20 bullets there (indicating), is that
correct? Twenty pieces of information.

MS. HARPER: Yes.

DR. GOOTZ: Maybe we should just, rather than go through, sort of open up
the discussion, just go through those and see if we can distill some of
those down to bullets.

A much smaller group of points and then as we do that, I mean some of
these are going to be open-ended so that we just won\'t be able to reach
an agreement. But, as we pare those down then address the questions on
that set.

In other words, have we satisfied questions one, two, three, four, and
five by paring down and coming up with a list of conclusions or specific
statements from the group. Do you think that might be an acceptable way
to proceed?

CO-CHAIRPERSON HESLIN: Could we ask the group?

A suggestion has been made as an alternative way to approach addressing
these questions. Does anybody have any comments on the approach put
forward? Does that sound like something that would be workable this
morning?

Keeping in mind that I think Gatz may be feeling the pressure that he
has got to have something here by the end of the morning for the
presentation this afternoon. So, we can go with this approach of
revisiting the bullets within the context of the questions?

(Audience is nodding yes.)

DR. GOOTZ: I have one more question to clarify. Is this the only things
that have been written down or that will be entered into our discussion
and our generation of this list of bullets that you will present?

I mean we have been writing I think \-- no, you have been writing stuff
down cause there has been so much said yesterday. What we of course want
to do is as a group make sure that we are all working from the same list
so that our contributions, whether they are well accepted or not, will
be the final sort of list of talking points or bullets.

So is that reasonable and agreed to that what we now will work on is
just that list?

DR. RIDDEL: I will be quite honest, and this makes no inferences to our
scribe, but the way I look at that list is that that is a bunch of
random thoughts that probably defies organization into our bullet
points.

I think we probably need, if we are going to come up with the bullet
points of things we are going to put into the presentation, we have a
lot of information but to construct that we are going to have to start
from ground zero.

Again, that is no negative \--

DR. GOOTZ: Okay. That is fine. Again, that is what we are trying to stay
away from today is yesterday. It was very complex, a lot of good things
said, endless number of issues brought up. But I guess as long as we can
use mainly this and any other specific comments as talking points, that
that is what will end up on the final set of bullets that you will take
forward.

DR. RIDDEL: Can we agree, and I have got a couple, very few,
introductory comments coming down. But to me the overriding factors,
dependent upon perspective, and we probably in this environment need to
take the perspective of public health first.

We have to make sure that whatever we do we can have basic assurances
that public health will not be threatened. Two, I think industry and
practitioners, and regulatory agencies too, but especially to look at my
perspective as a practitioner, we have got some really good tools to
treat BRDs, but its one of those things where, taking the first precept
into consideration you can\'t have too many tools in your armament.

So, we would like to see more products come to market for two reasons.
Should that stop, we are limited on tools and we are not assured a
supportive role by the pharmaceutical industries in the future. Because
once that pipeline shuts down it is going to be very hard to crank it
back up.

So, those are some pretty important concepts for me. And the bottom line
is industry, to maintain their role as a player has to be assured that
there are realistic, logistically feasible hoops that they can jump
through to get the products to the end user, meaning the producer, that
we need.

And now there are some introductory comments that I would like to order
and say these are the points that we need to base all of our discussions
on because if we don\'t do any of those three, if any of those three
falls out, the whole thing falls apart.

So I think we need to consider how we look at pre-approval studies and
how they may factor into any of those three issues, under those three
issues.

DR. GOOTZ: But, if that is presented as a framework, I guess what I am
hearing you say is basically you are looking for a framework that will
allow you to incorporate what is already be discussed and the notes
everyone\'s been taking over yesterday, to make sure all of the points
of view are reflected here.

DR. RIDDEL: I have got another step I would like to take so we can kind
of get on the same page.

DR. GOOTZ: Sure. I mean that is why we are here. I think today we are
trying to build a house and we have to have components that a house \--
got to get it done by 11:00 o\'clock, it has to pass safety codes, we
all want to be able to live in it.

All I am saying is that the blueprint for that house is up there
(indicating) or somewhere in this room. But, when the blueprints are put
on paper as bullet slides, my only point, sort of a point of order, is
that we are going to agree on final bullets here. And that is what your
going to \-- we may not agree, obviously, and that is fine.

I mean you can reject all of the things that we put forward. That is not
my point. My point is though that in this session this morning, we are
going to come to one list of bullets that come from this group. And then
it will be brought forward.

It may not be accepted. Our goal as a group is to make sure that the
house is sound, but the house still may not sell. So, do you follow me
in terms of how we are going to do it?

DR. RIDDEL: Sure.

DR. GOOTZ: Okay.

CO-CHAIRPERSON HESLIN: But, I don\'t think it is a question of being
accepted. I think whatever the group has to say, and it is said here, is
the information that is going to be passed forward.

MR. FLYNN: It is another way of answering the questions.

DR. RIDDEL: Bill, were you going to say something?

MR. FLYNN: Yes. I was just going to comment. First off too, remember
that everything is being recorded in all of the rooms so all of the
comments are being recorded so nothing is going to be missed from that
standpoint.

The purpose of this was really just to get some of the main ideas up
there. And although the questions that were provided in the agenda, they
may not be the best questions in the world or be a complete list of
questions, we wanted some sort of common threads so that when the four
groups got back together again their was some common points that we
could sort of compare across the board.

So, if we could try \-- and I don\'t want to be limited to just those
questions. But if we could try to be able to from each of the groups get
some feedback on each of those questions. Then we would have some way of
comparing different opinions across the different groups.

DR. RIDDEL: But we don\'t have to go down one, two, three, four, and
five? It can be incorporated in the body of our response?

MR. FLYNN: Yes. I think if you can identify \-- as long as we are able
to tease out of there where that question was addressed.

DR. RIDDEL: You have got to understand, I work in a university and our
greatest tactic is confuse and conquer. That won\'t work here. I was
hired under false pretenses.

MR. FLYNN: I mean it is up to you as to how you want to proceed. But if
we could try to at least be able to get some response on those questions
that are on the agenda to some degree so we can sort of compare notes
with the other groups to see where opinions differed on certain items.

And then you can embellish as much as you like with other points that
you think are important.

DR. RIDDEL: Okay. Now, Dr. Flynn, everybody else had the task yesterday
of trying to educate me. And while you are here, I will have to ask you
to do that.

There are a lot of things I don\'t understand about the approval
process. One of which is the concept of pivotal issues or pivotal
points. Should for some reason all four groups propose that it is
critical that each sponsor for every product they put forward has to
have information relative to rate of mutation, whatever 10^-8^ means,
and let\'s say that CVM accepts that as an acceptable tenet whereupon to
base part of the approval process.

Will that become \-- and this is for my edification

\-- will that therefore become a pivotal point and therefore be a
pass/fail bar that they have to pass at some point in time? Or has is
that used? That is just for me. Everybody here probably understands.

MR. FLYNN: I think the simplest definition that I can think of would be
that basically if it is a piece of information that we said we need to
have in order to make a decision for approving the product, then
essentially it is pivotal for the package.

If it is just additional information that we could make a decision with
or without then it is a non-pivotal piece of information.

DR. RIDDEL: I am assuming, that after probably the most common comment
that pertains to my next question, is that nobody feels that one-size
fits all. In other words, we can\'t describe a prototype package for
pre-approval studies that everybody can make any upcoming product fit.

How will the framework of the general concept pre-approval studies be
viewed as needed information, extra information, pivotal or not?

MR. FLYNN: Well, I think the concept, and that is right I mean I don\'t
think there is one study that fits all. And even the framework, the
concept there is that not all applications would necessarily require the
same level of information.

And I think I said in my talk that there may be certain applications
that don\'t require any specific studies. So, it just depends on the
particular use and class of drug.

So when you are thinking about the study it is not that this is one
study that every application for an antimicrobial product to be used in
a food animal would have to do that study.

I think we just want to open this up to what are all the different \--
what types of information would be helpful to try to address the
question. Then we would have to get into the stuff: when is it necessary
to apply that? When do we need to use that piece of information.

DR. PETRICK: Yes. Dave Petrick from Schering- Plough. Bill, I will ask
you and maybe some of the other folks from CVM here. Now industry
obviously has had a lot of discussions about this and how do things fit
and where are they as part of the approval process.

And, I guess what I would look at is some of the things that I am
getting out of this. And again, as not being a microbiologist, but it
just strikes me that there is certain information that we can collect
that for an antibiotic seems like it is something the Center would want
to have at some point in the review process.

I guess we can, or at least I am not getting the sense from what the
microbiologists are saying, that it can be much more pre-approval other
than either kind of the idea of a benchmark or information that should
be there at the start of the process to help with the post-approval
monitoring aspects.

So, when I look at it from my point of view or my perspective of
regulatory affairs, the question I always think of is how does that fit
in the process? And where does it go? One of the things that I was
turning over in my mind last night, it does relate to the
pivotal/non-pivotal aspects of this.

It seems to me that since we seem to be coming up with the idea that
this is data whether it is MICs or mutation ability or mechanism of
resistance development, that pre-launch all you can do is say this is
where it is right now. You can\'t put it in the concept of pass/fail.

If you do that, one of the things that I can think of that it sort of
fits with, is the batches that we run at the site of manufacture,
pre-launch. In other words, validating the process at the site of
manufacture. Well, you don\'t really need that pre-approval, but you
have to have it pre-launch.

I think in some aspects this data are the same kind of concept we are
dealing with here now. I think in this case it is going to come very
early on because the sponsor is going to want to know this information
early on in the process.

But, I think it is almost not that it is pre-approval, it is sort of
pre-launch materials that we need to have to assist in the post-approval
monitoring. I think we saw a lot of interesting things in the last day
and one-half of studies that could be run, studies that are under way.

And we seem to be collecting a lot of good information, but I don\'t
think the body of knowledge is there right now to be able to say it is
predictive of what the course of resistance development is going to be.

So I think if you look at it in that context and trying to put that into
the framework of approval, I think what I look at is there is
information there that the Center may want to require pre-launch, but
that we don\'t necessarily as tied directly to the approval of the
product from a safety and efficacy standpoint.

But it is something that the sponsor has to put forward so you can get
into a good post-approval monitoring framework. I don\'t know if that
makes sense procedurally, but in my mind it kind of seems like a good
place to slot it in the process.

At least with where we are right now with the state of scientific
knowledge that we have. And just Mr. Chairman, one point. I think from
the way these things generally run, I think you want to be able to go
through, at least in your mind, how the responses are to those five
questions.

And the last question they give us an opportunity to say what other
proposals would you make and I think that is where we can come up with
the bullets of what we think we digested out of the five. But, I think
it would be a good idea as Bill said, is to help the Center compile
this. If we could still address maybe those five issues at some point or
another. Even if they are addressed in a very, kind of simplified
manner.

CO-CHAIRPERSON HESLIN: I still wonder whether the blueprint has been
agreed upon. Because I am thinking that if there is this framework or
blueprint to sort the comments already and to have a home for additional
comments so they don\'t just get lost in a running list of things.

DR. SHRYOCK: Yes. I would like to request that the scribe record Dave\'s
comments. I think they are spot-on. If this is to be a pass/fail pivotal
type of study, then the amount of extra study that is going to be
required to establish in vitro as well as in vivo studies is tremendous.
And probably will be rate-limiting.

So, I would like to request, whether it is slide 21 or up to 30,
whatever it takes, to capture those comments. I think that is essential.
If we then want to go through and talk about in vitro studies, there is
quite a number that we could begin to discuss, pro and con, limitations,
bugs, answering these questions.

