(Crowd noises.)

DR. Comyn: We've got about three minutes 'til we're going to start, so
go ahead and get another cup of coffee and maybe a glass of water so you
don't get dehydrated, and we'll go ahead and get started at 10 after.
And Dr. Bradford will be our first speaker.

(Crowd noises.)

DR. Comyn: OK. Boy, you don't realize how dark it is here until you turn
all those lights on. OK, I think if you all want to find your way to
your seats and get another cup of coffee and some water, I think we'll
go ahead and get started.

Just a couple of administrative and session notes before I introduce Dr.
Bradford. Dr. Pijoan is going to give a -- he's going to speak for about
5 minutes after Dr. Thacker's talk, and we really appreciate that. He's
going to talk to us about their facility at University of Minnesota, so
we look forward to that. And OK.

All right, continuing our session three: Perspectives on Evaluating
Therapeutic Effectiveness Against Mycoplasma Pneumonia. I'm pleased to
introduce you to Dr. Jim Bradford. He works for Pharmacia. He's going to
be talking about pharmaceutical industry approaches, developing
therapeutic modalities for mycoplasma pneumonia, and designing studies.

He is a 1972 graduate of the Michigan State University College of
Veterinary Medicine. He was in private practice for 20 years in various
states, primarily dairy and swine. The last 10 years he has been at
Pharmacia, first as a technical services veterinarian, also as a
technical services manager. Now he is a global marketing technical
services consultant, and he is a board-certified veterinary practitioner
in food animal medicine. And I'm please to introduce Dr. Bradford.

DR. BRADFORD: Thank you. I'm going to speak today as a pharmaceutical
representative, but as was explained, my background is practitioner. And
so I look at things, a lot of what we heard over the last few days, as
very interesting and very helpful information. But when it comes to
doing pharmaceutical research, we're in an entirely different realm.

One thing I would like to do is compliment CVM and ONADE on pulling this
group together to help everyone, all stakeholders in this issue, better
understand the situation, the current situation, and how we'll go in the
future. Secondly, I would like to thank, from our own clinical
development group, Curtis Miller, who was the leader of the group at the
time that Lincomix® when through its approval process.

Now, that was a long time ago. It was 1976. And so some of the data I'm
going to show you is dated. I also wanted to show you some of the
timelessness of the data. Also, in that effort, two people who worked at
VMRI, Dr. Frank and Dr. Barnes, were involved in some of the work that
we did. Let's see. We can go to the next slide.

I'm not going to spend a lot of time talking about the disease; I think
we've heard as much about the disease as we need to know at this point.
It is a clinical and production disease, and it has a financial impact.
So we'll leave it at that and go on, but I do want to read the, just the
short version of the FDA approval for Lincomix®, and that is "for the
reduction and severity of pneumonia due to mycoplasma hyopneumoniae." It
is a very carefully worded claim, and you'll see as we go through the
research why it is worded that way. And that was granted in 1978. Next,
please.

I'm not going to go through this at all. I think two key points that
*Mycoplasma* *hyopneumoniae* is a potentiator, or at least it sets up
the co-infection for *Pasteurella* *multocida*.

And some APPs, and then PRRSV, Drs. Thacker and Halber have shown that
there's definitely an interaction in which mycoplasma is the potentiator
for PRRSV infection, and that it is additive to a swine influenza.
That's the situation today. OK.

When we think about clinical endpoints from a pharmaceutical trial,
we're not looking at "are the pigs coughing" or "what is their rate of
gain" or things like that. From a pharmaceutical swtandpoint, we have to
prove that we have some effect on the clinical disease. And quite
frequently, what I would refer to as a clinical endpoint would be
referred to as a pathologic endpoint in the discussions that occur
today.

And that is -- we're going to look at number of pigs affected, number of
lobes involved in each pig, the percent of lung involved. We did do
respiratory scores, and respiratory scores are still part of evaluations
today. When we worked with Dr. Thacker on her trials, she still looks at
many of these components as part of the evaluation process as to whether
a product or a preocedure or a change in an intervention has any effect.
So those are things that are still very good.

The only really clinical part of this is cough and respiratory
difficulty, from your standpoint -- or from a veterinary standpoint.
From a pharmaceutical house's standpoint, these are clinical endpoints
as well. Next slide, please.

In the pivotal studies, there were actually three studies -- there were
three different types of studies that were part of the pivotal study.
And *in vitro* MIC determination for the challenge strain that we
eventually used in a challenge trial, the second portion of the pivotal
studies, and then followed by field efficacy trials. The *in vitro*
determination was done with the best techniques available at that time,
with a single strain -- I believe it was strain 11. And that strain had
a MIC of .25 micrograms per mL, at that time.

Challenge trials then were done, similar to what challenge trials are
done today. It was with a lung homogenate, because *Mycoplasma
hyopneumoniae* does not function, or does not create any disease if you
introduce it as a pure culture. It really likes being in that lung
material, so lung homogenates are still used.

We did that trial to determine a dose titration and a duration of
treatment. Then we took it to the field to see does it really work in
the real world. Next, please.

Challenge models were problematic even in the 1970s. Finding herds free
of mycoplasma pneumonia are just as difficult as they are today,
although now I think there are more clearly identified herds and flows
where you can locate mycoplasma -free pigs. At that time, these pigs
usually were cesarean-derived or offspring of cesarean-derived pigs.
That challenge model usually gives us a very mild disease compared to
the field challenge because it is mycoplasma. There should be nothing
else in there; there should be no *Pasteurella*. There should be nothing
else in there. This is just to see if we get an effect against
mycoplasma alone.

All animals are at the same stage of infection. And I think as a result
of that, you can get a false sense of efficacy. Because if you infect
pigs once, and they're all at the same stage of infection, when you
place the medication in place, you're going to get an effect on all
animals at nearly the same stage of infection. That could give you a
false sense of efficacy; that's why we do the field trials.

You can also treat at the very earliest -- in a control trial -- at the
very earliest appearance of clinical signs, which may give you an
advantage. Or in some cases, you may actually, if you were going for a
prevention claim, you would treat before the appearance of clinical
signs. Next slide, please.

This is the design of the trial that we did, the challenge trial that we
did. I didn't put specific numbers in there, because I think specific
numbers are determined by the challenge that's induced in how you can,
as far as numbers of pigs. But you can see we had three pens each, at 7,
14, and 21 days, and at zero, 110 ppm, 220 ppm, and 320 ppm. This is to
bracket where we suspected would be the effective dose, and compare it
against a negative control.

The 7, 14, and 21 days -- at that time, feed was delivered at 7, 14, and
21 days. That's why -- you do build some practicality into your trial.
Today feeds may be delivered differently, and the dose, the duration
that we might look at might be different. We can go to the next slide.

Treatment was at the onset of clinical signs when that clinical disease
was present. The cough began at about 8 days post-infection; we had
about 14 percent of the pigs coughing at that point. We expected it to
be a little bit later than that, but we initiated treatment on day 8.
Next.

