# Doubletree Tape 4

3/7/02

*(This tape was difficult to transcribe, difficult to hear the people
off mic and they talked over each other)*

Dr. Brad Thacker:

and the second thing is I wanted to, I felt more confident if I have
other parameters.

(Dr. Cindy Burnsteel:

Okay, for the model study basically just lung lesions, percent lung
lesions in the treated compared to the control and not really defining
success failure per say with other parameters. Okay. The next question
is what clinical and laboratory end points would be used or needed to
demonstrate effectiveness and I guess we've kind of covered that too.
Some of the groups said that the clinical endpoints would be clinical
scores, identification of bacteria, possibly production parameters and
then laboratory end points, PCR, immunohistic chemistry. So, but just
based on our conversation from the last question none of that really
applies with model study or yes? No? Okay.

Dr. Brad Thacker

Well, maybe number of organisms. That would depend on how the expeirment
was conducted(inaudible)

Dr. Eileen Thacker

The bottom line stills comes down to the industry reduction of lung
lesions (inaudible)

Dr. Brad Thacker (inaudible) again you are verifying that your model is
working

Dr. Cindy Burnsteel

Okay. The next question is, what are the time points for declaring an
animal for being a success or failure and why do you pick these? On what
days would you evaluate success or failure? I guess this is at
slaughter. At slaughter. Okay. For people who talked about doing an
efficacy study, I don't know it doesn't have any days here, I don't know
if he came to any days or---

Dr. Brad Thacker

(inaudible) A laboratory study or a field study?

Dr. Cindy Burnsteel

A field study.

Dr. Gregory Moore (ELANCO)

Well, you know, if you go for, if you use prototype PRDC. We did some
nursery studies. We did some early entry into the grow (inaudible)
studies. We did some heavy weight stuff to cover the gamut, okay, that
was for PRDC and the same principle should be applied to mycoplasma, I
don't want to say induced but PRDC associated with mycoplasma. When you
hit that wall it seems that that is a, has been suggested as a
mycoplasma involved phenomenon. We may want to do trials in those heavy
pigs to evaluate that or we may just want to focus on the nursery where
we can, where we can have more animals, sacrifice more animals and show
more of a benefit.

Dr. Eileen Thacker

Excuse me though, why redo these with mycoplasma if you've already done
it. What are you going to show different now, looking for mycoplasma
then what you showed before? Was the drug effective against the
mycoplasma under those trials?

Dr. Gregory Moore (ELANCO)

Number one, in the first trials we didn't so mycoplasma because it was a
management decision.

(female voice)

But it was there with PRDC.

Dr. Gregory Moore (ELANCO)

It was there and I already asked that we not do clinical trials again,
we use the data that we generated and saying all these herds were
exposed anyway so we should be able to get an addition to the claim
based on other datas that are also at the agency. We should have to do
anymore. Especially with \--

Dr. Eileen Thacker l

Now, with the PRDC, how did you know that the level, the production
parameters and this is where I get confused with field trial stuff and
putting specific organisms down. To me, what you are saying is that you
are what a label claim for PRDC unless you can definitely show that the
lung lesions were reduced associated with, due to mycoplasma just
because you reduced increased production parameters what about the
growth promotant (inaudible) we talked about growth promotant of an
antibiotic. We talked about perhaps you got rid of a pest secondaries
that reduced the lung lesions, we've already said that because it was
not pathognomonic. How can you say that the studies you did before
actually were reduced mycoplasma induced lesions? That's my question and
why I throw out to this room the problem with doing a field trial with
any God only knows, how many pathogens. What are we proving? Either that
or the CVM-FDA might as well just give label approval for an antibiotic
against PRDC what ever that is.

Dr. Cindy Burnsteel

And I know there was some discussion in our group of whether PRDC
existed or whether it was really just mycoplasma that had advanced, you
know, if you took care of the mycoplasma you didn't have a disease so.

Dr. Brad Thacker

We don't know that.

Dr. Cindy Burnsteel

Right. Exactly.

Dr. Chris Minion

Because you can't do that , we don't know how to do that(inaudible)

Dr. Cindy Burnsteel

Well, we know that if we just have the mycoplasma we don't know, anyway.

Dr. Chris Minion

(inaudible) If we have a therapeutic that proves to be effective against
mycoplasma, maybe it will be effective against PRDC, well no. Somebody
needs to do a study obviously, it could be a very important kind of a
study but use that there's a criteria in determining whether or not it's
therapeutic against mycoplasma, I think that is putting the cart before
the horse.