We can do that. And I think what we will come up with is that these will
not be predictive. They will be highly variable. They will be
tremendously complex and of uncertain value. We can do that with the
animal studies as well.

We can list all of those points if you want to spend the time to do
that. I think we have got a great start with some of the speaker\'s
presentations.

So, my suggestion would be that if we can decide how to use this
information and it should be interpreted up front, whether it is to be
pivotal or informational. And then if it is informational or
supplemental, whatever we want to call it, then we have got to rely on
that post-approval surveillance system as the safeguard.

And that is yet another workshop to be held, I am sure. So that would be
my suggestion. If we get this pivotal issue up front and then we can go
into in vitro studies, list a bunch of those out, pros and cons. Do the
animal studies, pros and cons. That should take us through the
discussion.

DR. RIDDEL: I would like to point out as you make these comments, you
need \-- everybody should understand where I am coming from. For me to
get up and talk about pivotal studies and in vitro studies and in vivo
studies is a joke. And so we are going to have to couch things in a
framework that I can have some credibility to get up there and make
comments.

Because I don\'t have the background to talk about a lot of things that
you all talk about. Period.

MR. HALLBERG: John Hallberg from P&U Animal Health. I guess what I go
back to is a suggestion I made yesterday in that we need to provide
information. And it will be \"pivotal\" is suppose that we, as a
company, bring forth mechanism of action of the antibiotic, in vitro
potential for resistance generation, either literature or in vivo ideas
of cross-resistance.

And then use our understanding of compound metabolism, PK/PD to define a
good efficacy plan. Have an idea of baseline MICs for the target
pathogens and some of the select zoonotics. And then have a definition
of \"sensitive\" for MIC testing in the future.

And then what this allows us to do is to define a plan to use a new
compound, and this is a truly compound based thing. It is not one-size
fits all.

So, if we come in with a beta-lactim, a macrolide, or a fluoroquinolone
it is going to be compound-dependent. And then at the end of the day you
are going to sit down with the agency and work out a plan on how to set
up the post-approval monitoring.

But, basically no compound is off the table when they come in the door
because in theory, from what was said, if you can show a proper use of
this compound that does not generate adverse effects in zoonotics or
potential human resistance on human therapeutics, then that compound
should go forward.

So, I am proposing that after seeing everything that went on yesterday
and I will open that up for discussion.

DR. SHRYOCK: Tom Shryock again. Slide 21 is getting better, but we need
to really do a lot of wordsmithing on this.

MS. HARPER: Okay.

DR. SHRYOCK: Okay. So, let\'s start that process. In vitro pre-approval
studies should be informational and non-pivotal.

MS. HARPER: Okay.

DR. SHRYOCK: That would be my suggestion. Comments from the group?

DR. PETRICK: Tom, why don\'t you put in there a sentence as to why you
believe that to be so.

DR. SHRYOCK: Okay. The reason this should be informational is because
the studies, both in vitro as well as in vivo \-- in vivo studies being
pathogen load, and in vitro resistance selection \-- are highly
variable. They will not be predictive of protecting public health.

And the need to establish baselines for post-approval surveillance can
replace these studies. Comments?

DR. PETRICK: I think that is the answer to the first question.

DR. SHRYOCK: Okay. That is good.

DR. RIDDEL: He\'s going to take over.

DR. SHRYOCK: No, no.

CO-CHAIRPERSON HESLIN: If that is the answer to the first question,
would it be helpful to list the questions and sort this information that
is appropriate to the question so there is some framework for presenting
it this afternoon?

DR. GOOTZ: Tom Gootz, Pfizer. Can I make a suggestion?

CO-CHAIRPERSON HESLIN: Sure.

DR. GOOTZ: It might sound a little dumb, but it might work. As you are
scribing here, now we focused \-- thank God down \-- on a very specific
issue. Can you italicize that bullet so we link it with question number
one?

We may need two, three or more bullets that are all linked to question
number one. I think we are making progress here.

First of all, \--

MS. HARPER: Is that okay?

DR. GOOTZ: Yes, that is better ideas. So we will stay focused like a
laser beam as the president says on the first issue as to question
number one.

I would like to \-- and don\'t write this down in terms of adding to
Tom\'s bullet. But I would just like to say that hopefully the ultimate
goal in pre-approval studies as many people have said is to establish a
very good, hopefully credible scientifically-based information or
baseline of microbiology data from which post-surveillance studies that
Bob has suggested and talked about, can spring from.

So, where was the drug with respect to it is potency against field
isolates before it was approved? A little bit about mechanism of action.
Mutation frequency, things like that. The four talking points that the
CDC mentioned yesterday. And make that as information in the submission.

My point is, again you brought the pivotal versus required or
informational issue, and that is very important. There probably would be
a movement to make all of this stuff pivotal.

But, my comment is a lot of these things like microbiology or a PK
number, an AUC, I don\'t see how that can be a pivotal thing. Who\'s to
say that a compound with an AUC at a certain dose of X passes, whereas a
similar compound with an AUC of Y against the same indication is okay?

On a level playing field, if that is the case then I think we should do
as scientists. Do good microbiology studies to establish a baseline.
That gives a lot of information. But I don\'t see how mutation frequency
can be pivotal. I mean I really don\'t.

Number one, you are going to get one, so you will have a number.
Hopefully more than one number looking at your key zoonotic pathogens
that you are concerned about. We are all concerned about.

But I don\'t see how just setting down a yes or no approval as a pivotal
study for a mutation frequency is really defensible scientifically or
really has that much of a precedence in the organization.

MS. HARRIS: Sorry. Mary Harris from Pfizer. I think that kind of goes to
question number two: \"What role does the data play?\" And I think it is
pretty clear that we think it is non-pivotal to an approval decision,
but it is important information for establishing baselines for
post-approval monitoring.

MR. WATTS: Jeff Watts, P&U. Just to kind of put a little different
perspective on this. This is not one-size fits all for the simple fact
that none of the companies that are working in this area are in the \"me
too\" business.

Even if we are working in the same class of drugs, we are looking for a
competitive advantage with our particular compound. So those compounds
may break the rules to some extent. And so that is why we have to have
some flexibility and you have to keep things open to allow for the
different characteristics of drugs, even if they are in the same class.

CO-CHAIRPERSON HESLIN: Would it be helpful to go back through these
comments and have these people decide which comments really go with
which question?

DR. RIDDEL: Yes.

CO-CHAIRPERSON HESLIN: I was just going to suggest that at some point
here maybe what we could do is go back through these comments that were
made yesterday and so far today and try to relate them to a particular
question. To put some form and structure to this.

I think it would be helpful in terms of the presentation to make sure
that the comments you are making are roughly related to the questions
and it is categorized in that way. Does that sound like a reasonable
thing to do? Go back over the list?

DR. SHRYOCK: Not yet.

CO-CHAIRPERSON HESLIN: Not yet. But at some point?

DR. SHRYOCK: Maybe later.

CO-CHAIRPERSON HESLIN: Yes, at some point. So you still just want to
generate the comments at this point and then go back?

DR. SHRYOCK: I think maybe it would be helpful \-- we have got some
momentum going here on some of these potential pre-approval studies.
Maybe if we go through some of those we can talk pros and cons that are
the questions that we need to address.

And we will back fill that way, then we can go back through slides 20
through number 1.

CO-CHAIRPERSON HESLIN: Okay.

DR. GOOTZ: Tom Gootz from Pfizer. To that end, then I guess keeping like
on bullet number 22, it mentions what a pre-approval study should have
in it, what it should include. You have mechanism action, which is
great. We discussed that. Some assessment of cross-resistance. That is
great.

Mutation frequency, compound metabolism, PK/PD, baseline MICs, a
definition of sensitivity \-- there you mean susceptibility, hear my
ears susceptibility instead of sensitivity.

And at the end of that sentence just for clarity, I think we are talking
about both field isolates and a reasonable number of zoonotic pathogens.
Aren\'t we?

DR. PETRICK: No, target organisms.

DR. GOOTZ: Oh, sorry. Target organisms and some zoonotic pathogens.

DR. SHRYOCK: NARMS isolates.

DR. GOOTZ: NARMS isolates.

DR. RIDDEL: The concept of having susceptibility studies for target
organisms is not a public health issue, right? That is an efficacy
issue?

DR. GOOTZ: It is. PK/PD could be considered that too. Again, I think
what we are trying to do is bring a body of information to CVM to
characterize the compound. Because that was something that was mentioned
yesterday several times.

We as sponsors are supposed to characterize the compound. And as was
pointed out a minute ago, even compound mechanics within a class
hopefully are going to have some pretty different characteristics.

So, while some of these things don\'t necessarily address the safety, it
gives you we think a better picture in total of what the compound is and
what we hope it will do in respect to efficacy.

So, other things that could be compound mechanic specific, we might
determine levels under the metabolism, levels of drugs in feces. And
also the degree of binding of the drug to fecal matter. Since that is
sort of the PK area with the zoonotic pathogens that you are concerned
about.

And just a piece of information, without the extensive studies, just
some idea of what the levels are there.

Somebody yesterday pointed out, I think it was from the CDC, that in the
zoonotic pathogen group. And we will just use E. coli since it always
seems to be genetically the best characterized. That it might be useful
to look at susceptibility of the new product against genetically defined
zoonotic pathogens, meaning E. coli.

With the idea of getting understanding in a known genetic background,
with one resistance mutation to the class. Let\'s say it was quinolones,
after the standard Chart A type of mutation. What that does in terms of
the MIC? Again, that is all pre-approval. It is a baseline of
understanding.

So, the idea was \-- and this can be a separate bullet \-- some limited
testing and genetically defined zoonotic pathogens that have known
mutations in them.

Again trying to move forward on some of the microplates. Other people
probably have \--

DR. SINGER: Randy Singer, University of Illinois. I don\'t know a lot
about what industry currently does for instance assessing
cross-resistance and mutation frequency, but I can see that written that
way, in a very general and loose fashion it could end up being a real
weighty exercise.

If you had to go out and look, almost in a monitoring effort, for every
mechanism that might exist that would confer cross-resistance or any
kind of mutation that you can\'t induce in vitro but that might already
exist and can be transferred in confer resistance. Some might interpret
those ideas, assessing cross-resistance and mutation frequency as a
major endeavor.

And so I am not sure, without really specifying clearly what that
entails, I am not sure anyone would want to get into that mess.

DR. WALKER: Bob Walker, FDA. When you are determining the baseline MICs
and definition of susceptibility, I think one of the things that needs
to be tied very, very close to that is the quality control guidelines or
quality control ranges for your compounds against quality control
organisms.

An example of this is it is my understanding that florfenicol was taken
off the NARMS list because there is no interpretive criteria for E. coli
on it. And so if you had the quality control organisms and the ranges
for those organisms then you can validate your MICs and generate your
susceptibility data. But without that there would be the potential for
considerable variation from laboratory to laboratory.

CO-CHAIRPERSON HESLIN: Your earlier comment about one of the statements
up here being rather broad-based and a concern about that. Is there some
alternative language or something else that needs to be up there?

DR. SINGER: For now maybe it works because this is simply a bullet list.
I am just thinking in the future as a working document it could end up
being a real open-ended type of study that the industry would have to do
to get the drug approved.

DR. SHRYOCK: Just to follow-up on Randy\'s comment and use Tom\'s
analogy here. Maybe we are deciding what kind of house we do want to
build today. And maybe we have decided that we want a two-bedroom
instead of a four-bedroom house.