The clinical endpoints in this trial were to give us a percentage of
lobes with lesions, which is an incidence measure, and a percent of
total lung with lesions, which is a severity measure. Go to the next
one.

Based on the challenge model, on percent of lobes, no difference in
incidence. And look at the very high incidence of lesions. Lincomycin,
as are all the other antibiotics in mycoplasma therapy, or suggested as
being effective for mycoplasma therapy, are static antibiotics. They are
not sital antibiotics, so they do not kill the organism. And there will
be lesions and there will be organisms in the lung. So that's an
important thing to realize. There was a statistically significant
difference between 220 and 300, compared to 100 and zero, on percent
lobes, which is incidence, and also severity incidence, percent of lung.

Now, in the challenge model, again I think the thing to note is the
percent of lung involved in this study was about 10 percent. Studies
I've seen since with challenge models -- either we've cleaned up our
challenge model or pigs are a little bit less responsive, because now 5
percent, 3 to 5 percent --

Dr. Eileen Thacker: It varies.

DR. BRADFORD: It varies quite a bit?

Dr. Eileen Thacker: Yeah.

DR. BRADFORD: OK. And it varies quite a bit in individual pigs as I saw
in the trial that we did recently. But at any rate, again, 220 and 330
both were statistically better than the zero and 110. We don't prevent
infection, but we do reduce the severity. Duration of treatment and the
percent of lungs with lesions, although there is no statistical
difference, it is apparent that at least in these two doses -- which are
the two doses that were considered, because there is no difference
between 220 and 300 -- there was a numerical difference based on the
number of days that the medication was fed.

So statistically, this is not different than this. This is not different
than this. So 7, 14, and 21 days at either dose gave similar results
statistically. Next slide, please.

So the conclusion was, in the challenge model, the lincomycin at 220 and
320 ppm resulted in significant reduction in severity and incidence. The
optimum treatment regime based on lesion and performance data, which
performance data I didn't show because performance data is not part of a
clinical efficacy package, was 220 ppm for 21 days. OK, that's based on
the challenge model. Let's go to the field trials.

Field trials were conducted in herds with history of MPS. OK, these pigs
were already on the farm; these are pigs like you see today without
PRRSV. But still, pigs in the system at all different stages of
infection when we started the trial. And probably a little bit more
variation in infection than what we see in all-in/all-out units. In
other words, these pigs were in continuous flow units at that time, so
the stages of infection may have been more variable than what we would
see today, with more defined populations going in and out of the
all-in/all-out units. Next slide, please.

Four trials, as you can see, where we conducted the trials would not be
where there would be a lot of pigs today. But at that time pigs were
raised all over the United States.

Dr. Eileen Thacker: Did you do your four trials in (inaudible)?

DR. BRADFORD: Probably (laughter). Probably so. Indiana, Florida,
Alabama, and Minnesota were where the trial barns were located. The pigs
were 8 to 12 weeks of age on entry. In an effort to determine that
mycoplasma truly was an issue in these barns, we killed six cohort pigs
before we even started the trials, and identified lesions, gross lesions
typical of mycoplasma pneumonia which were then submitted for
confirmation. The trial was run before the confirmation came back, but
indeed they did have mycoplasma pneumonia.

Three sites, tested four inclusion rates. Again, including the 330 ppm
to see if we had a better effect in the field with that, and also
including the zero and 100. One site tested only zero and 220 because of
limitations at that site. Next slide, please.

We looked at the gross pathology, the number of lobes involved in
estimated percent of total lung involved. And this was -- I think today
we could do a lot better job on estimating the percent of lung involved,
but it's still a visual assessment. Microscopic pathology, we looked --
took a section of the right cardiac lobe, sampled, and looked for
histopathologic lesions typical of mycoplasma. We also recorded
production parameters of average daily gain and average daily feed
intake, because that's what you sell to the farm.

OK, replications for treatment, there was 15 -- remember, the site in
Alabama did not have sufficient, or didn't have the right facility, so
we got 15 sites at 220 and zero, and 12 sites each at 110 and 330.
Percent of pigs with MPS lesions, very high; no difference. This is --
the pigs were killed in this case at, after the 21 days of therapy. And
that's something that you need to talk about in your trial design,
because I think one of the points you mentioned in your trial designs is
what about relapse, what is -- the question of how do you measure
relapse.

Lesions are going to be there for a long period of time. And this is not
a particular -- it just says that all the pigs got exposed and all the
pigs had the disease. Next slide, please.

In the field, the percent of lobes infected was significantly different
between zero and 200, nearly significant but not at the 100. And so,
again, we settled on the 200. All these pigs were fed for 21 days, by
the way. So this again shows that 220 ppm or 200 grams per ton would be
the effective dose. We can go to the next slide.

Percent of total lung involved on all pigs, definite difference here:
220 ppm reduces severity by 49 percent; 110 by 27 percent. And the --
that's percent of lung, and A and B are different at 0.10. This speaks
to the difficulty of being able to control the situation in a field
situation.

We had *Pasteurellas* in here; I'm sure we did. I'm sure we had -- we
had one trial scrapped for *Haemophilus parasuis*, because the lesions
were -- it was impossible to determine what was what when you opened up
the pigs. But there are other organisms in here that are creating some
of the issues. The advantage that Lincomix® has in this type of
situation is it's not effective against those other organisms; it only
works on mycoplasma, so it has a narrow spectrum in that lung. So any of
the improvement that we get is due to effect on a.

The other thing that we use to help us understand the effect of the drug
was to attempt to age the lesions, and Kent Schwartz talked a little bit
about this yesterday and I think the comment that he made is, "Y'know,
if you look at one part of the lung, you might see this, and another
part of the lung, you might see that." But still, as an attempt, to
attempt to age the lesions, and we had the pathologist at VMRI do this,
rate them as acute, early or late acute. And the definitions I haven't
exactly, I haven't included in here. But let's assume that they were
able to do this in sub-acute, regressing, chronic, resolved, and other
pneumonias.

And the point is that in those that were treated, there were
significantly less acute lesions. So the pigs that were already infected
when we started the trial passed on through that. Pigs that were not
treated continued to develop acute lesions. So new infections were
occurring in those pigs that were not being treated, and far less new
infections were occurring in those pigs undergoing treatment. Next
slide, please.

So the trial conclusion on that was lincomycin administered in the feed
at 220 ppm for 21 days is effective in the reduction of pneumonial
lesions. That's what the claim is; that's how the claim was achieved.
Can we go to the next slide, please?

Based on 25 years' experience with this drug in the field -- and '76 was
only four years after I graduated from school, so I've been there for a
lot of it -- it is possible to measure clinical endpoints of mycoplasma
pneumonia, both the clinical trials and in field trials, and we continue
to do that today. Bill says that, Bill mentioned that they don't do as
many slaughter checks. We do, in cases where we're trying to evaluate
the effect of the drug for one reason or another.

I also agree with the comments made yesterday that what occurs early in
the production phase may have already been healed and gone by that time.
But as has been described by many of you, late in the production phase
now may be where this disease is occurring. And so we can still see
substantial lung involvement in those pigs late in the production phase.