Dr. Cindy Burnsteel

I know and I guess that's the hard part if you have those mixed
infections how do you know it worked against the mycoplasma component of
that infection.

Dr. Brad Thacker

I think that one of the things that our group talked about a little bit
too is just the labeling from the stand point of who's making the
decision about how is the medication is actually used in the field then
and it was kind of a feeling that between the need for the company to
market, provide marketing information and the fact that almost all
antibiotics recommendations now are made by veterinarians any way. What
was the value of FDA requiring of field data. I was very supportive of
you know, pharmacokinetic data, *in vitro* (inaudible) data, model data
but beyond that the, the industry will, will take care of that.

Dr. Cindy Burnsteel

And there was some discussion in our group too from industry that you
know, they're not going to even be bringing a product up to us that they
don't think is going to work and it certainly is not going to be worth
it for them if it doesn't. I guess that's along the same lines.

Dr. Nabil Anis (CVM)

(inaudible) Not many products that work in the model, and don't work
when you take it to the field.

Dr. Chris Minion

That's right, it depends on the model I guess.

Dr. Nabil Anis (CVM)

(inaudible) Good model, good data

Dr. Eileen Thacker

That's true about vaccines and everything else too. These\--

Dr. Nabil Anis (CVM)

(inaudible) We have to approve drugs based on substantial evidence, does
it work here, not work there

Dr. Eileen Thacker

Every farm?

Dr. Nabil Anis (CVM)

Not every one.

Dr. Eileen Thacker

How do you differentiate them? Which one are you going to tell the
producer or the veterinarian? It's not going to work it? That's what I'm
asking. You guys are taking a tremendous load onto your shoulders by
saying we are going to only approve products that control respiratory
disease and mixed infections.

(male voice)

I think there's a big---

Dr. Eileen Thacker

I think you're taking the world on.

Dr. Brad Thacker

There's a big difference here too between drugs that are already proved
and are used---

(female voice)

Are being used.

Dr. Brad Thacker

This is like GATT.

Dr. Cindy Burnsteel

Right.

Dr. Brad Thacker

Right. You know when they get together for these GATT meetings for trade
talks, they're not making new regulations they're just codifying what
everybody's been doing illegally since the last meeting.\--

Dr. Cindy Burnsteel

Doing.

(male voice)

Doing the legalisms (inaudible)

(laughter)

Dr. Brad Thacker

So, and so in a way I mean, and so some of these issues and it really
only amounts to a few issues presently with, I mean are there any new
drugs coming out for mycoplasma?

Dr. Eileen Thacker

(inaudible) That are not approved for anything else?

Dr. Brad Thacker

The issue as I look at it is Pulmotil® is used for respiratory disease
in pigs that doesn't have the mycoplasma thing. The tetracycline\'s are
used for respiratory disease they don't have the mycoplasma thing.
Tylosin is a drug that could be, maybe used, it has to be reformulated,
so is there anything I missed, clyent, Denaguard® already has a label
claim for mycoplasma (someone else "well, maybe" (inaudible). So, in
essence we are only talking about changing the, the label claims for
drugs that are used in the field already. Some of them are used
extensively with justification for treating for mycoplasma already, like
CTC. Pulmotil® somewhat, It's registered for mycoplasma in Europe,
right?

Dr. Gregory Moore.

Australia, Europe

Dr. Brad Thacker

So, so the pragmatic way of think, I mean in some ways there's a certain
pragmatism here to that we need to consider.

Dr. Cindy Burnsteel

Right and we had that discussion in our group too that everybody's using
these, or that a lot of people are already using these drugs and, and
really what we'd be doing in just kind of making legal what's being done
in an extra label use right now. I guess my only concern and I don't
know if it's a concern, I'll throw it out to others in my group is then
what if you get a new drug that come in that just wants mycoplasma, on a
claim, what do you do?

Dr. Eileen Thacker

Okay, Dr. Nabil the question that comes into play is okay, I'm a
practitioner I've got a drug, it says mycoplasma on the label, I put it
into a farm situation and it doesn't work, why is that your fault?

Dr. Nabil Anis (CVM)

It's not my fault we are mandated by the congress to approve a drug
which is safe and effective. The label claims says it works against
mycoplasma it should work in the field not just in the model. It's like
you put it in a tube and it works (inaudible)

(talking over top of one another)

## Dr. Eileen Thacker

Well, but the law --I mean it's going to work under some circumstances
in the field. Why wouldn't it work at all if I took it out to a field of
pigs that were infected with mycoplasma.