This probably will mean we are all coming back to Rockville, Doubletree
for another meeting to perhaps define some of these particular general
types of studies in a better way from a microbiological or animal
science perspective.

I think perhaps that is beyond our immediate charge today, so perhaps as
a sub-bullet within 22 that we should have something to the effect that
further discussion and definition of these particular types of studies
will be required.

And, as a component of that a literature review would be implied or
necessary. Because I think there is a lot out there that we don\'t have
to go out and find new genetic mechanisms of resistance for macrolydes
for example. There is plenty of them out there. How hard would one have
to look when there is already a plethora of information out there.

CO-CHAIRPERSON HESLIN: But further study, for purposes of this list,
would capture it?

DR. SHRYOCK: I think that would suffice on my end, yeah. I would
certainly open \-- and it is way beyond us to talk about how we are
going to mutation frequency studies in a few hours today. There are so
many variables. But we can decide those kinds at a later time.

DR. SINGER: Randy Singer. One thing that I think would be useful since
the post-approval process for one drug directly would influence the
pre-approval of a following one would be maybe for FDA-CVM to be the one
to maintain some sort of database that keeps apprised of what the new,
what the literature reports in terms of new genetic mechanisms
identified for resistance, etc.

Because that would influence how post-approval monitoring is done as
well as what types of systems need to be addressed for a pre-approval
study in a future situation. But having some uniform database of what is
out in the literature as well as maybe what doesn\'t make it into
literature I think would be useful.

Maybe that is just again being naive at this point. But I think it would
be useful.

DR. RIDDEL: The final endpoint of any approved product, as far as
determining when mitigation steps have to be taken will be the
post-approval monitoring program.

And in that regardless of what compound you put up, the nearest
pertinent human antimicrobial is the test product for
susceptibility/zoonotic pathogens in the NARMS program? In other words,
they don\'t use enrofloxacin, they use ciprofloxacin?

Is there any validity, since this work\'s going to have to be done
anyway, of entering in a blinded fashion a product into this program
before it is approved so you are generating data and you make a smooth
transition into the post-approval monitoring program?

You identify this as the type of compound you\'d have to put out
information \-- relative to that if you are going to give it
characteristics, metabolism beforehand and since you don\'t have to use
the exact product, then proprietary information may not be a stumbling
block.

Could that be entered into, obviously it is not post-approval, but could
that be a pertinent, relevant information gathering system that is going
to impact it? And if the product is not being used, you are really just
collecting baseline data until it hits market. Right or wrong?

(People nodding yes.)

DR. RIDDEL: Unless there is some other fact or some other antibiotic
which is causing resistance patterns to that class of antibiotics.

I was just wondering, because that came to me last night and I figured
it was really naive.

DR. GOOTZ: Tom Gootz, Pfizer. That sounds reasonable. I am just
wondering though if there are a lot of new products coming on line or at
least being submitted, put it that way, would NARMS have the capability
of adding sort of all of those that would be in development?

And if they are limited \-- again, I have no idea. This would be their
issue. If they were limited in any way would then that stop timely
introduction of a new antibiotic into that system? I don\'t know.

DR. RIDDEL: But, that baseline data is going to have to be collected
somehow, right?

DR. GOOTZ: Well, NARMS has a large database obviously for the fresh
field isolates which is what we would be doing in industry. The concept
sounds reasonable. I am just wondering if they would agree to putting
them in.

And whether that is the correct vehicle for us to college that data. I
don\'t know.

DR. RIDDEL: Well, if for example another fluoroquinolone was being
considered, would they have to change what they are doing if they are
using ciprofloxacin as the test antimicrobial for evaluating resistance
to those pathogens?

DR. GOOTZ: No, it could be \-- I thought you said you wanted them to try
to add your drug to our drug \-- maybe I misunderstood you.

DR. RIDDEL: Well, I guess I was reading something last night that they
don\'t add your drug, they add \-- they do add your drug?

DR. GOOTZ: No, I am agreeing. That is right. They use cipro.

DR. SHRYOCK: It is cipro. Perhaps \-- Scott\'s here he could probably
tell us all about this.

It is feasible to do what you are suggesting Gatz, but the logistics in
there may be a little tricky. It may be sufficient that that would be
one of the things that we would want to further define within the use of
NARMS data.

For example, if a new product is going to be used in poultry, you go and
you request as a sponsor X number of poultry isolates over a period of
years to get a baseline. And you test those strains in-house.
Alternatively, if it is a compound of a similar class you could just
look at the data.

In order to insert a new chemical entity into a NARMS panel, it is my
understanding that it would take at least a year\'s lead time if it even
fits logistically within a 96 well panel. And there are some constraints
there.

And why should sponsor A be favored over sponsor B if you only have one
slot? There are some potentially technical issues along those lines that
could ensue.

So perhaps just using those isolates in some fashion would suffice to
get the kind of information pre-approval that we need if it is a new
class or one that is not currently being evaluated. Just as an
alternative idea.

Scott, I will put you on the spot if you care to be on the spot.

DR. EWERT: Good morning. This is Kathy Ewert from Bayer Animal Health.
Just a follow-up to what you are saying there Gatz.

The problem that I can see with the NARMS panel right now for example
with cepholosporins or with fluoroquinolones would be if a new
generation of those products came on to the market which is what is
happening now. We are into fourth generation fluoroquinolones.

And those products for example have a broader spectrum of activity and a
different set of MICs would be generated for those compounds. Different
breakpoints, excuse me would be generated for those compounds over
ciprofloxacin.

And so then at some point the NARMS panel may be changed from
ciprofloxacin to a fourth generation fluoroquinolone that is being used
more commonly. And it might be unfair to compare a fourth generation
fluoroquinolone with ciprofloxacin that is on the market as a third
generation fluoroquinolone.

So I think that is a dynamic process that could change. And one of the
things that I mentioned in my presentation was that perhaps we should
look at more than one drug within the class. Because even though you
confer cross-resistance, that resistance is at a different level.

Fluoroquinolones \-- within the class you can see resistance, but there
is different levels of resistance and so that needs to be addressed
somehow.

CO-CHAIRPERSON HESLIN: Any other comments? I am sorry, you needed
something clarified?

MS. HARPER: Yes. The last comment, I don\'t know if I captured it
correctly. Could you look at that?

DR. EWERT: I am sorry?

CO-CHAIRPERSON HESLIN: The last comment, whether that reflects in
essence what you said.

DR. EWERT: No, I didn\'t say it may not accurately reflect. I said it
may be necessary. And that more than one compound within a group may be
necessary to accurately reflect what is going on. Do you agree with
that, Tom?

DR. SHRYOCK: Yes. I think that is a positive \-\--

MR. LADELY: Scott Ladely, USDA. I don\'t think we need to dig into this
too deep because it is burning our time.

What we are currently doing is we have 17 spots on a plate. That is a
big limitation. We are not looking at macrolides at all because we
don\'t have enough spots on the plate.

Every year they are evaluated. We try to represent animal and human drug
classes that are currently being used. We maybe need to look at doing
more than one plate for each isolate.

They are evaluated annually and adjusted. Maybe we need to drop off some
of the older drugs that have resistance because we know they have
resistance.

But we need to move on to discuss these other issues instead of the
flaws in the current monitoring system.

CO-CHAIRPERSON HESLIN: Any other comments? I think there are a few folks
here we haven\'t heard from in the last day and one-half or so. So, if
you have some perspective or some input, feel free. This is your
opportunity.

(No response.)

CO-CHAIRPERSON HESLIN: Is this then the point to go back through the
list?

DR. RIDDEL: I guess go to the top of the bullet points and we can just
\--

CO-CHAIRPERSON HESLIN: Yes, I think we are going to do that, but the
question is do it now or later and I am not hearing any other comments.
That is why I am wondering whether it is now.

Do you all need time to talk among yourselves about some of these
issues?

DR. GOOTZ: I don\'t know. There are other issues that you mentioned that
you want to move on to. Do you want to be any more specific?

MR. LADELY: \-\-- what we are doing as far as monitoring \-\--

DR. GOOTZ: I know.

CO-CHAIRPERSON HESLIN: Can you suggest our next step to move forward?
What would you like to discuss next?

MR. LADELY: Back to the list. Try to work them out.

DR. GOOTZ: Well, let\'s do this \--

CO-CHAIRPERSON HESLIN: Maybe by revisiting the list that is going to
expand the discussion as well. Can you shoot up to the top?

I guess what we are doing here is looking at these earlier comments or
suggestions trying to, maybe if necessary, force fit them to a
particular question and making sure the comment is reflected the way you
want it reflected as a group. And if there is a minority view or
whatever we can add it as well.

What question would this first bullet be related to?

DR. VAUGHN: This is Steve Vaughn at CVM. Let me try to help this a
little bit. The first three bullets get to that and I think slide 21
that Tom wordsmithed are really the first parts of this.

CVM needs to have what would be considered pivotal information submitted
in the pre-approval phase of drug development. That information would be
used to make a decision as to whether or not there was an adequate basis
to go forward to approval.

I think what we are hearing is that that information would not be
predictive of whether resistance or loss of susceptibility would reach a
public health level or not. So rate and extent would be hard to do in a
pre-approval decision.

But, nevertheless there needs to be information submitted upon which the
center can make a pivotal decision as to whether it has adequate
information to go forward with the approval of the product. And that
speaks more to the completeness of the package then it does the
predictive value of the content of the package.

So, if we can focus I think a little bit more on what needs to go into
that package that would be of value, much of that information I think is
already being generated by pharmaceutical companies in their discovery
phase. And we take a look at that kind of information.

I think that really gets to the point of the five questions.

DR. EWERT: Kathy Ewert, Bayer Animal Health. There was a discussion in
another group about pivotal versus non-pivotal studies and perhaps Steve
you can give us the agency\'s take on what pivotal involves.

It is my opinion that if a pivotal study is submitted it has to be
accepted by the agency prior to approval of that compound. Whatever the
pivotal study is. For example, efficacy. There are certain criteria that
the agency looks for for acceptance of those studies and acceptance of
that phase component.

This is what we are looking for, is some kind of direction. If indeed we
have to do these studies, what are the factors that the agency sees need
to be evaluated so that we can move forward.

DR. VAUGHN: Well Kathy, you missed the point. Bill, before you came in,
defined pivotal.

DR. EWERT: Oh, I am sorry.

DR. VAUGHN: And to the extent, just to reiterate it, pivotal is merely a
term that we use. It is nowhere in the law or the regulations. It is
just a term that we use that is information upon which we will make a
decision about the approvability of a particular product relative to its
safety and effectiveness.

Now, what kind of decision we make doesn\'t make it pivotal or
non-pivotal. I hope we don\'t get hung up on that. It is pivotal in the
sense that we need to be able to say we have an adequate basis to ensure
the safety and effectiveness of the product in the post-approval
environment.

And what the scientists here are telling us, as I am hearing it and you
guys can correct me certainly, is that the kind of decision that would
be unacceptable would be one that would be predictive.

On the other hand, the kind of pivotal decision that we would make is
there adequate information in the file that this product can move into a
post-approval environment.

But there needs to be a pre-approval package and what are the elements
of that package or the attributes of that package? And that may include
studies of various kinds that give us the kind of information that
builds that base of information.

DR. GOOTZ: Tom Gootz from Pfizer. Just a clarification. If we didn\'t
submit anything for the compound that would be pivotal in the sense you
would say there is nothing in the document, therefore our pivotal
judgment is to refuse to accept the compound, right?

So we are going to put things in the submission, we are going to do
studies. We are going to try, I think, as sponsors to do good
microbiology studies. Ones like described generally on Tom\'s slide.