The approval process to provide substantial proof of efficacy was
rigorous, and has withstood the test of time. When we go out today into
PRRSV herds -- and I'll show you a little bit of data in a few minutes
-- we still have a very effective drug in influenza herds. You can go
into herds with the complete mish-mash of porcine respiratory disease
complex, and still show that a product works. So I think the clinical
and field trial efficacy is still very important.

Production parameters are important; an auxiliary component of the
research process, but at the time that we took this through, and I
believe today, they're not part of the approval process. Next slide,
please.

So if we design a plan today, and I sat down and talked with our
researchers about this, we'd still do the laboratory work, and there are
plenty of people who have run mycoplasma MICs recently, and the MIC 90
is still about 0.5. Where people, we also know better today what the
level of lincomycin is at the site of infection. In the
bronchio-alviolar fluid, we've determined that. And so that gives us a
much greater level of confidence that we can achieve that level and
maintain that level, using the feed-grade antibiotic.

The challenge, validated challenge models run in production-line
facilities for dose and duration, studies I think are still important.
And field trial efficacy trials with dose and duration confirmation, we
still do all of those. Now, would they be different? Yes, I think they
would. We go to the next slide.

I just want to show you that one of the things that we've done here is
to determine in the epithelial lining fluid, the level of lincomycin
that reaches that epithelial lining fluid, which is about 1.2. This is a
calculated number based on lincomycin behaving the same whether it's
injected or whether it's consumed orally, but it achieves a level of
about 1.2 micrograms per mL. And that's about 2.6 times above the MIC
90. So we can show that the drug actually gets to the site of infection.
Next slide, please.

If we designed it today, the field efficacy trials would be much larger
because the experimental unit has changed dramatically. And we think
that there would definitely be multi- location, just like it was this
time -- four or five locations. And we would probably do them globally
as well as multiple sites in the U.S. They would be production units;
they would have to have this history of respiratory disease.
Co‑infections with PRRSV would be not only acceptable, would be welcome.
Because when we go to -- when we look at it from my side and we have to
go market it, a pure infection is not going to do me any good; I'm going
to have to prove it in the real world.

Here's where we're going to get into much larger trials. What is going
to be our experimental unit? I don't think today that we would pick a
pen or a room. I think we would pick barns and sites. And so that
greatly expands the size and scope of the trials. Next slide, please.

We would still use those clinical endpoints because does give us some
very definite things to measure. I think some of them could be measured
more accurately than they could have in the past. I think the imaging
and with grid systems, or even with trained people who have gone through
the pigmon program and can do consistent, repeatable results, I think
this might be a little bit more tightly measured. The fluorescent
antibody test, or the amino-histochemistry, or PCR would give us
indication that that really was mycoplasma at the site where the lesion
occurs.

And I think that's the key point of all we heard yesterday is mycoplasma
by itself, no big deal. Mycoplasma in a lesion that's causing pneumonia,
it's at least associated with the pneumonia if not the cause of the
pneumonia. Next slide, please.

Just wanted to show you -- Teddi Woolf suggested yesterday that maybe I
should bring in some of the serology, and Bill showed some of theirs
this morning. And Carlos alluded to this yesterday. Gary Bosch, who was
technical services veterinarian and marketing manager for Pharmacia, as
part of the beginning of a master's thesis, was involved in the
collection of well over 150 herds. And what we were trying to understand
was the inter-relationship between PRRSV and mycoplasma initially. Most
of these herds had mycoplasma serology, influenza serology, H1N1,
because at that time H3-N2 hadn't started around. They had the nested
PCR swabs, and that would be the three that we -- and PRRSV serology. So
we've got PRRSV, mycoplasma serology, SIV, and PCR.

And I'm not going to bore you with going through the details of all of
this, but what we identified were four patterns. And Bill said, and
Bill, I like that, this is not hard science; this is looking at enough
of them to see a pattern. And I think you have to look at a sufficient
number. Our database today now holds over 250 herds, roughly, and
they're global.

But the black bars are PRRSV virus, and PRRSV sero-conversion certainly
has an impact on *M. hyo* sero-conversion, and that's what we were
looking for -- the interrelationship. The PCR helped us determine, as
Carlos said, if it's in the nose, it's going in or it's coming out. So
it's undoubtedly a time of spread. This was the confusing part that, I
think that Carlos alluded to yesterday. We have mycoplasma spread fairly
early, these PCRS here. But we don't get the real sero-conversion until,
or the high spread until late, but yet PRRSV is very active.

We were able to correlate in two types of herds PRRSV and mycoplasma. In
the stable herd and the herd approaching stable. The unstable herd you
can't correlate anything with anything, and pigs die (laughter), and we
are not going to put our drug in that treatment, in that treatment mess.
So that was the first thing we learned, this group here. In these two
groups lincomycin has a place, and we know how to place it today.

QUESTION: Is vaccine use for mycoplasma not part of that, of all those?
Or is it a mixture -- some of them had vaccine use, some of them don't?

DR. BRADFORD: Some of them have vaccine and some don't. And as a matter
of fact, these slides are actual slides -- and I haven't really, I'd
have to --

Dr.Carlos Pijoan: (inaudible) start and then it stops, and then it comes
back (inaudible)?

DR. BRADFORD: Exactly, exactly, I was just trying to look for one that
had an example here. I think the, well, I'd have to look at those a
little more closely. But the idea is that, yes, there are vaccinated
herds, there are unvaccinated herds. And the two pieces that I'll show
you next are in vaccinated herds, and this is where we've actually put
the medication in place using this type of an approach.

This is a cull percentage in a large production system. This is the mean
cull percentage, the average cull percentage was 8.57 percent in the
Linco groups -- or the non-Linco groups prior to an intervention. This
is the cull percentage with a mean of 5 percent. And what we were doing
was just tracking what would happen when we put something in a system.
Next slide, please.

This is another system; this is percent culls. And they had been on a
Lincomix® program for a long period of time. And what we were doing in
this herd was monitoring, and they came to a budget cut, and budget cuts
have a lot of effect on what medications, what medication or if any
medication program gets used. And here was the lincomycin that was being
pulled. This is percent culls. We'll go to the next slide.

Percent mortality. And then the next slide, these are the pigs that they
don't get paid top dollar for. That mean right there is about is 11.564,
but that's across all groups. You can see that when they were under
medication they were sailing along a little bit better. And I'm not
pointing this out to point out the Linco efficacy. What I'm using this
\[for\] is to say that there are ways that you can measure the impact of
the drug that are not strictly production. And maybe culls and mortality
would be part of that. Y'know, we always say that this is not a
mortality issue, and it's not a mortality issue in the lab. It is a
mortality issue when we get to the finishers. So, I think that's the
last slide.

I'd like to thank the CVM again for the opportunity to speak, and I
don't know where we are on time.

DR. Comyn: We're actually great. We've got time for some questions. And
just so we can record them, I'm going to carry to microphone around. Is
that OK with you?