Dr. Brad Thacker

No, I think with, I feel and view if it's a new drug ---

Dr. Cindy Burnsteel

I just throw that out I don't\--

Dr. Brad Thacker

Yeah, I mean I think there should be some and I don't think the
companies would have a problem with that because they're going to, with
a new compound that nobody has any experience with they're going to have
to generate a lot of that data, right?

Dr. Nabil Anis

Right.

Dr. Brad Thacker

I mean, Pulmotil® as a new compound you have to do a lot more then Teddi
(Wolf) has to do with CTC, because CTC's been out there for 30 years.
Everybody really kind of understands how it works or what it does. You
know? And so yeah, to me it's two different issues. A new drug versus
just modifying the label on an existing one.

Dr. Eileen Thacker

Okay so on a new drug then what are we telling them to do

Dr. Gregory Moore

A new drug, that would be open for, completely open for discussions with
the agency. I mean we do on the baseline data just like we would do for
any drug that is going to move into phase three research trials and we
go through the model. We go through the MIC's. We go through all the
base work that those justification studies in models you know, and
establish the efficacy there and the reductions of lesions but once you
get to the field then it's open for discussions with the agency as to
what can be done, what's practical, what's reasonable, what's logical
and what's economically feasible.

Dr. Cindy Burnsteel

And they might not be you know, a new animal drug may be for just one
indication you know, if we have these other four products out there
might not be something that's economically something they're going to
tackle anyway.

Dr. Brad Thacker

That's the company's problem.

## Dr. Cindy Burnsteel 

Right. Exactly.

Dr. Gillian Comyn

Well, but also technically I mean you know, for us, you know
regulation-wise an animal drug is any new claim even if it's being added
onto, I mean wouldn't it be considered still a new animal drug?

Dr. Cindy Burnsteel

As long as it's not an old drug, yes.

Dr. Gillian Comyn

Or it could be a drug that's had previous approvals but the point is
that just, the new animal drug, you know how it's defined I mean, that's

(male voice)

(inaudible) It's an SNADA, rather than a new animal drug

Dr. Gillian Comyn

Right as a supplemental but it's still a new, it's still a new
indication or a new, or a new claim.

Dr. Gregory Moore

Yes, but I think that's why we're here though. If we say it's a new
animal drug and we're asking for the addition of an organism, we're not
asking a, a change in the claim because\--

Dr. Gillian Comyn

Well, it is a change in the claim. It is. I mean, we're not, we're not
giving broad claims now. I mean \--

Dr. Cindy Burnsteel

But also, I guess what you are trying to say maybe is that if you are
using of the same dose, same range, and same everything else that
additional safety data may not be required and that it wouldn't be such
a big deal.

Dr. Brad Thacker

Pneumonia but just adding another organism to the other pneumonic
organisms that they have already demonstrated and the same species, just
another --

Dr. Cindy Burnsteel

I mean we still have to, or it still has to be (demonstrated), the
effectiveness still has to be demonstrated, but I guess the question is,
is a model study sufficient or do we need a field study and then we were
still at that point. Maybe if we can you know, work on a model study,
validate it you know, maybe that's I mean we're not saying no, it's not
the way to go at all, that's what we're here for.

Dr. Chris Minion

May I make a statement here? The problem that you have with this
organism is not like the problems that you find in the medical community
with cancer or anything like that when you've got well defined patient
populations that you can put into a defined study and answer the
question we want answered, is it effective in the field. You can't do
that with *Mycoplasma hyopneumoniae* because you get into populations of
animals and you don't know what's in those animals. You have no clue.
You can't define the animal population. You can under control conditions
where you get a disease. You know how, on clean animals but that's not
what you find in the field. We\'re not technically at a point where we
can go into the field and say is it effective in the field in that sense
because there\'s all kinds of viruses out there and other bacterial
pathogens that play into this complex disease that you want to cure, so
just because you have an effective drug against *Mycoplasma
hyopneumoniae* doesn\'t mean that it\'s going to be you know, effective
against PRDC because there are other components there. You don\'t know.

Dr. Cindy Burnsteel

And that\'s the disconnect, if it works in the model studies is it going
to work in the field?