The problem I am having, maybe because I am missing the point, is you
guys keep saying pivotal and in our minds that means that there is a
quantitative link to it. A better way is data should be, and what we
have done which should address the pre-approval issues for you, industry
and the League of Concerned Scientists and congress, is that we are
going to put together a very good package of microbiology data including
pharmacology data like for PK.

All of these things we generally mentioned. And you could call those
supportive studies. You could call those the types of the studies that
you would require for competence and good faith to review a package.
Which is what they say in the human health side.

And you may want to ask us to do more stuff because of the pressure you
are getting from all of these other groups with respect to the concerns
over zoonotic pathogens. Which we will certainly try to do that and put
those in that package of studies that are called required.

But, unless I missed the point, and I probably have, the word pivotal to
us implies a heavy burden in the sense that there is a quantitative
assessment to it. It isn\'t a term that we are used to thinking of in
terms of well, you checked all the general boxes, we see things in the
submission, so we are ready to go.

Pivotal to us means that if we say that cipro as an example frequency of
resistance mutation in salmonella typhe and you name the strain, is
under a standard test done in three different labs. If that mutation
frequency is 1.5 to 2.5 times 10^-8^ and we, with our new same class
compound, get a number that is 6.5 times 10^-7^, a pivotal study would
say thumbs down.

What the scientists have been telling you and some of your own folks and
even the CDC yesterday are trying to tell you that that type of
microbiological data, you can use any word you want. It is not
predictive, it is variable, it is this, it is that.

They are trying to tell you that there is not a black and white, yes or
no data based on microbiology so why are we calling it pivotal? Why are
we calling it pivotal because unless I am missing the point pivotal
means pass/fail.

DR. VAUGHN: No.

DR. GOOTZ: No it doesn\'t?

DR. VAUGHN: No. Pivotal, and we are getting hung up on terminology here
and we are not going to have a report for Gatz if we are done. Pivotal
merely means that we are going to make a decision, we need that
information to make a decision.

It doesn\'t say what kind of decision we are going to make. It doesn\'t
mean it is going to be pass/fail. It doesn\'t mean we are going to go
thumbs up/thumbs down. And that is the purpose of this workshop.

And part of the what information is of value? is one thing that we are
trying to derive from this workshop. But it also comes with
qualifications as what kind of regulatory decision can be made in a
pre-approval mode.

Even though it is still pivotal, it is information we would require to
be submitted. The type of decision comes from the caveats and
qualifications that you folks are giving us to put around that kind of
information.

Does that help?

DR. GOOTZ: No.

DR. RHODES: Can you give us an example of an alternative decision that
wouldn\'t be pass or fail?

DR. VAUGHN: I think, you know obviously we are going to need to have,
and I can\'t say whether we will or not, but it is becoming obvious to
me that we need a post-approval workshop to talk about what is the
structure under which antimicrobials would be marketed.

That wasn\'t stretching very far at all was it? You don\'t want to do
it. All right.

But, within that scheme we need to know what information is going to be
important pre-approval. And whether or not we made a decision \-- let me
try an example. That might be the easiest way to do this.

For labeling we use in vitro microbiology information. We use
pharmacokinetic information. The type of decision we make there: is it
accurate, was it done in a fashion we believe they are real numbers. But
do we say based on the blood level profile or the MIC data we are not
going to approve that product? No.

So even though that information is pivotal for labeling, it is not a
decision where we say yes the product is approvable or no it is not
approvable. But we are looking at the voracity of the information we are
going to put on the label.

So there is different kinds of decisions that are made even though it is
pivotal. So let\'s try not to get hung up on the term pivotal, but
let\'s focus on what is the kind of information that is important to
have and how should we use that information in a pre-approval regulatory
environment.

DR. EWERT: Kathy Ewert, Bayer Animal Health. I think what we are all
trying to envision as scientist here working in the development process
is that we need to be able to focus on something and we have to have a
finite end to this.

What I hear you saying, Steve, is that well you can submit this and this
and this study and we will take it under advisement. And we will
consider it and see if it meets our requirements. And I just feel like
\-- I have this recurring dream where I try to get somewhere and I
can\'t get there. I mean \-- really, I do have that dream.

And I am having that same sort of feeling. That well, we will meet this
requirement but then another door opens and whoops, there might be
something else we have to do. And I think what we are looking for,
whether we call it pivotal or non-pivotal or required or whatever, we
are looking for those end points so that we say well, if we do this
study and it satisfies the requirements, then we can move forward.

For example you used pharmacokinetic data. Well, that is a very
quantifiable study and we know as companies that if our pharmacokinetic
data isn\'t good we are not going to move ahead with development. We are
certainly not going to submit it to the agency.

So I think \-- anybody else want to chime in here? I think that is what
we are looking for.

DR. PETRICK: Well, I will disagree with Kathy on this one.

DR. EWERT: Uh-oh.

DR. PETRICK: Because I think I understand what we are getting at here.
In the context of if the study is reproducible, then it is a valid
study. So, the label for MICs or the label for the C-max and the AUC is
what it is. If it the study in the reviewer\'s mind is a fair
representation of what would go on the label then you have met the
criteria.

And it was pivotal from the concept of the fact that it was on the
label. And the Center isn\'t going to allow it to be on the label unless
they use that as part of their decision-making process. It is like the
SBA on the human side. And it could appear in the FOI, there is no
reason it couldn\'t. Because again, the Center used it as part of their
decision-making process.

So, I think if we go back to point 21 that we worked on, I think that is
kind of what we are suggesting are the studies. So what we give as a
sponsor is MIC data. What the Center says is well, was the MIC data
generated accurately? Would it be reproducible? Is it done in the
appropriate manner?

If the answer is yes, it is what it is and it is not a pass/fail
criteria. It is just there. Just like the kinetic data. Was it done in a
reproducible manner? Is it a fair representation of what the product is
doing to target species? And if it is it is there, it is not a value
judgment of it ought to be better or it ought to be higher or it ought
to have a higher C-max or anything else. It is just there.

It is pivotal from the standpoint that it went into the decision-making
process. And I think it is a decision-making process is it here or is it
isn\'t here? So the pass/ fail is nothing more \-- and correct me if I
am wrong \-- but I think the pass/fail is nothing more, if we agree that
for an antibiotic there ought to be MIC, there ought to be PK, there
ought to be \-- it is a question of it is present or it is absent and I
think that is the pass/fail as opposed to it is a certain number.

Is that what we were \--

DR. VAUGHN: \-\-- caveat \-\-- putting in the record if we feel that
something should not be \-\-- predictive decision.

DR. PETRICK: Right. And I think that is what we are getting at. I don\'t
think anybody, at least from the discussions we have had in this room
and then discussions we have had out of this room. It just strikes me
that what we are getting at is no one saying we have got a predictive
mechanism or predictive studies right now, but you can put these items
out here and post-approval those items would help you make a decision.

So, it makes sense to us that they become there \-- they are submitted
and when we move on from there, post-approval, into the processes as you
said what do we do down the road post-approval? Which is probably going
to be the subject of another workshop.

I think it makes sense that you move ahead in a logical fashion. If we
can get to the point where we say right now we are not science \-- it is
not we, but science isn\'t at the point where we can do model studies
that are going to predict rate and extent of resistance development.

I just don\'t think we are there. I think there is a lot of good
information that can be generated and interesting things to pursue
scientifically, but I don\'t think there are things that we should be
pursuing from a regulatory, pre-approval standpoint.

DR. EWERT: Steve, I don\'t disagree with you at all.

CO-CHAIRPERSON HESLIN: Could you step to the microphone please when you
speak, we are trying to get this recorded.

DR. EWERT: Kathy Ewert, Bayer Animal Health. I don\'t disagree with you
at all. I think that is correct. But there is a finite amount of work
that needs to be done and that is I think what we are looking for.

DR. PETRICK: Right, and I think that is point 21.

DR. EWERT: Okay.

DR. PETRICK: I think that is the list of studies \-- I think that is
what we are saying is the package of information that gets put in that
either it is there or it is not there. Or, and we can go a step beyond
going back to a comment over here.

You have a discussion with the Center that says for this compound, for
these reasons it is accomplished in this manner. It isn\'t necessarily
additional work because there is plenty of literature information that
says this family of compounds does this. So the Center says yes, there
is a literature reading that accomplishes that.

DR. EWERT: That is fine.

DR. PETRICK: Is that \--

DR. GOOTZ: Tom Gootz, Pfizer. Just quickly. So, to cover bullet 21, the
microbiology doesn\'t seem to be that new, quite frankly.

Has the agency always called that type of data pivotal? It is in the
writing and that is how we have been responding to it as pivotal data.
It is in your guidelines.

DR. VAUGHN: Well, once again I have yet to see it written, the word
pivotal, in any of my documents. It is just a term of ours.

DR. GOOTZ: But you are using the term now \--

DR. VAUGHN: As a basis of this information upon which we make a
regulatory decision. \-\--

DR. GOOTZ: Okay. So a new term, kind of, has been introduced.

DR. VAUGHN: Or dismissed.

DR. GOOTZ: I move we dismiss it. And second. All those in favor? All
right. Any opposed?

MR. LUCAS: Don Lucas, Roche. Dr. Vaughn, I would

\-- my recollection is that quite often studies are classified as
pivotal or non-pivotal, particularly regarding efficacy. So it is not a
term that is foreign at all to me. Certainly in the production area.

MS. HARRIS: Sorry, I didn\'t want to prolong the \-- oh, Mary Harris,
Pfizer. I don\'t want to prolong the pivotal discussion. But, on top of
pivotal and non-pivotal being used extensively in efficacy studies,
outside production drugs too. There is a known set of guidelines or
standards or criteria for those kinds of studies.

I think that is another big gap we face in how we are defining these
microbiological data for the public health issue.

DR. SHRYOCK: Tom Shryock, Elanco. Perhaps to try to bring some of this
pivotal/non-pivotal discussion back to our charge here, to address
questions on slide 21. If we look at question 2, \"What role could these
various types of data play in evaluating microbial effects?\"

Supposing we were to take this list of different studies and ask what
role those could play to provide some guidance, context, whatever you
wish to call it, for the Center so that they would be then able to make
decisions about the data in some way. Knowing there are limitations to
the data that is derived, that sort of thing.

Just throwing that out. Would that be a helpful exercise to complete? It
would start then to address some of these specific questions, role,
factors, pathogens, all of the rest of that. Just as a way forward, a
suggestion perhaps.

CO-CHAIRPERSON HESLIN: Any reaction from the group on that?

MR. MUSER: Rainer Muser, representing myself again. I am not going to
talk about pivotal, but in a way it will come back to it. It has been
helpful in other areas to have a list of studies or standards, whatever,
by which you can go.

And the usual practice, and correct me if I am saying it wrong, was if
you wanted to deviate from it you would have to justify it. And
gracefully, FDA sometimes if they wanted to do something different they
have to justify it to industry, too.

I believe it might be helpful if we make sure that it gets recorded,
what was said earlier. It would be helpful to have a list of studies or
maybe standard protocols for whatever studies the experts, and I am not
one of them, may come up with.

A list of studies and a list of study protocols that can be then used
for providing the information that is needed. And if a company feels
that a new antibiotic needs a different type of study, I am sure they
could justify it and then it would be taking the place of one of the
studies in the standard list.

I think that might help to cut through this discussion of pivotal and
non-pivotal. Thank you.

DR. RIDDEL: By standard study, Dr. Muser, you mean the things that have
been listed as far as having PK/PD data and baseline MICs, those kinds
of studies?