DR. BRADFORD: That's fine.

DR. Comyn: All right.

Dr. Carlos Pijoan: I have a question about (inaudible). We have all
kinds of (inaudible), and most people use their own (inaudible) process
and (inaudible). But I think more and more Bob Morrison showed
quite(inaudible) a long time ago, that the way that the average of those
lobes in not 10-10-25(inaudible) then there's another benefit that's
being looked at, which is (inaudible) percentage of weight being
affected lung and the un-affected lung(inaudible), affected pig
(inaudible). And that's a lot of work and we didn't see much difference.
(inaudible) But I do think that corrective scores is an important thing
to consider as an additional\... (inaudible)

DR. BRADFORD: I would certainly agree with you, Carlos, and I think that
as the technology improves, I've often wondered what we can do with
ultrasound and other methods as well just so that we could either
predict in the live animal, or I think today, if we were doing the
trials, we would do serial kills along the way. If we were going to use
slaughter as an endpoint and look at lesions there, I still think we
would do serial kills of a percentage of the population as we went
along, so that we could see the progression of the disease in that unit.

Dr. Carlos Pijoan: (inaudible) especially in the challenge trial, where
we usually convert models to percents, we're looking 5%, 10%(inaudible)
percent (inaudible), those small lesions(inaudible), I think, we cannot
do more precise(inaudible).

DR. BRADFORD: I'm in full agreement with that. If any way that we can
put precision to those measurements, which are undoubtedly are very
coarse, I think that's a massive improvement. Brad?

Dr. Brad Thacker: (inaudible) that we use and was developed by Dick Ross
(?)(inaudible) to diagram the percentage of the area that (inaudible --
then he is miked) Is it on now? OK, well, anyway, so it's done by -- and
there's several artists that we've had. I'm not a very good artist, so I
never get to do that job.

But, and so in addition to that image score, a lot of times I'll also do
an evaluation, somewhat like the pigmon system, except that, for each of
the seven lobes I evaluate, instead of using the pigmon formula, which
is not correct, I use actually a formula that I developed at Michigan
State, which is almost to the percentage point the same as Bob's. And
there actually is the one, if you really want to reference once, you
should use the one in Diseases of Swine, which is from a guy in Denmark
or the Netherlands, which is almost the same as well.

Because what, like 65 percent of the lung weight is on the right side.
The problem with weighing lungs is it works pretty well for APP where
you're getting a lot of infiltration of inflammatory products, but for
mycoplasma the weight isn't that much different, whether they have
lesions and the lesions aren't that much. So. The one thing, Jim, that
on the statistical process control charts, I get a little worried when I
see a chart that isn't the right one, having been through those courses.

DR. BRADFORD: I understand.

Dr. Brad Thacker: And so an eye chart is not an appropriate chart to
look at proportional data, because it needs to be a P or an NP chart
depending on whether the denominator is consistent or not. The other
thing is that I look at cull and mortality data as a production thing
for me, and that we really pay a lot of attention to it. You have to be
a little careful, though, in a herd in evaluating that to make sure, and
with any use of SPC charting, that the process is the same.

So what I'm getting at is on many of our farms, we market pigs by a push
strategy, which means that they're pushed out of the system, because if
we've got to make room for the weaned pigs coming on. So for instance,
culls and lights, on a lot of the farms I work with, that percentage is
much or more affected by what's coming out of the farrowing barn than
how the pigs are growing. It's rare, and Bill, I don't know how many
farms you work with that truly have a pull strategy; I don't -- it's so
rare.

Dr. Bill Hollis: Not in the last two years.

Dr. Brad Thacker: Right. So you have to -- and it gets real complicated,
so the SPC charting is only meant for a process that is consistently
done. In fact, in a manufacturing sense, if you have, say, a machine
that's running 24 hours a day with three different operators, it's
really not correct to use an SPC chart for that machine; it should be
for each operator on that machine. So it gets -- I like to use them, but
I think it's -- because they're powerful tools. But there are some
mathematical limitations to it.

DR. BRADFORD: I appreciate those comments. And the SPC charting is
actually -- I'm using it looking as more of looking at a large volume of
data as a tracking tool rather than as a specific decision tool in this
case. The, in those systems that I showed, those systems are in constant
operation with -- you've got to believe that in a large system like
that, the changes that you describe in pig flow certainly would be
seasonal and would be, could impact on that. But those were done across
large numbers of pigs in a large season. We hope that over that amount
of time that that balances out the differences in those types of things.

Dr. Bill Hollis: I don't think it needs recorded; you can repeat it. I
think you can answer for me, if you would, I think you can measure the
standard deviation market weight to try and bring some level, or adjust
for that level. I mean, it wouldn't be the real data, then. What you're
looking for is the difference in the data, not the specific endpoints.

DR. BRADFORD: Yeah, I think that's true, and I think the data set that
we have has all that information in it as well.

Dr. Don Walters: I just have one brief comment on the SPC chart, in that
the limits should be recalculated when you institute a known process
change; that allows you to visually see the impact much more clearly.
And then a comment for the benefit of our FDA host, on some of the
practical implications of the sometimes very rigid boundaries we place
on new label claims.

And that is, that for medication products like this in feed, and feed in
particular, when we put a strict number of days that this medication
must be used -- such as 21 days for lincomycin, 21 Pulmotil, 21 Tylosin
-- we are forcing virtually every producer that uses those products to
be out of compliance. Feed is not delivered on a daily basis typically.
It's delivered in batches, and it depends on how long those batches of
feed last as to how long that medication will be in front of those pigs.

Water, we can control what day it goes out, what day it goes out. But
feed, we cannot. You're virtually forcing everyone out of compliance
when you have a rigid number of days on your label claim. One way we
address that, recently on the Denigard approval for ileitis was to have
a lower limit, and then you have upside flexibility. For example, the
claim reads "feed it for not less than 10 days," so that you can either
have a two-batch or one-batch or three-batch, depending on how long the
batches last, and be in compliance.

Now, it really hasn't hit the industry between the eyes because there
haven't been any enforcement action based on these monitoring and
forcing compliance with these 21-day medication things, only if residues
were resulting as a problem would it have hit people between the eyes.
But I think in the study design phase of these new approvals is when you
need to build in these allowances for measures to help you draw a lower
limit of time that medication needs to be fed, and give you some
flexibility on the upside.

DR. BRADFORD: I would like to concur with Don on that statement. And
also on inclusion rate issues. When a company like us with Lincamix that
has four legal inclusion rates, in the case where Bill mentioned,
ileitis with some mycoplasma control from an inclusion rate that's not
labeled for mycoplasma pneumonia. The producer's looking at production
improvement, and if they get production improvement, as someone said
earlier, they don't really care about histology, nor can they spell it,
nor do they care what percent of the lung was infected. They do care to
have a cost-effective therapy added, and I would concur with Don on his
comments.

DR. Comyn: Thank you very much Dr. Bradford OK.