Dr. Chris Minion

It might work in the field very well. And it might control the
*Mycoplasma hyopneumonia* in the field very well and PRDC but by the
time you give the drug to those pigs infected it may be too late,
whatever the mycoplasma is doing to that immune system is already
initiated the process to cause PRDC in those pigs. You may have
eliminated the mycoplasma but you still get PRDC in effect, clinical
disease. And you don\'t know, I mean there\'s too many variables, you
can\'t define them that well.

Dr. Eileen Thacker

And if you take that drug and put it into some PRDC if you reduce the
life of mycoplasma you may be never able to tell. I mean that\'s the
other problem. I mean maybe the mycoplasma is there, it\'s adding a
little bit, it\'s making everything else worse but to measure it that
could be a whole other, I mean if you\'ve got PRRSand you\'ve got
pasturella and you\'ve got SIV in there and you get rid of mycoplasma
you may or may not be able to tell. But that didn\'t mean that the drug
didn\'t work against the mycoplasma.

Dr. Brad Thacker

But that, but that\'s a study design issue with the power of your study.

Dr. Eileen Thacker

But that\'s PRDC, Brad. They have to define PRDC, right?

Dr. Brad Thacker Well, it\'s still a study design issue because you are
assuming that if (inaudible)

Dr. Brad Thacker

That\'s what they are asking.

Dr. Brad Thacker

I know, that\'s what I\'m saying is that the ability to detect a
difference in the study design. If there is truly a difference there,
you set your power (inaudible) at 80% or whatever and if you can\'t
detect a difference at that point then we say there\'s no difference.

Dr. Cindy Burnsteel

Okay, there\'s a question. There\'s a comment in the back.

(talking and laughing)

(male voice)

As I said before I left for the phone call I think we can, I think we
can tell whether or not the compound is affecting porcine respiratory
disease contact. I think we can tell within any group of pigs what ages
are present and so what I would say the label should be for treatment of
a PRDC when these organisms are present.

Dr. Cindy Burnsteel

For treatment or control?

(male voice)

For control of PRDC (inaudible) because that\'s really all we can say
right, Eileen? I mean beyond that\--

Dr. Cindy Burnsteel

That\'s if we do a field study, that\'s not if we do a model study.

Dr. Eileen Thacker

(inaudible) PRDC, because the fact that mycoplasma is there doesn\'t
mean that it\'s doing anything, we don\'t know that.

Dr. Cindy Burnsteel

But there\'s also not a hundred percent general consensus on PRDC
either, is there?

Dr. Brad Thacker

Well, but there never is, is there? Because is varies from herd to herd.

Dr. Eileen Thacker

That\'s what I\'m saying.

(male voice)

Because the veterinarian is a very sophisticated animal we will supply
him with PK data, microbiological data, on this spectrum of bugs, I mean
that\'s what\--

## Dr. Brad Thacker 

If I can\'t, as a clinician if I can\'t tell if a product\'s going to
work, I don\'t have a job, right? If I can\'t diagnose a disease, if I
can\'t develop an idea for the producer how much the disease is costing,
I don\'t have a job.

(male voice)

I think a lot of the frustration here is we\'re trying to figure out
what to put on the bags and the bottles so that anybody can just go out
and apply this stuff in any situation and I don\'t think you can do that
in here, I think. (inaudible).

Dr. Gillian Comyn

I think maybe part of it too, I mean you know, just, you know, you have
to show that, that the disease, it\'s not just that it\'s present, that
it\'s present but it actually is causing some disease and therein lies
your problem. I mean that\'s the whole thing in a nutshell. You know, if
you\'re going to say pneumonia, you know you have to say associated with
and not just, you can\'t assume you have pneumonia just because there is
something present. Yes, the chances are that it probably due to that,
but I, that\'s not, you know what I\'m saying? I just feel like you have
to have something more to nail that on.

(A lot of people talking over one another)

Dr. Cindy Burnsteel

We need to associate the disease with the organism or lesions.

Dr. Brad Thacker

When I was at Michigan State, I did a linco 200 trial on nursery pigs
and there were, you know, the pens were co-mingled and by the time the
pigs went to market the linco treated pigs when compared to positive
control and negative control, they had less lung lesions. So what would
be your interpretation about that. Was linco effective against
mycoplasma pneumonia and they grew faster (inaudible).

Dr. Eileen Thacker

What bugs were in those pigs?(inaudible)

## Dr. Brad Thacker

*Mycoplasma, Pasteurella*.

Dr. Eileen Thacker

(inaudible)you isolated those?

Dr. Brad Thacker

No, APP that we saw, we never... (inaudible).