MR. MUSER: Yes. There ought to be a possibility for experts to agree on
if I want to study any of these \-\-- that are listed here, this is an
acceptable protocol to do it.

DR. RIDDEL: I guess, again out of my ignorance, I have heard several
people address this over the last four and one-half hours now. But those
things are listed in point 22 that are relatively repeatable in your
early evaluation of your product. Have fairly known protocols for how
you perform those.

While they may not be totally predictive they give you a basis for
understanding the potential for what a compound may behave like. And
four, you have that information already. For the most part.

Okay. On the other hand, FDA-CVM says they want that information. I am
having a problem with all of the time we have spent getting to this
point. We have the information and that is what CVM wants.

Now, maybe they want us to say a lot of the in vitro models that were
presented in the first day and one-half lacked predictability and
therefore have no role in this at this point in time until a model can
be presented that would be in the laboratory that operates under GLPs as
predictable, repeatable, and valid as to an MIC data. Right? That is
what you wanted?

If somebody were to define an animal model or a laboratory model that
could take and evaluate an antimicrobial for its potential to in part
reduce susceptibility to microbes of zoonotic potential, and it was
predictable, repeatable, and had been validated, and was do-able. Then
that model would be fine.

But, we have not been shown in the workshop to date, any such model.

MR. HALLBERG: Good point. And we can\'t wait for one at this point. We
have got to move forward and get things moving.

CO-CHAIRPERSON HESLIN: We are scheduled for a break at 10:00 o\'clock.
Maybe we should end for now and you can continue your discussions among
yourselves. We are going to reconvene at 10:30.

(Break)

CO-CHAIRPERSON HESLIN: There had been some discussion at break about
focusing on certain aspects of information that has been generated so
far. And I don\'t know whether that meant not covering the rest of it.
Whether we should do a run through of all of the bullets, the comments,
as sort of context and background, and then bring the focus down to
particular slides for further presentation.

I think that is what Gatz is trying to do right now.

DR. SHRYOCK: We can run through the bullets and see how they slash out.
I think we have got a good start on that.

DR. RIDDEL: Run through the bullets beginning with one?

DR. SHRYOCK: No, the one\'s you\'re going to present. The nice
background ones. What was going on looked good.

DR. RIDDEL: Yes. I hate to waste your time while I am typing that stuff
in. But, if we could \-- here is what you can help me do.

If we can come to an agreement on some \-- I think you all are pretty
happy with what the pre-approval studies may entail. Which is \-- what
is on here is in text form, but I am going to put in bullet points and
we can go through it.

Is there in any of these bullet points, are there caveats or addenda or
points of information that should be added as we are presenting them?

MR. HALLBERG: Well, the one caveat would be is number one, pre-approval
studies do not or are not available to predict the rate and extent of
resistance development. Those don\'t exist today and we know it.

And that these pre-approval studies \-- and I would maybe change the
information that studies provided by the sponsors in a pre-approval
setting should provide key information on the following list of
information. And they may include individual studies, they may be
wrapped into one study. But that is for the sponsor to determine how it
is.

DR. RIDDEL: Now, the best way to phrase this is \"rate and extent of
changes in microbial susceptibility\" rather than saying \"resistance\"
or what is the best way of saying this?

DR. PETRICK: I would say it exactly as you have it, just to respond to
the specific question, resistance development.

DR. RIDDEL: I am sorry. Say it again?

DR. PETRICK: I would do it exactly as it says up there \"rate and extent
of resistance development\" that is the discussion for the framework and
the conference and I would stick with that.

And my colleague here says maybe and add pathogen load as well.

DR. RIDDEL: Well, shouldn\'t that be a \-- since you don\'t have a rate
or extent of change in pathogen load, but can you say the same thing for
\-- every group I talked to and the best information I can get out of my
interpretation of what you said is that pathogen load studies are
irrelevant in the pre-approval phase.

Or there are no models that can \-- what is going to be the best way of
putting that, because I don\'t think I can add \"and pathogen load\" all
at the end of that sentence.

DR. PETRICK: With limited value to addressing pathogen load.

DR. SHRYOCK: I think we had some of that wording on one of the prior
slides, 21 or whatever it was, that suggested that pathogen load studies
are not able to satisfactorily protect public health because \-- however
we had that worded before with the variability, the extrapolation.
Whatever we had up there in 21.

DR. RIDDEL: In which point, Tom?

DR. SHRYOCK: I think it was slide 21. It was the one we started with
this morning. Pathogen load, in vitro. That would be \"These studies are
highly variable and not predictive relative to public health\" that
would be the line. It could also apply to the pathogen load studies.

I wouldn\'t get into specifics as to why that is the case.

DR. RIDDEL: So, could you say pathogen load studies are highly variable
and not predictive relative to public health? Leave the in vitro and in
vivo?

DR. SHRYOCK: Take out the in vitro.

DR. PETRICK: Why don\'t we just strike it?

DR. RIDDEL: Strike the whole thing?

DR. PETRICK: No, no, no. You have it correct \-\--

DR. SHRYOCK: I would be stretching to come up with a way.

DR. PETRICK: I know \-\--

DR. SHRYOCK: It is redundant, I agree.

MS. HARPER: They want you to strike in vivo.

MS. HARRIS: If we are still on caveats, can I add a couple that Bill
Flynn mentioned? That not all uses and classes of drugs require
pre-approval studies.

DR. RIDDEL: Drugs or do we specifically say antimicrobials?

MS. HARRIS: That is fine.

DR. SHRYOCK: Antimicrobials. That is fine.

DR. PETRICK: But aren\'t we saying they should all have the same \-\--

MR. LADELY: If it is not for a human use. My understanding is that \-\--

(Group is talking amongst themselves while Dr. Riddel is working on the
Powerpoint presentation - the microphones were not picking up enough of
the conversations to transcribe.)

MS. HARRIS: \-\-- Are we trying to say that CVM is not requiring
something that we think is required?

DR. PETRICK: I am saying that if we are going to take the position that
all antimicrobials should have this information, then I think we should
be consistent. Or, we should say that for most, or something.

That is all I am saying. I mean I don\'t \-\--

DR. EWERT: Let me ask you \-\--

CO-CHAIRPERSON HESLIN: No. I think this open discussion is better than
coming to the microphone. I would just ask you to speak up a little bit
to try to pick up the voice.

DR. EWERT: Just a question of clarification. I was under the impression
that the framework document has been written and if within the framework
document one of the requirements for drug approval was pre-approval
studies, now the framework document is, CVM people, that is still a
reality, right? That is not going away, is it?

So, if it is a reality then we need to work under the context of what
CVM has already performed with the framework document. And that is a
correct statement then, that not all uses and classes of antimicrobials
require this.

Maybe we should say require the same pre-approval studies.

\-\--

DR. EWERT: Right. For an example, \-\-- this is an example from \-\--
would need the pathogen load studies, whereas a single injection of
therapeutic would not \-\--

So that has been delineated in the framework document.

DR. RIDDEL: Is that good enough?

DR. SHRYOCK: The next slide should probably be what studies we would
like to put forward.

MR. BIENHOFF: Also, is there someway of stating there that it is not
necessarily \-\-- some of these requirements?

DR. VAUGHN: You tell us.

DR. EWERT: That is an open-ended comment. I am not going there.

DR. PETRICK: Steve, I think he has got a point there \-\--

DR. VAUGHN: I don\'t read that \-\-- is it up there?

DR. PETRICK: I know. It is a good point though.

\-\--

DR. RIDDEL: Okay. The pre-approval studies may include \-- no changes on
this? Actually, which did you mention as far as this compound
metabolism?

MS. HARPER: If you are in a \-\--

DR. RIDDEL: Then also leave degree and volume in there?

MS. HARPER: Yes.

DR. EWERT: By a definition of susceptibility do you mean breakpoints? So
does that mean that we have to establish breakpoints for non-target
pathogens, for food-borne pathogens?

\-\--

CO-CHAIRPERSON HESLIN: I am not sure he got all of that.

DR. RIDDEL: Well, I \-- this is the list we came to as a consensus, and
now we need a consensus or at least a valid opinion as to changing it.

MR. LADELY: You are going to have to monitor more of your target
organisms.

MR. WATTS: Monitoring and doing MIC studies are one thing, but \-\--
NARMS \-\-- because interpretive criteria by definition \-\--

DR. EWERT: And we don\'t have \-\-- food-borne pathogens.

MR. BIENHOFF: Can this be \-\--

DR. EWERT: You could say baseline MICs without interpretive criteria.

\-\--

DR. EWERT: Gatz, just put interpretive criteria for target organisms.
Everybody agrees with that?

MR. BIENHOFF: \-\-- is this part of the process?

DR. SHRYOCK: That is actually, a lot of times \-\-- breakpoints.

DR. EWERT: But, \-\-- generated \-\--

DR. SHRYOCK: \-\-- breakpoints for pre-approval?

MR. BIENHOFF: \-\-- want that.

DR. SHRYOCK: \-\-- could be sponsor options \-\-- tentative breakpoints
early on. \-\--

DR. EWERT: But then the NARMS pathogen has to be split out into another
bullet \-\--

DR. RIDDEL: What do you want baseline MICs for? What should sponsors
want to provide information to CVM in this arena as far as MICs?

DR. EWERT: That could be both target and NARMS pathogens.

DR. WALKER: I think that captures it.

DR. RIDDEL: Okay, and then how about \-\--

DR. WALKER: Are we generating this baseline MIC data or are you \-\--
conditions?

MR. BIENHOFF: They should be generated under QC conditions and \-\--
valid database.

\-\--

DR. RIDDEL: Which one, here?

DR. EWERT: Yes.

\-\--

DR. RIDDEL: Okay. Now, what do I need to do to modify this point?

MR. WATTS: Put a period after target organisms.

DR. RIDDEL: And delete the rest?

MR. : Move it down \-\--

DR. RIDDEL: Like that?

DR. EWERT: Just get rid of it, that part.

DR. RIDDEL: And you want this caveat also in there?

MR. BIENHOFF: Yes.

DR. RIDDEL: Anything else?

DR. EWERT: Can we add something in there that these studies may not have
to be novel studies, but the information can be generated from
literature. I will just defer that to everybody else in the room.

I mean if we are already dealing with a certain class of drugs, it seems
foolish to repeat a lot of these studies.

MS. HARRIS: Can we shorten that to just say that pre-approval study data
may be collected from \-\--

DR. PETRICK: And instead of saying studies you could just use
information. Pre-approval information may not

\-\-- model studies.

DR. RIDDEL: Leave it at that?

DR. PETRICK: Wouldn\'t that cover it?

DR. VAUGHN: We don\'t want it coming out of Reader\'s Digest.

MR. : Would Hog Farmer\'s be okay?

DR. VAUGHN: Yes.

DR. RIDDEL: Leave it or not?

EVERYBODY: Leave that in.

DR. RIDDEL: Do you want to \-- we have the first statement on the first
slide about what things don\'t seem to work. Do you want to delineate
those or just leave those as general statements?

I am going to have to tell a lot of jokes to stretch this out to 25
minutes guys.

Do you all see anything else?

MR. BIENHOFF: I suggest you go through the other bullets to make sure we
are not missing anything.

DR. GOOTZ: You may want to pull some of those out.

DR. SHRYOCK: Did we want to try to capture any of our discussion? And I
hate to bring this up again, but the discussion on how this information
is to be packaged relative to informational purposes through support
post-approval \-\--

DR. PETRICK: That might be the last bullet \-\-- hold that thought.

If we could go back I think that maybe that is the conclusion point.