(End of Side A)

**Dr. Eileen Thacker:**

(Tape starts mid-sentence)

Dr. Comyn: \-- I just have to do it, y'know. OK, Dr. Thacker obtained
her D.V.M. from the University of Minnesota and her Ph.D. in pathology
from Michigan State University. She worked in the field of chicken
immunology as USDA for two years. She joined Iowa State and has been
working there for eight years. She is board-certified in microbiology.
And we appreciate her giving this talk again today; she's going to be
speaking on -- do you have the, OK, you've got that -- and she's going
to be talking about mycoplasma pneumonia disease model. Thanks.

**Dr. Eileen Thacker:**

OK, before I get started I want to talk a little bit about this meeting
and about the whole thing. I got started working with the people here at
FDA-CVM thanks to Mike Apley at Iowa State, who they had called, talked
to Mike, 'cause they work with Mike a lot, and asked who they could talk
to about mycoplasma and he said, "Call Ma Thacker." That's what he calls
me, Ma Thacker.

And so it started in June of last year. I went out, we discussed
respiratory disease. I managed to totally confuse them. So then they
decided that then in September they would see about coming out to Iowa
State, and then they were also going to go to North Carolina to see
swine respiratory disease. Well, and Princess Nabil and Janice, we had a
great time; we showed you a good time in Ames, right?

Well, unfortunately that also fell over September 11^th^ so they had the
fun trip of driving home to Washington, D.C. They weren't able to get to
North Carolina. So then this meeting started to come about, and I think
it's wonderful and I think as an industry and as veterinarians, we do
have to address this.

As I've told a number of you, I'm chair-elect for the animal health
division of the American Society of Microbiologists, and I was asking
Chris, "How many are there?" And he thinks between 45,000 and 60,000
people in that organization. That organization now, when we got to their
meetings -- and Brad and I have both seen this -- there are whole
sessions on anti-microbial resistance. Many of them are finding it --
and Chris is going just be going crazy, 'cause he's not going to agree,
I know -- but it's easy to blame the veterinary profession and us for
the anti-microbial resistance.

And it's not just swine, it's not just cattle. We got abstracts for this
year's meeting, blaming dogs and cat therapy in the hospitals,
nosocomial. What is this saying to you guys? They could eventually make
it very difficult for veterinarians to use antibiotics, and it may come
to the point where you cannot use a product that doesn't -- you have to
come up with a diagnosis, you have to have the label claim that says
that organism, you have to use it for the exact set period of time, and
it's going to be regulated.

My question then is what do they do with all that Cipro with the
anthrax, where they gave how many thousands of people -- and you know
they followed just like that (she snaps her fingers). How many of us --
and I'm just as guilty; they give me antibiotics when I've gone in for a
cold, my children for ear infections, so on and so forth.

I'm not saying anti-microbial resistance isn't a problem, Chris, but we
also have to look as veterinarians that, if they restrict our use of
antibiotics -- and I have heard it with a number of talks -- the humane
issue becomes very important. So as we look at this, it's easy for us to
just think, "Oh, if we ignore it, it's going to go away." But there is
the potential that it could have a great impact on our profession as far
as our ability to use antimicrobials.

So we need to help the people in FDA-CVM to figure out how to approve
antibiotics for our needs, for our wants, and for our -- to meet our
clients' requirements.

OK. And I think it's wonderful that, like, Carlos and the University of
Minnesota are looking at eradication; this is something that's going to
become very important. Vaccine use is going to become increasingly
important because that again will hopefully diminish our use, our
requirements for antibiotics. But we are always going to have be able to
use antibiotics for a humane issue -- even a food safety issue. To me, I
would rather eat an animal that had been administered antibiotics than
one than hasn't and is sick. But public perception is everything, right,
guys?

And so we have to be sure that, as I think as a group, veterinarians are
not as proactive about these things as we need to be. And look at Roy
and these guys are talking about the Japanese want antibiotic-free
animals. And we look at farms, and farms that can eradicate the
diseases, and that's wonderful. But there's going to be an awful lot of
the clients that we can't eradicate it. And so when we look at these
antibiotics, and what I'm going to talk about when I talk about model
systems, is something that we have to decide what we need on the labels,
what we need to help these people determine.

And while Dr. Bradford said, "Oh, all they care about is production,"
and I'm sure Carlos is running into this, and I know people are calling
me, "Well, what antibiotic can I use to eradicate mycoplasma?" So we've
got a number of different needs within the industry. We've got people
that want to use antibiotics to improve production. We've got people
that want to use an antibiotic for eradication. So those are going to be
two different measurements, and so the poor people in FDA-CVM are
looking at this and saying, "Well, what do we do here at this point?"

And so I think it's something that we really do have to address as an
industry -- not just you poor pharmaceutical people that are trying to
get a product approved, but we also have to get this across to the
veterinary medical field and the veterinarians that we have a stake in
this. And I practiced for seven years, and I'm married to a guy that's
out with pigs all the time. Anybody that knows me knows I don't really
like pigs; I do research on pigs and so on and so forth. But the point
comes down to is we have to look at the needs of the veterinary
profession, humane treatment of animals, and what's best for the public.

So based on that, when they asked me to talk about modeling, I'm going
to just talk about what we need to do. Next slide.

So what are we going to look at? I mean, depending on what our goal is
-- productivity, clinical disease, percentage of pneumonia, both
macroscopic and microscopic. And then we also have to look at the number
of organisms. Reduction and/or sterilization. Now, there's going to be
very few cases where we can sterilize. But these are potential goals,
and what this goal is, is going to determine what we measure and what
the model will have to consist of.

That's the bottom line. I mean, there is no set answer at this point to
give these poor people that are trying to determine what to do to
approve antibiotics.

So what do we need to measure? Maybe all of the above. Maybe we, y'know,
we need to show production, clinical disease, percentage of pneumonia.
And perhaps we need to know the number organisms. And depending on what
we're looking at, we can do that. Now, like Dr. Bradford said, the other
thing is our technologies have changed immensely since 1978. Next slide.

When we look at mycoplasma, and of course the FDA-CVM would have to pick
one of the hardest organisms to work with, period, ever in the world, I
have an advantage -- and people think the reason I got into mycoplasma
is because of a big interest. Well, like I told you, I came from
chickens preferring viruses.

But see, I have a secret weapon. I have two secret weapons: I have Barb
Erickson that has grown mycoplasma for 30 years, and is probably one of
the few people in the world that can do it. We train people from all
over the world to do it. They go back; they try to do it and it doesn't
work very well. And I have Nancy Upchurch who has been making her media.
In order to isolate this stupid little bug, we have to make all of our
media from scratch. We never change anything.

But then all of a sudden, like within the last six months we've been
having a hard time getting it to grow. We never know if one of our
suppliers has changed a product that we don't know about, getting
negative swine serum is always a headache. I mean, everything has to be
made from scratch; everything has to be done just right. We moved; we've
got a different water source now. We're in a different environment;
mycoplasma might not like being in the vet school versus VRMI. God only
knows! I mean, sometimes I think it's the phase of the moon.