## Dr. Eileen Thacker

So, then what you need to do then is you need to do a field trial and
identify all the pathogens and then you say this drug works with against
all these (inaudible) pathogens. Is that what you do?

Dr. Brad Thacker

Under, yeah, under these conditions.

Dr. Eileen Thacker (inaudible)

Dr. Brad Thacker

How many times does he have to show you that?

(people talking over one another)

(male voice)

You are showing efficacy against this clinical pathological syndrome not
against the bugs.

(male voice)

(inaudible)

Dr. Eileen Thacker

What\'s the difference? We do have the viruses, PRRS (inaudible).

Dr. Brad Thacker

No, not in 1984

Dr. Eileen Thacker

See that\'s the big difference, Brad.

Dr. Brad Thacker

So my, in that case it was Enzootic Pneumonia and my endpoint was growth
rate and lung lesions

Dr. Gillian Comyn

Okay, all right.

(male voice)

Brad, I think from a company standpoint that\'s dangerous because all
the sudden now something like CTC is going to be working as viruses.

Dr. Eileen Thacker

Absolutely, absolutely.

(male voice)

(inaudible)

Dr. Brad Thacker

I think you need, I think need both types of data to a point.

Dr. Eileen Thacker

I\'m not saying that I\'m just saying on the label that they
(inaudible).

(many people talking and laughing at once)

Dr. Gillian Comyn

Okay, time out. It\'s time to go home. Yeah just go to Starbucks on the
way home and have a nice cup of coffee and a scone and everything will
be just right, you know. Well, this has really been a, just an excellent
discussion tonight. I mean, I know I\'ve learned an awful lot and
everybody, every point of view has come out which is great and are there
any further comments before we close? Frank.

(male voice)

Explain to us what happens next. Is there a guidance document that is
going to come out, what are you planning?

Dr. Gillian Comyn

Basically, you know Christopher we\'re going to do, you know to go home
and you know, kind of talk amongst ourselves you know, about what we
discussed. Also we have to go back and get some of our review work done.
I notice you all noticed that we\'re all here, so we\'re going to be
working extremely hard over the next week or so. Yeah, I think
eventually from what I understand at a point where we are, when we get
to a point of publishing some recommendations about mycoplasma, about
study design, we\'re gong to publish an FR notice at that time, that way
it will be more even handed, everybody will see it at the same time. We
feel that\'s most appropriate. Is that, I believe that\'s what we
decided so.

Dr. Cindy Burnsteel

We also have to go back and Steve Vaughn is not here and he is very
interested in what has been said (inaudible) what they said and and the
views that have been brought out and so we need to get back together,
although most of us are here, we need to get together as a whole group
and really kind of hash out the different points of view that, that have
been brought up here, the different ideas.

Dr. Gregory Moore

We\'re to understand, we really won\'t hear anything that\'s official or
semi-official until after the comments period is over and is it going to
appear in the public document or public forum, how is it going to be
presented.

Dr. Gillian Comyn

It\'s going to be presented in an FR notice and of course I would assume
you know, we always put them right on the web page you know, that day
when they are, when they are. And you know, I\'d like to point out too
that Steve, our boss is, this workshop was actually his idea and he\'s,
he\'s very interested in really you know, we\'re trying to look at this
really scientifically and out of the box, I can\'t stand that term,
I\'ve heard it so much but you know, we really want to learn about it
and do a better job on our end evaluating these sort of claims and in
the bigger, the bigger picture is that we learn a lot about chronic
diseases as an entity in themselves. So, I think what we learn from this
is going to be applicable to other chronic conditions in other species
as well. So, this has been extremely valuable and I also will mention
that there\'s a comment period open about the workshop, 60 days. The
link is on the CVM website, please feel free to submit comments, if you
have you know, colleagues who would like to comment, anything to do with
mycoplasma and swine, the workshop you know we need to hear that
feedback. It will certainly help is in our process and in, you know at
the point when we do publish an FR notice you know, this will have a lot
of, this will provide some, some ideas for us I think. So, with that
I\'d like to thank you all and I really am so appreciative of our
speakers. Good Job. Thank you Don. We have an evaluation form in the
back of the notebook and if you have a couple of minutes to fill that
out and just put them in the back that would be great. That with you
know, comments, e-mail us, call us you know, let us know what you think
you thought about the workshop and what ideas you have about, about the
disease and about study design we\'re glad to hear it and anyway, thank
you very much. We really appreciate your participations and have a good
trip.

(End of tape Four)