DR. RIDDEL: Does anybody see anything in the first five points that we
need to incorporate?

MR. LUCAS: Is there opportunity to call this list? Or is there a reason
to call this list at this point?

MR. : I don\'t know.

MR. : Maybe if we look at these first three. They just catch my eye
right off. That is a sort of repetition of the first day and one-half\'s
questions that we heard presented in the presentations.

DR. RIDDEL: Yes. I guess that is what we are doing. This is a summation
and comments of yesterday and this morning. What I would like to do is
just go down through there and if there is some salient point that needs
to go to the other \-- the blue presentation is going to be the working
document.

DR. GOOTZ: Yes, some of these that were questions, maybe we can try to
craft them today. If we can\'t do that with some of them \-\--

CO-CHAIRPERSON HESLIN: And there might be value in keeping these here to
show the range of discussion on some of these issues as well. Yes?

DR. VAUGHN: The last sentence in line number four I think is good advice
\-\--

DR. SHRYOCK: Should we perhaps take that line out where they \-\--

DR. PETRICK: Is it appropriate to call these resistance studies? \-\--
we are really talking about is the information that makes sense for CVM
to have. And I would hate for the MIC data to now be determined by a
resistance study, or that the PK/PD \-\--

I think we are saying that that information is something that should get
into CVM at an early stage.

DR. EWERT: How about if we say information supporting susceptibility
\-\--

DR. PETRICK: Yes, I think that is a good point. \-\--

DR. GOOTZ: Are you after specific in vitro selection resistance studies
\-\--

DR. EWERT: What we are just saying is that we need to do this early on
\-\--

DR. PETRICK: Right. I think what we are saying is that this information
should come into CVM early in the process. Not something that \-\--

DR. RIDDEL: That doesn\'t really belong. That statement, I understand
where you are coming from, that doesn\'t belong in what we would propose
to be what should be in pre-approval studies.

That is a cautionary statement to industry that this is an issue that
you need to look at early on and develop your product. Wasn\'t that what
you were meaning Steve?

DR. VAUGHN: No. Actually, I am looking at it as advice to CVM to
consider this early on. This sequence, when studies should be conducted
\-\-- talk about developmental plans. This is the kind of information
and what I have heard a lot of people voice, is this information needs
to go in early rather than later because of the potential impact on the
\-\-- pathogen \-\-- it has been said enough times that \-\-- this is
something that should be sequenced early in the regulatory review
process.

DR. SHRYOCK: Perhaps in the first slide under bullet three, \-\-- maybe
that would be an appropriate to put that because it is talking about not
all pre-approval studies are required in all cases. That also puts the
time sequence associated with that thought.

\-\-- really what you want to do or not do.

MR. WATTS: \-\-- you know the bottom line is a lot of this we will never
see. If we have a compound that fundamentally has problems early on, the
discovery team

will \-\--

MS. HARRIS: Yes, but if you have this difference of opinion \-\-- CVM
\-\--

DR. EWERT: I agree. I think it needs to be done early because if there
is a problem that the agency sees, that needs to be addressed.

DR. RIDDEL: Is that where \"delayed\" should be?

MR. : Just put these studies and get rid of the word \-\--

MS. HARRIS: I think we ought to also put in, not just the development
process but the regulatory review process.

DR. RIDDEL: Is this okay? Anything \-- do you have an important item to
be incorporated?

(No audible response.)

DR. RIDDEL: What about point 8?

MR. : The first part sounds good.

DR. RIDDEL: But, does the word and terminology threshold apply
specifically to the post-approval \-\-- program and any action based
upon that?

Any information that you all come up with as far as the pre-approval
study you say would be information you could see being presented in that
package? Would they have any basis other than the baseline
susceptibility studies, \-\-- pathogens, for establishing thresholds?

Thresholds are going to have to be an agreement between the agency and
industry as to what percent or what change is going to result in, and I
am assuming but I could be wrong, that mitigation will be at various
levels.

It wouldn\'t necessarily be that you are out of here the first time?

DR. VAUGHN: Gatz, I think 7 and 8 both \-\--

DR. RIDDEL: Pardon?

DR. VAUGHN: Both 7 and 8 \-\-- some level of \-\--

DR. RIDDEL: Do you want that information to go before slide 3 where we
start talking about pre-approval studies or do you want it to be
informational material following those pre-approval studies?

MR. HALLBERG: Before.

DR. RIDDEL: Okay. Do any parts of this need to be changed, altered, or
deleted?

MR. : \-\-- as a separate bullet so that it doesn\'t get lost?

DR. SHRYOCK: I think we will ultimately come back to that even after our
\-\-- studies will be funded \-\-- to the post-approval programs to be
discussed. That is really the safeguard.

DR. RIDDEL: So, \-\--

DR. SHRYOCK: \-\-- established with a threshold. I would take that out
\-\-- there is going to be a baseline of information generated, but we
don\'t know \-\-- threshold at some future date.

DR. PETRICK: With just the baseline.

DR. SHRYOCK: But you will have a baseline pool of information which
could be used retrospectively \-\-- but to say you have got X number and
then \-\-- Y. What does that mean? You can\'t do that pre-approval.

DR. PETRICK: You are establishing thresholds. Or should it be thresholds
should not be established at pre-approval.

MS. HARRIS: Let me try this. Pre-approval studies should not focus on
establishing thresholds. \-\--

DR. RIDDEL: Okay. I am sorry. If there is agreement on that can you tell
me that again?

MS. HARRIS: Pre-approval studies should not focus on establishing
thresholds.

\-\-- something about baselines \-\--

DR. GOOTZ: The completed package in pre-approval studies will be used to
establish baseline \-\-- contribute to establishing baselines.

DR. RIDDEL: Establish baselines or thresholds?

DR. SHRYOCK: No, baselines.

DR. RIDDEL: What about the next sentence?

MR. HALLBERG: And then you can put \"and design to help design the
post-approval monitoring phase.\"

DR. RIDDEL: Is that phase or program?

MR. HALLBERG: Program.

DR. RIDDEL: Would or could?

DR. EWERT: Could.

DR. VAUGHN: Maybe useful in?

\-\--

DR. PETRICK: I would say that gets back to the \-\--

DR. RIDDEL: Back to the document?

DR. EWERT: I have got a question on categorization. When are the drugs
going to be categorized and by whom? Is this the company decision or is
this the agency decision? When do we do that. I haven\'t heard \-- I
haven\'t seen anything about any drug categorized \-\--

DR. RIDDEL: Categorization is an important point, right?

DR. EWERT: Yes, categorization is because it drives what needs to be
done.

DR. RIDDEL: Okay. If that is important, what do you want to put in
there?

DR. GOOTZ: The sponsor will initially determine the categorization of
the drug. Something to the effect, the sponsor would need to at a very
early stage convey that to CVM or reach agreement with CVM \-\--

DR. RIDDEL: CVM?

DR. GOOTZ: Yes. You must somehow agree or something \-\--

DR. RIDDEL: Should it be pre-approval process or just process?

DR. SHRYOCK: Process.

MR. MUSER: I have a question for the experts. Is it possible that
pre-approval studies after they are available change the categorization?
If so then it should be \-\--

DR. SHRYOCK: If it is possible to change the categorization. We haven\'t
even had the discussion around all of the parameters of categorization.

MR. MUSER: I would like to change that to make it responsible. It might
be good to have it.

DR. SHRYOCK: Yes. I think a lot of this is dependent on discussions we
haven\'t yet had.

MR. MUSER: Right.

DR. SHRYOCK: As to how things shift or the caveats of low, medium, or
high exposure. That all gets matrixed in there.

MR. MUSER: Right.

DR. SHRYOCK: And we are not there yet.

MR. MUSER: Right.

CO-CHAIRPERSON HESLIN: But, is that comment something that should be
included in the slide?

MR. MUSER: I think it should be included.

DR. PETRICK: But what do we say? That we need to have a discussion next
to assess categorization of new antimicrobials? I mean what is really
the \-- what is the crux that we are getting at here?

MR. MUSER: \-\-- pre-approval studies and pre-approval \-\-- risk
assessment. For \-\-- risk assessment will lead to a categorization of
the drug. And not the outcome of pre-approval studies.

But the information on the pre-approval studies would relate to
potential resistance development of a resistance mechanism which is just
not enough to categorize a drug. To categorize a drug according to the
framework document, you look at the use pattern, we look at the
appropriate classes or similar classes \-\-- risk assessment would be
necessary to categorize the drug.

DR. EWERT: But the way the framework document is written now, that
categorization has to take place before the pre-approval study can be
\-\--

DR. RIDDEL: Can we say only extenuating circumstances (changes in human
medicine or NARMS data) would alter this categorization later in the
process? So what you don\'t want is for a category II compound for some
reason, the day you are getting ready to submit the package, then all of
a sudden it changes, becomes a category I.

DR. EWERT: Right.

MR. MUSER: The framework document at the moment \-\-- gives you an idea
of what type of or the extent of studies or the extent of \-\-- to do
depending upon your category. If you do it by the end of the day I think
it comes back \-\-- complete picture. \-\--

One could then revise the categorization, the official categorization
and confirm it or change it.

DR. EWERT: Well, that is fine. You could just say something like final
categorization must be confirmed subsequent to completion of
pre-approval studies.

MR. MUSER: Subsequent to completion of the risk assessment.

DR. EWERT: Well, whatever.

DR. SHRYOCK: In slide 3 we already have a statement that gets into this
and then says: \"Not all uses and indications for all antimicrobials
will require pre-approval studies.\" You could put another bullet on
there that says depending upon categorization or pending categorization
or something like that.

It links that concept but it doesn\'t get too specific. We can\'t be so
certain today about how the \-\-- you acknowledge it but don\'t go much
further than that.

CO-CHAIRPERSON HESLIN: That would satisfy your concerns?

MR. MUSER: Oh, yes. That is fine.

DR. SHRYOCK: \-\-- I was looking for Tom\'s version.

DR. RIDDEL: So, what is there?

DR. SHRYOCK: Just put something to the effect not all uses and classes
of antimicrobials require the same pre-approval studies as determined
via categorization criteria.

\-\--

DR. SHRYOCK: Right. Then put that into parenthesis criteria to be
determined.

MR. BIENHOFF: Is there as fare \-\-- as far as categorizing \-\-- CVM
\-\--

DR. SHRYOCK: I don\'t know what those parameters would be. I don\'t know
if anybody knows that answer.

MR. BIENHOFF: I guess the point is to try to avoid some of the \-\--

DR. SHRYOCK: The only way that you will actually get a categorization
changing from say a 2 to 1 would be through your post-approval
monitoring \-\-- rising to a sufficient level of concern. \-\-- after
the fact.

MR. BIENHOFF: Right.

DR. SHRYOCK: So in essence, what difference does it make if it then
becomes a category I \-\--

Does that make sense?

MR. LUCAS: Tom, might did not find some unexpected cross-resistance
\-\--

DR. SHRYOCK: Through your pre-approval testing that would relate it to a
category I drug \-\--

MR. MUSER: Even after approval \-\-- will not really have an impact on
your pre-approval study because it is \-\-- this would have a heavy
impact on \-\-- mitigations from these thresholds. \-\-- pre-approval
deja vu.

MR. LUCAS: The point I was making though was if you were in your
pre-approval testing program looking for instance at cross-resistance
with this drug. And some unexpected set of cross-resistance showed
itself, would one of those drugs being a category I drug, then it is
immediately pulled up. So that would be a way, during the pre-approval
testing, for the category to change.

DR. SHRYOCK: That is why you do studies.