But the bottom line is that isolation of the organism -- and I worked
with a company within the last year, and they wanted to get new field
isolates, and I know Bayer people were asking me for field isolates.
Everybody asked for field isolates. This study that they were looking at
in an antibiotic, they wanted to isolate mycoplasma; I don't know
anything about it other than they asked us to help them work with it.

We had, received -- made up little kits with our mycoplasma media; we
told them how to collect the lung samples. We got over 200 lung samples.
We got so we would do PCR first to see if the bug was even there. And of
that 200 samples, we were able to isolate mycoplasma from three of them.
Three.

When people ask for mycoplasma isolates, I had a graduate student that
spent eight months down in the diagnostic lab working and working and
working, and she got six isolates. So what we see here is a pathogen
that is very, very difficult. So you guys really set yourselves up; I
mean, you had to pick something really difficult.

So we have to look at that. Field isolates grow very slowly. I mean,
field isolates -- it'll be eight weeks before we even know they're
there. And this is one of the reasons that I think some of these herds
can be very low-positive, where we see that 5 percent serum-positive.
It's because the organism just grows very slowly.

Long-term effective culture on the organism, they've, no, we've shown in
our lab that after about 9, 10 passages, the proteins that Chris talked
about change. So trying to keep low-passage organisms can be very
difficult, especially since we sometimes have to passage it three times
before we can even tell the bug is there.

Are there bacteria overgrown -- and our biggest enemy from
*Mycoplasma*mycoplasma *hyopneumoniae* culture is *Mycoplasma
hyorhinis*, which if it's present will just overgrow the culture, and we
cannot tell if hyopneumoniae is there or not. Or if it's there, it's all
in material because we can't get rid of the *hyorhinis* very easily.
Next slide.

So, as far as starting to look at modeling for this, I mean, I agree
with Jim: first we've got to see if it works in vitro. I mean, you can
do MICs and Ching-Ching Wu at Purdue has a wonderful system; she has a
lot of different isolates. Most of the isolates are old, though, because
it's so difficult to isolate the organism, we don't do it on a routine
basis.

We also have some in vitro culture techniques that we can look to see if
it affects the adherence to the cilia and things like that. But we have
to be careful about taking anything we do in vitro with *Mycoplasma
hyopneumoniae* and putting it into the pig, because of that location
that we talked about yesterday. It's not intra-cellular; it's not in the
blood. It's out on those cilia. And like Chris says, it has multiple,
multiple mechanisms to do what it's doing.

So we can look at this pig alone, and one of the concerns that really
comes up is that we provide the challenge inoculums for almost everybody
that's doing everything. We use strain 232, which is the pig number that
was infected with strain 11, Jim. It's very old. We use a lung
homogenate; others use culture. The reason we got away from using
culture is because of the extreme variability. Inducing Mycoplasma
pneumonia is very variable to begin with. When we used culture, we had
even more variability.

And because of the changes of the organism in the media, we have gone to
producing a lung homogenate. What we do is we take -- and boy, I hate
making lung homogenate 'cause you're chewing your fingernails the whole
time -- we both them, strain 232 lung homogenate from a previous pig
into pigs. We usually do at least nine. We weigh it, grow it up to 28
days, we collect the infected areas of the lung, we keep each pig
separate, we culture it for bacteria, we isolate -- we do complete viral
isolation, we only select the ones that are negative for everything.
Then we put that back into pigs that are negative and try, do the whole
thing again -- not collecting lung but just confirming that we didn't
infect them with bacteria or viruses.

Could we miss something? Absolutely. But it does induce the most
consistent pneumonia that we've been able to get. Unfortunately, even
doing that, production parameters are very poor in our experimental
models because we tend to use clean pigs. We get a fairly consistent
percentage, although we can get everything from 3 percent average
pneumonia up to 12 to 15 percent. So it's variable, and it's not, y'know
-- Brad, thank God he's my statistician -- but it's not unusual that our
standard deviation is larger than our mean. So it's not easy; it's not
an easy organism.

And then when we look at the number of organisms -- now, Chris, Brad,
and I have within the last year developed and have almost completed
validated a quantitative PCR. We've determined that probably using
bronchial alveolar lavage fluid is the best measurement, because if you
take a swab you have no idea what kind of a volume you're doing when
you're doing quantitative versus just seeing whether it's there or not.
Y'know, you have to have some way to measure your function.

Culture, we -- the classic, the gold standard has been taking a gram of
lung tissue, grinding it up, and for each pig we do 10 tubes, because
typically our challenge gives about 10 to the 8^th^ color changing units
per amount. What's a color changing unit? Well, we're not quite sure. I
mean, do you know how many organisms that is, Chris? We have no idea
what that means; we can't tell you that that's five organisms or 200
organisms or 1,000. So we're hoping that by developing this quantitative
PCR, because we know the genetic size of *Mycoplasma*, we can, we'll
actually be able to tell how many organisms we have. So if it gets to
that point, we are developing the tools that we can do that.

Field trials, what mimics the real world? How many of the herds that you
do? I mean, how many herds would you have to do to mimic it? I mean,
between systems, between pathogens, between identification of the
pathogens, what are the roles of the med, pathogens, what do we measure?
And so we're dumping this on the FDA-CVM people and saying, "OK, we're
going to do field trials," and because we show this works, it means that
this is working. And so I think we need to help them determine, "OK,
these are the parameters that we have to have identified". I mean, we
always have to look at the antibiotic effect on secondary pathogens,
too.

Whether some of the antibiotics, by reducing inflammation, you will
probably -- and we have actually shown that. We're going to be talking
about that with a trial we did with Pharmacia with a co-infection with
PRRSV, is it's oftentimes without reduction of obvious pneumonia. We saw
good response of clinical disease. So that is going to help a lot of our
clients, so that's a measurement that you can observe.

But looking at that, is that going to help the person that Carlos is
working with to eradicate mycoplasma from that herd? Because that isn't
going to tell Carlos that if he tells people to use lincomycin they're
going to be able to wipe, to clean up their herds from mycoplasma. But
if you medicate the sows with this antibiotic, we're going to be able to
reduce the number of organisms or get rid of the number of organisms,
and therefore they won't pass it on to their pigs, so that pigs coming
out are going to be clean. And therefore you can establish clean herds.

So that's a whole other question that we have to have answered. Next
slide.

So you can also go to model field trials; I mean, with our
co-infections, everybody has different co-infection systems --
*Mycoplasma, Pasteurella*, APP, PRRSV, SIV, Circo \[Circovirus\], but
where do we stop? So every single antibiotic has to go through the whole
possible range? I mean, these field trials, these trials cost these
companies hundreds of dollars, thousands of dollars -- I don't do
anything for hundreds (laughter).

So that's the question. Y'know, we've got the PRRSV, *Mycoplasma*, we've
got the *Pasteurella*, *Mycoplasma,* we've got the SIV, *Mycoplasma.* I
mean, where do we stop? I mean, now we can start looking at Circo and
whatever. But the point here is that -- and this is what the breakout
sessions are supposed to help us do -- help these poor people take what
we're doing and what most of us, if you've heard a lot of answers coming
out of these groups and any of us speaking, I missed it. I must've dozed
off or something.