DR. PETRICK: How significant is categorization? I guess I am having
trouble right now with what we are proposing to do and how the data are
to be used. What is the categorization drive? Will somebody help me with
that again?

I mean if we are saying categorization is going to impact or what
studies \-\--

MR. MUSER: I think it is more than that. If I recall it correctly, \-\--
but I believe there is a camp in the scientific community that says that
categories should not be approved for veterinary use period.

So from that point of view it would be worth it to

\-\-- if they want to go through with it to show that yes it did, \-\--
initially isn\'t that category \-\-- should be taken into another one
and it can\'t be approved?

DR. PETRICK: Yes. And I guess that\'s it. Unless something in the Center
has changed, I believe the idea is that even vancomycin could be
approved as a food additive for chickens if the \-\-- that is kind of
like the \--

MR. MUSER: \-\--

DR. PETRICK: Yes, okay.

MR. MUSER: And because it is a \-\--

DR. PETRICK: Right. Okay.

MR. MUSER: \-\--

DR. PETRICK: Yes. And I guess that is what I am wondering. Have we
gotten to the point now that categorization isn\'t as critical as it was
at one point?

MR. MUSER: In our mind it is \-\--

DR. RHODES: Well, wasn\'t it yesterday that the CDC was basically saying
that no category I drugs would be \-\--

DR. SHRYOCK: I think \-\--

DR. RHODES: But he said specifically no category I drugs could be used
as feed additives. \-\-- So I am looking at it from that point of view,
obviously. \-\-- which category a drug is in is going to drive \-\--

CO-CHAIRPERSON HESLIN: Just a time check. I think we have about 20
minutes more to go to get Gatz ready.

The good news is, if I am reading that right there is about 13 slides
that there seems to be substantial agreement on.

DR. RIDDEL: I think I had some blank ones at the end.

What do I need to do to craft the first point in this to what you want?

DR. GOOTZ: Isn\'t that already obvious \-\-- from the framework
document?

DR. SHRYOCK: \-\-- but why does it mean \-\--

DR. GOOTZ: \-\-- consistent with the framework document.

DR. SHRYOCK: \-\-- state the obvious \-\--

DR. GOOTZ: Can I ask you a question? Where are we in this outline?

DR. RIDDEL: I think we had gone back when Kathy asked about
categorization.

DR. GOOTZ: Oh, okay.

DR. RIDDEL: But we really were at point 9. We used seven and eight. Nine
brought the discussion of categories and we put in a couple of slides. I
guess we are now back to looking at 10.

Based on a couple of questions that were presented in the agenda, should
the group comment on use of sentinel or surrogate organisms or just skip
that? We did have a discussion about sentinel organisms.

DR. GOOTZ: Wouldn\'t that be more appropriate for post-approval
surveillance in part, later on? How to? How are we actually going to do
that? It may not be needed to be ready now.

DR. EWERT: Well, it looks like the whole direction for the pre-approval
studies is getting out of the animal and mostly in vitro studies here.
And so the whole idea of sentinel organisms was, in animal studies,
whether they were pre-approval or post-approval. But it looks like we
don\'t have to make animal studies pre-approval.

So I would agree with what you are saying Tom, that maybe a
post-approval issue \-\-- but it is still something we need to make a
comment about. I personally feel very strongly about that \-\--

DR. RIDDEL: So do you feel strong that they should or shouldn\'t be
used?

DR. EWERT: I don\'t feel that it is an adequate representation to what
is going on \-\-- unless we can show some correlation between the
percent \-\-- food-borne pathogen.

MS. HARRIS: I would like us to have a comment on both sentinel organisms
and dose optimization \-\-- they were \-\-- I think we reached a
concurrence \-\--

DR. RIDDEL: So have several slides on what pre-approval studies may
include. Does that cover what you want to include in pre-approval
studies? And do we go with the next vein as to working into a
post-approval monitoring program?

Or how do we being to put information about sentinel organisms, optimum
dosing, things like that?

DR. EWERT: Well, it looks like to me by the nature of the studies that
we could put up here \-\-- pre-approval. Those items are no longer an
issue.

DR. RHODES: \-\--

DR. EWERT: Pardon me?

DR. RHODES: Or they are not on the table. \-\--

DR. EWERT: Right.

DR. RIDDEL: Should we address them and speak to why they are not
included in our proposed pre-approval package and why we don\'t believe
they have a place there and why they might have a place somewhere else,
but why they don\'t belong here?

DR. EWERT: I think we can give our opinion. But somehow that will be
your job Gatz, to bridge \-- I mean why you are talking about it, but
those aren\'t factors in the study \-\-- but it would be nice for this
group to go on record with what we think.

Because just because we think, this group believes, the studies should
be done in vitro or through literature, doesn\'t necessarily mean that
that is what the agency is going to come up with. So, there are
different pieces of this that they may pull out as far as
recommendations.

So I think it is still valid to talk about it. You just have to give a
caveat or two.

DR. VAUGHN: One thing you might do Gatz, is just say \-\-- consider \--
sentinel organisms are considered as optimization as potential
pre-approval information that we feel should not be included for the
following reasons.

Those reasons may apply to both pre-approval and post-approval \-\--

MR. BOETTNER: I think we say it when we discuss the design of concept
studies \-\-- study concepts or study models of this \-\-- but you still
should do probably some in vivo studies in the context of pre-approval
studies.

DR. EWERT: But that is not what we are saying here. Other than
pharmacokinetic data, many of those studies that are being described up
there are laboratory studies.

I don\'t disagree with what you are saying. But I am saying that is not
what we are saying as a group.

DR. GOOTZ: \-\-- PK/PD \-\-- I think we say if why would a nice AUC
number be relevant to the selection of resistant zoonotic pathogens
\-\-- they wouldn\'t necessarily \-\--

MR. BIENHOFF: \-\-- as far as the mechanism goes that is development of
resistance \-\-- how you are treating the animal may \-\-- I think the
AUC data \-\-- antimicrobial.

DR. GOOTZ: Somewhere, I think on the previous slides \-\-- something
about \-\-- levels of drug in feces \-\-- so this is really the systemic
PK/PD issue that would bear upon the selection of resistance in zoonotic
pathogens.

It would be whether or not that drug, regardless of its PK is excreted
in feces. Therefore, we should know something about the level of our
drug in the feces of our indicator \-\--

DR. EWERT: But what does that have to do with a sentinel organism?

DR. GOOTZ: I don\'t know.

DR. EWERT: I mean that is what the question is. If you go back, Gatz can
you just go back and look at the slide where the group has suggested the
different study types and \-- I can\'s see in any of those studies \-\--
sentinel \--

DR. RIDDEL: In this presentation or the other one?

MR. : \-\-- animals \-\--

DR. EWERT: But NARMS doesn\'t have sentinel organisms.

MR. : \-\-- they are looking at salmonella, generic E. coli, generic
enterococci, campylobacter.

DR. EWERT: But I am not talking about \-- I am talking about sentinel
the way Dr. Walker talked about it, the way the agency is now looking at
it. Where as generic E. coli is representative of food-borne pathogens.
That is the type of sentinel I am talking about. And I don\'t see this.

CO-CHAIRPERSON HESLIN: Was it on a slide or on the earlier list?

DR. EWERT: No, it was on this slide or the previous slide.

DR. PETRICK: It is this slide right here.

DR. EWERT: Or is it the other slide that says pre-approval \-\--

DR. PETRICK: But I think again, where we were coming from is that the
information is good to have. The PK/PD, the fecal levels, but I think
the time to collect it is up front, but the usefulness may not be
apparent until we get into post-approval.

But I think you want to have it up front so it is there to be useful if
a problem develops or if you start going down the road of mitigation,
one of the things you can say, well a mitigating factor isn\'t going to
be the level that is being excreted if it is never excreted in the
feces. So, you move that off since that is not a place you are going to
go.

You may say well let\'s look at the area under the curve to address the
resistance issue that is developing. Maybe if we increase that or maybe
\-\-- can be higher and we can adjust the dose \-\--

I think it is information that we can collect that is efficacy in one
stage, post-approval maybe it becomes something else.

DR. GOOTZ: Well, it is part of the baseline data, but again I think we
are focused on safety \-\-- selection of fecal zoonotic pathogens. The
only relevant part of that is number one, whether the drug is out \-\--
number two, it would be nice to know fairly early on how much is there.

DR. PETRICK: Right. And I guess that would be the degree of binding,
right?

DR. GOOTZ: Yes. Oh, and the binding \-\--

DR. PETRICK: Right.

MR. SCHMID: But this doesn\'t tell you anything about the \-\-- it could
be binding to bacteria. I think the recommendations of the \-\--
susceptible indicator organism \-\-- could be a very meaningful tool to
\-\-- potential side effects from \-\--

DR. GOOTZ: So you are proposing pre-approval in vivo studies \-\--

MR. BIENHOFF: \-\-- as in contrast \-\-- if you have a drug that is
excreted \-\-- it may or may not \-\-- again, it all depends on the
compound.

DR. GOOTZ: I think it is a \-\-- point. It is just hard to practice in a
pre-approval study. But again, \-\-- but in terms of so far as selecting
resistance pathogens, I am not aware of \-\--

MR. BIENHOFF: All I am saying is this is just a data plan.

DR. RIDDEL: As far as the concept of sentinel organisms. I heard the
group just saying today, especially with some input from Kathy, that
they don\'t provide a valid comparison for human food-borne pathogens,
or at least that information is not there in literature, right?

And we didn\'t put in our list of information to put in the pre-approval
package anything about sentinel organisms. Unless you have changed your
mind, then it obviously is a topic that has been discussed at CVM and we
probably need to justify why we considered this but did not include it.

DR. PETRICK: And I think you have captured it \-\--

DR. EWERT: That looks good to me.

DR. RIDDEL: That is good enough? Okay. The concept of optimal dose. That
is not in the pre-approval package. Why?

DR. GOOTZ: that may need to be determined and modified and later on
after field studies. \-\-- make your best judgment on the dose that
should be used. \-\-- the sponsor may find that the dose isn\'t high
enough or it is too high.

DR. RHODES: I think you have to be very careful there because we talk
about modifying the dose post-approval. But it is just not practical
from a sponsor\'s point of view. You would have to go back and repeat
your 1-3-5 studies on the target animal. You would have to redo all your
residue studies to include them \--

DR. PETRICK: Maybe what we should look at is then benefits gained. The
system that we have right now establishing flexible dosage based on
efficacy and safety is the best system that we have. And any benefit in
modifying that or working toward an optimal dose from a resistance
standpoint isn\'t as critical as that flexibility for the practitioner.

I think we go back to right now we say the minimal dose for efficacy
from the field and a maximum dose based on safety from a target animal
and residue sampling. And I think that is a good place to be and I
don\'t see anything that we have discussed so far from resistance that
should make us turn away from that process.

That was a harm group \-\-- in the system. Both receiving with the
industry and with the practitioners. I think everybody believes there is
a great deal of benefit from that flexible dosage scheme. So right now,
I don\'t think we want to modify that based on resistance when we don\'t
even know what the right dose would be to prevent or to limit resistance
development.

I don\'t know how we capture that, but I \--

DR. GOOTZ: I think \-\-- misleading when I said \-\--

consideration, but that also \-\--

MS. HARRIS: I guess I would like to propose a single statement to deal
with the issue. I don\'t think we should call it optimum dosage, we
should call it dose optimization \-\-- and I think we should say \-\--

MR. LADELY: It has a place. Dose for resistance is good for evaluating
risk. In risk assessment it has a place. In therapeutic treatment of
animals it does not. \-\-- practitioner judge what drug should I use,
maybe that risk assessment should come into play. But as far as having
any bearing on pre-approval, I don\'t believe it has a place.

DR. VAUGHN: I don\'t think we can make a judgment on what would be an
optimum dose \-\--

DR. WALKER: \-\-- lot\'s of studies out there showing that there is a
direct correlation \-\--

DR. GOOTZ: I think those were \-\-- inadequate levels in the lung \-\--

DR. WALKER: \-\-- there are studies out there \-\-- the AUC values are
good \-\-- selecting for resistant organisms.

DR. GOOTZ: Right, but we are \-\-- that you are going to hold
responsible for salmonella, campylobacter, E. coli. So, a PK \-\--
systemic therapy \-\--

DR. WALKER: \-\-- we really don\'t look at the serum concentration \-\--
mucus secretions are very high \-\--

DR. GOOTZ: I am not aware of direct studies that have been identifying
or concerned with the \-\-- campylobacter is becoming susceptible to
macrolides, but we are not going there \-\--. I am not trying to argue,
I am just trying to say that what are safety issue \-\--

DR. WALKER: What I am saying \-\-- but also maximizes resistance \-\--

CO-CHAIRPERSON HESLIN: We are running out of time. I wonder if there is
some way to bring this to closure, possibly, what is being proposed up
here.

DR. RIDDEL: What about that third point?

DR. VAUGHN: There are a lot of \-\--

CO-CHAIRPERSON HESLIN: Well, is this too much to bite off?

DR. RIDDEL: You really haven\'t said anything about why dose
optimization has a place in the pre-approval package with those first
two points.

MR. BOETTNER: But, \-\-- no study models available in pre-approval
studies \-\-- resistance development, so how can you determine the
optimum dose \-\--

DR. VAUGHN: Something to the order of the variation, the variables that
are encountered in a field situation are such that it is difficult to
realistically design an adequate number of studies to provide \-\--

CO-CHAIRPERSON HESLIN: I see several heads nodding at that one. Can you
live with that?

DR. RIDDEL: Say it again.

DR. VAUGHN: Due to variables involved in a field use situation \-\--
design an adequate number of studies to provide \-\--

DR. RHODES: How about just to assess resistance development?

DR. VAUGHN: Relative to resistance development.

DR. RHODES: I think it is important to say, just as you alluded to the
practical field use of these antibiotics, even if we as an
industry/government organization go out to the practitioner and say you
know, if you use twice as much of this drug and you have twice as long a
withdrawal period, it is going to be better because we won\'t develop
resistant pathogens for humans.

But we know that half of the amount is efficacious. What are the cowboys
going to use? They are going to use just enough drug in order to get
that animal feeling better and they are really not going to care much
about development of resistant pathogens.

So they are going to take that bottle and they are going to read the
dose. They are going to say you know what, Joe Schmoe down the road says
if I use half as much of this it works out just as well for my cows, and
they are going to use half as much.

Realistically that is the kind of thing that is going to happen in the
field. And so it becomes a very theoretical exercise to set a dose based
on resistance development.

DR. VAUGHN: You know, Bob\'s right in terms of in a given situation as a
general rule, the higher the dose the higher \-\-- less the likelihood
of the development of resistance. But, you also have to look at the
environment in which the animal is treated and the impact on the bug.

Because it is not \-\-- one concentration of drug that any particular
bug is exposed to. \-\-- zero. So the potential for resistance \-\--
there are a lot of factors to include in the situation to optimize the
dose.

Bob\'s right. I mean I don\'t want to give you the impression that
Bob\'s not right about the C-max thing, but it is situational. \-\--

CO-CHAIRPERSON HESLIN: Okay. You can live with that one?

DR. PETRICK: That looks good.

DR. RIDDEL: Steve, I don\'t know what the word inferential means so I
can\'t use it.

DR. VAUGHN: That is all right. That is fine. It is like pivotal.

DR. RIDDEL: I am all over that one.

DR. GOOTZ: It has a lot of meanings to a lot of different people.

CO-CHAIRPERSON HESLIN: Are there any other bullets that we haven\'t
looked at?

DR. RIDDEL: Yes.

MR. BOETTNER: About number 16 \--

DR. RIDDEL: Yes?

MR. BOETTNER: I think with our pre-approval studies we do generate a lot
of information about resistance development techniques and we also said
that we generate baseline data. But looking ahead for post-approval
\-\-- thresholds that set forth specific compounds \-\-- how can we
determine which of the compounds we used contributed to the resistance
development?

DR. RIDDEL: Tough one.

MR. BOETTNER: Very tough. But we have to assure \-- but we are saying
that we are setting also basic information for post-approval studies.
Post-approval studies, this is resistance monitoring, while in efficacy
it means setting stress \-\-- and mitigations.

Does this really relate to a product? So what needs to be done to
identify this product or this class \-\--

DR. GOOTZ: So the question is then \-\-- post-approval surveillance
\-\-- that would be the answer to that today.

DR. SHRYOCK: I think it is a good point, but I am not sure how to fit it
in a pre- situation.

MR. BOETTNER: It doesn\'t really fit into that I don\'t think. I think
it is very, very important \-\-- we may develop a lot of information out
of pre-approval studies which then does really not help us with the
overall objective. \-\--

DR. PETRICK: But I don\'t think there is anything we have proposed today
that is going to \-- that is limiting or negative from the standpoint of
it is not good information to have.

I agree with you because there is that the factor, but I think for right
now \-- I think we have to address it at another context when we can
focus it on post-approval. It could be the same thing. \-\-- how is
post-approval monitoring done and when we take these examples they need
to be identified in such a manner that you can compare it to a farm.

\-\-- trace it that closely so you can look at where did that organism
or where did those organisms come from. Is there a pattern reached from
that research. And then focus on \-\-- I think that is how you focus it
then.

If the idea is to catch things early, \-\-- go all the way to the farm
level and the individual producer of that \-\--

DR. RIDDEL: There were some significant comments in the other document
about use patterns and there were some good comments made about use
patterns. Do you want to put any comments in here?

Do we just want to stop at the pre-approval package or do you want to
provide some insight that we have put together over the last day as far
as how some of this one, is either more appropriate for the
post-approval phase, or how maybe the pre-approval information should be
utilized in the post-approval phase?

DR. GOOTZ: \-\-\-- post-approval you are probably talking about another
four or five hours \-\--

MR. BIENHOFF: I guess \-\--

DR. PETRICK: The only other question I wonder if we need to \-\--
preliminary slide some where. Because we do talk at some length about it
can\'t be a one-size fits all and have we captured that in one of the
early slides about flexibility approaches based on the individual
product. \-\--

If we haven\'t captured that I think we should. If we have, then I think
we have got \-\-- I couldn\'t remember.

DR. GOOTZ: Didn\'t we capture that in the discussion on categorization
\-\--

DR. PETRICK: Well, in the course of this we say you have to kind of
tailor it for one of your studies and your approach has to be tailored
and one of the things we talked about is making sure there is enough
flexibility in the process that both the Center and the sponsor can work
through it.

As long as we have captured as something we discussed then I think we
have gotten the rest. The only other salient point I saw in those last
five \-\--

MR. BOETTNER: \-\-- means is that we can \-\--

DR. RIDDEL: Very quickly we will run through what we have and if you
think that there is something that we need to add that is pertinent to
one-size doesn\'t fit all, say it.

And I can go back if I am going too fast.

DR. PETRICK: Oh, there we go. It is that first point \-\--

DR. RIDDEL: Okay.

CO-CHAIRPERSON HESLIN: And we can quit while we are head?

MR. BOETTNER: I have a question.

DR. RIDDEL: Yes.

MR. BOETTNER: The original list of questions you made from our
brainstorming session, will you provide a printout of this as well for
the participants of this breakout session?

CO-CHAIRPERSON HESLIN: I think we can do that. I will check on that.

DR. RIDDEL: Well, if you remember on that we have one comment, and I
think Dr. Mevius pointed this out, pertinent to food-borne pathogens had
two positive comments and no negative comments. So I don\'t know that
that is good working material. Maybe for your interest, but I am not
sure it needs to \--

MR. BOETTNER: What would be a basis for at least the slide or
presentation \-\-- this afternoon \-\-- comments

which \-\--

CO-CHAIRPERSON HESLIN: I will check to see whether we can get copies of
that if you just want to take it for your own information.

The room needs to be apparently set up for the next session, so we are
really pretty much out of time. But do you have a comment or question
just to close it out?

DR. SHRYOCK: I think the one thing that we were going to circle back
around on was how these studies would be interpreted or used. It was at
that discussion around the word pivotal.

What that particular aspect meant. When we generate all of this data,
how is that to be used. I don\'t have a quick bullet point to lay out
here.

DR. PETRICK: Maybe that is a good place to put it, right there in the
transitioning to a post-approval \-\-- and the comment is that the
pre-approval data lays the foundation for transitioning into the
post-approval monitoring program. Maybe that is sufficient to address
it.

DR. GOOTZ: Also, I think that we are in agreement that all of this, this
whole package of pre-approval microbiology that we talk about, in and of
itself is pivotal, it is important. But, that individual microbiology
studies cannot be perceived as pivotal.

Let me rephrase that. We all agree that all of these things are
supportive. We all agree we are going to resistance emergence in vitro.
We are going to do good field studies, MICs. I think gene transfer, but
I am getting fuzzy. Other things that we put on that slide.

That unit as a whole, all of that data is important to establish
baselines pre-approval. In that sense, from the organization\'s point of
view you said you would use the word pivotal. In the sense that if you
don\'t have them at all we don\'t go forward.

But, are we in agreement to say that but we cannot use a single study
such as a result from a gene transfer or the result from a single
selection of resistance frequency with one organism to be designated as
pivotal?

DR. PETRICK: I think to stay away from the \-\-- to not get \-\--
pivotal. I think what we are getting at is the results do not lead to
pass/fail decisions.

DR. GOOTZ: One result itself. I mean the whole package could lead to
that, if it is a crummy package. If all of the information is bad.

DR. PETRICK: Yes, but the only way the information is bad is if it is
not done \-\-- reproducible \-\-- product actually is. \-\--

DR. GOOTZ: Well, my position is that there be somebody looking at it and
say that we have new drug X which belongs to macrolides just for the
sake of argument. The selection of resistance in one study, one
microbiology study which is part of an entire large package, indicates
the frequency is one times 10^-4^. One study, one organism.

Is that sufficient in and of itself to really put that drug on hold from
the resistance perspective. I would hope not. I would hope that what we
are talking about when we say important, pivotal, whatever studies is
the entire package.

Because obviously it should be of high quality. It should contain, I
think we agreed on a set number of things. We shouldn\'t be trying to
skip things for a short-cut. But that the importance of that package is
really looking to the agency to look at it totally, but not dissect it
and say one result in and of itself is sufficient to, and I won\'t use
the P word, to stop further consideration of that compound. One of those
subheadings of microbiology such as gene transfer or selective
resistance.

CO-CHAIRPERSON HESLIN: I need to interrupt to say that we are out of
time. There is a public comment period after the discussion panel. So
there will be \--

DR. VAUGHN: We need to fix the last bullet \-\--

I think what your concern is, is that any result, not necessarily a
single study \-\-- to make a pass/fail determination because the \-\--
the idea is \-\--

DR. GOOTZ: \-\-- if everything else is actually very reasonable having
\-\-- organisms that have a high \-\-- I think that would be sensible if
that is what we want to try to put.

(Breakout Session Concluded at 12:25 p.m.)