So what are the answers? And I think that this is what the industry has
to get together and help these people determine. And I think we need to
be moving forward, and I will tell the FDA-CVM people: we need to start
getting this put down because we could really get the veterinary
medicine, veterinary medicine could really start to lose antibiotic
usage. And we have to think about humane usage.

I'm not talking about over-usage or growth promotant. I'm talking about,
they could say, "Roy, you can no longer use an antibiotic unless you
show that that pathogen is there, and that you show that it's sensitive
to that antibiotic, and you go by these dosages -- or you can't use it."
They could do that.

And like you said, that they aren't really enforcing it now, but we
don't know. So I think this is something that we need to be aware of as
an industry, that there's a lot of talk this way. And I think the
FDA-CVM, and I applaud you for getting together a group like this to
address this, and we need to be doing moving forward in a way to help
you figure out what you need to do. And it's not just for mycoplasma in
pigs; it's for -- I know a lot of the bovine respiratory diseases are
the same. Unfortunately, a lot of the things that we have to get labels
for don't kill the pig. If they kill the pig, it'd be easy. It's easy to
measure. APP is wonderful that way. But unfortunately in the real world,
a lot of the things that we have to deal with on a daily basis.

And that's where there's interest in the industry in eradication. If
there wasn't, Minnesota wouldn't have the Center for Eradication that it
does. Now, we can show that; we can use models to show antibiotics that
do work. We did, many of you are familiar, we used some of our
techniques. At that point we didn't have our quantitative PCR; we were
able to culture and show that chlortetracycline reduced the number of
organisms effectively within a model.

And that may be what the industry needs to see, because then Carlos can
take that and say, "Well, y'know, if you put CTC in, we've shown that it
reduces it, and if you do these other strategic management factors you
may be able to eradicate it." On the other hand, if we don't know, if
all we see an antibiotic does is reduce productivity losses, that's not
going to answer that question. So, y'know, I think that this needs to be
looked at.

So I think there's a lot of questions. I don't know where the answers
are. But I think as an industry we need to start figuring some things
out, because we can ignore this but we may end up having a difficult
time if we do down the line. Not next week, probably not this year, but
down the line it may become harder and harder for us to use antibiotics.
And you know how difficult it is right now. It's going to be difficult
for FDA-CVM to pass a fluoroquinolone alone right now, because of the
popular perception and things like that, and the government perceptions.

Even if we could prove justifiability, popular sentiment. And we know
how powerful a tool it is; look at PETA. Any questions? Comments? I
don't know if that's what the FDA wanted from me, but -- (laughs;
audience murmurs, pauses, applauds.)

Dr. Comyn: There's time for just a question or two, and then Dr. Pijoan
will come up and talk to us for a few minutes.

DR. EILEEN THACKER: Did I answer all the questions?

Dr. Comyn: You sure did. Thank you. That was great. Any questions? OK,
Dr. Pijoan, the floor is yours. Dr. Pijoan is going to be talking to us
about the Center for Swine Disease Eradication?

DR. CARLOS PIJOAN: Well, actually, not the Center, but some of the
facilities may be of interest to you.

Dr. Comyn: All right.

DR. CARLOS PIJOAN: Well, first of all I would say that following this
presentation today, there's a couple of things that to me come up pretty
evident when we start thinking about what we're going to do after lunch.
And there's a couple scenarios here.

First of all, if you do challenge trials, in-house challenge trials,
which I think they are still the primary thing that needs to be done if
a new drug is to be looked at. Then we historically had a difficulty
with group sizes, because most people don't really have -- well, most
universities, most research facilities don't really have large places to
put numbers of pigs. And so we end up with small groups.

We have now developed, in the Swine Disease Eradication Center we have
an actual farm that we can do things like that, that we rent, which is
all the way in South Dakota, it's on the border of South Dakota, and
it's 10, 15 miles from any other farm. And so we have done a lot of our
PRRSV research there, and we can do aerosol researches, and we can
certainly do mycoplasma research there. And that's a farm that will
probably take 350 adult pigs, or maybe 600 or up to 700 or 800 small
pigs. So that suddenly you start looking at a scenario -- and I think
like what we've done can be easily done elsewhere; it's not just
exclusive of Minnesota. But it's just a different way of looking at it,
of having a whole farm that we have where we can do challenge studies.

So that allows us to start thinking, if we're going to do challenge
studies, that we don't necessarily have to be limited by size. We can be
creative and we can look for places where we can do the relatively large
or larger sizes of animals that we have historically done.

Then the next question is this field trial situation. And I think that
Jim really hit it on the nail. We did a lot of work for vaccine trials
-- not for the companies and not for the licensing, but actually for the
producers, in which they were interested, large producers were
interested in seeing if these vaccines were useful or not to them. And
in designing these trials, it very quickly became evident that what was
going to be the *n* of these trials. And so we started with the pen
situation, and then of course we said, "Well, no, because the next pen
is infected, too." Well, let's think of a room: well, no, because the
next room is connected, and this and that. So now it has to be a site.

And so now your *n* is a site. As Jim said, those become very large
trials very quickly, because each site has 1,000 pigs, and you start
looking at repetitions; you need your control group, your vaccinated
groups. You're going to be running a lot of pigs, and it's going to
become a very, very expensive measurement. But if we are realistic about
this thing, with the production systems that we have in place right now,
which we have group production and site production, we really have to --
if we're going to design field trials, we probably will have to design
them on a basis of looking at repetitions which are site repetitions.

Then the other thing that is coming up is this question of eradication.
And Eileen referred to it. You all are aware that there's been a lot of
work for eradication of mycoplasma in Europe. That eradication protocol
-- and they have done thousands of farms in Europe -- the protocol
essential consists of eliminating all pigs of less than 10 months of
age, and I discussed yesterday that in our system this may be not a very
feasible thing to do or it may not work very well, because we have these
late infections.

But the other part of that protocol is that they actually use an
antibiotic treatment of the remaining sows. And this antibiotic
treatment is usually Tiamulin, but it has also been successfully been
Lincomix®. Now, in all my reading of all these trials and all this
eradication work that has been published, I have yet to see anybody
justifying the use of these antibiotics. I've yet to see anybody saying,
"These antibiotics work in this-and-this way; they reduce the microbes,
they eliminated them." I see nothing like that.

This was a thing that was developed essentially by practitioners more or
less, and it kind of works and it's been used and nobody knows how or
why is it being used or how is it working. But I predict that this stuff
will be done here in this country. Label or no label. And so one of the
things that we have to start thinking is maybe one of the things that,
as a group here where you're licensing antibiotics, maybe we should
start looking at antibiotic license for eradication protocols. It's a
very specific usage; it's usually injectable, it's in a very close,
short span of time. It's in adult swine. And essentially the idea is to
stop, in this case, sterilizing treatment.

I have my doubts that it works, but I cannot doubt that there are so
many farms that are being done in Europe and so many people in Europe
successfully doing this, there must be something there that we have to
look at. But the point I'm making here for you guys is that there are
already people doing this European-style eradications in the U.S., and
they are using drugs. And so far as I know, there is no drug that is
licensed for this protocol. But I don't think that people are going to
sit around and wait for years and years to be licensed, so that's
something that I think is going to be needed for us to develop a
suitable protocol or to look at those things.

Because I do get a lot of questions., and one of the main questions that
I get is what antibiotics I am going to use. Of all the antibiotics that
are there, which one will work better in an eradication protocol? And I
don't have the answer to that question. So that was all the intervention
--

Dr. Eileen Thacker: Carlos, for your sake, just doing field trials will
not answer that.

DR. PIJOAN: No. No, this is probably a control challenge situation --

Dr. Eileen Thacker: Right.

DR. PIJOAN: \-- that we need to do, and that has not been done in
Europe, has not been done in Europe, and that, y'know, we are using, or
they, are using antibiotics with very little handle on what exactly are
they doing. And I even have doubts if you can do the eradication without
the antibiotics; I don't know.

Dr. Eileen Thacker: But you might want to mention that the literature
has shown Tiamulin and of course, lincomycin has it on the label. That
would be one of the reasons they would use (inaudible) antibiotics.

DR. PIJOAN: Well, yeah, the following -- I am trying to repeat so that
it gets in the -- yeah (laughs). Eileen is saying that the literature
has reported both Tiamulin -- mostly Tiamulin -- and also Lincomix®as
the antibiotics that work in this system. But there are also
publications of people looking at no antibiotics with sometimes success,
and not always success. So I think we need to explore this a little bit
more.

Dr. Roy Schultz: Carlos, I just want to mention, y'know, other systems
in ours -- it's legal under the veterinary profession to do that.

DR. PIJOAN: OK, so Roy shows --

Dr. Roy Schultz: You don't have to (inaudible) me!

*(Laughter.)*

Dr. Eileen Thacker: That's true, Roy.

Dr. Roy Schultz: That's true. You indicated that Europe was doing it
maybe quasi, but it's legal for them (inaudible).

DR. PIJOAN: Well, they work under a veterinary prescription system.

Dr. Roy Schultz: Right.

DR. PIJOAN: Yeah. (*The introducer takes the microphone into the
audience.)*

Dr. Comyn: OK, we've got another question back here. Here you go.

DR. KORSLUND: I guess this is kind of related to my better, faster,
cheaper comments earlier this morning. But is there any methods under
the current law that we can get away from efficacy a little bit and just
address safety and potency under FDA regulations, so that we have some
freedom to do some of those things. Probably not under current law, but
is there any prospects for doing that so that veterinarians have freedom
to experiment or to -- because, quite frankly, I don't see any licensing
process that can keep up with the knowledge and the clinical practice.

We obviously have to keep the food supply safe, but why do we have to
prove efficacy for 101 different experimental protocols that may or may
not work for, say, an eradication program?

Dr. Gillian Comyn: Well, I think I would probably have Dr. Messenheimer
address that. However, I think that some of this will get answered, I
believe, with Dr. Burnsteel's talk, we'll have more time, I think we'll
have more time to talk about it after that. But yeah, I mean, we get
asked that a lot. So this is one of the reasons that we're doing that.
And I think Dr. Burnsteel's talk will give you an idea of our statutory
requirement, y'know, that it's not just that, y'know, we sort of get
bureaucrat disease (laughs) and decide, "OK, I'm just going to do this
today." And we understand where you're coming from. This is why we're
here.

But I think if you can understand a little bit more about the statutory
requirement, and then we understand, y'know, what your needs are, then
perhaps we can work with that a little bit more. So, Janis, would you
like to say anything? Yeah, Cindy, I think Cindy will address some of
what you're asking, Dr. Korslund, and certainly we can discuss more
after that.

DR. PIJOAN: (off mic; inaudible) -- some of these clearances can be
done, because seems like the eradication of mycoplasma is coming up very
quickly. And how long -- *(the mike is returned to him)* -- I'm just
asking a question about how long does it take to -- let's suppose that
we want to clear an antibiotic X for using a sow treatment in an
eradication protocol. How long does a thing like that need to take?

Dr. Comyn: I think Dr. Bradford can probably answer that. And again, I'd
like to let Cindy take the floor on that, because I think she'll give
you a little bit -- she can give you a very nice idea of our statutory
requirement and why it does take so long. I think I'd like to give the
floor to her, and I'd like to let Cindy talk about our side of things.
Let me just put this back here and introduce her.

**Dr. Burnsteel:**

Dr. Comyn: All right. Dr. Cindy Burnsteel is one of our colleagues in
the Office of New Animal Drug Evaluation. She is a veterinarian
practitioner, and she has been with us for how many years now?

DR. BURNSTEEL: Two and a half.

Dr. Comyn: OK, all right. Cindy is a 1991 graduate of the
Virginia-Maryland Regional College of Veterinary Medicine. She has 10
years experience as a large animal practitioner, primarily in bovine
practice. She joined the Center in September of '99 into the Division of
Therapeutic Drugs for Food Animals. And she is presently acting team
leader of the antimicrobial team starting Monday. So all questions go to
her about this (laughter). OK, I'd like to welcome Dr. Burnsteel.

DR. BURNSTEEL: OK, I'd like to get started. I'm not going to answer
exactly how long it's going to take a drug approved, but hopefully
explain the process to you a little bit because it's a somewhat daunting
task of being the first one to talk about the legal aspects of this. And
the good part about that is that this information hasn't been covered by
any of the other speakers (laughter), so it'll all be new.

Most of the animal drug applications that we receive are for new animal
drugs. And to tell you a little bit about what that means, basically all
of the animal drug applications are new animal drugs. To be an old
animal drug, the drug would be approved before 1938 and not have had any
changes to the manufacturing, to the drug, and to be continuously
marketed. So new animal drugs need to be approved.

And in order to be approved, FDA must find, among other things, that the
product is safe and effective for its intended use. And then there's
this whole thing about the methods, facilities, and controls used for
the manufacturing.

And this is pretty much the GMP, the manufacturing process. But for the
remainder of this talk, we're going to talk about the effectiveness of a
drug. So what is the statutory standard for demonstrating effectiveness?
And this is found in the Federal Food, Drug and Cosmetic Act, and is
defined as: "Drug effectiveness is evaluated on the basis of the
information submitted in the application, and must provide substantial
evidence that the drug will have the effect it purports or is
represented to have under the conditions of use prescribed, recommended,
or suggested in the proposed labeling."

So that the drug must have labeling, and that's part of the -- somebody
asked a question to Brad Thacker yesterday on whether or not he just
needed this drug, or did he care what was on the label. And we do care
what's on the label.

In 1996, Congress passed the Animal Drug Availability Act, which amended
the Federal Food, Drug, and Cosmetic Act. The purpose of ADAA was to
facilitate the drug approval process. And basically it further defined
adequate and well-controlled studies and substantial evidence of drug
effectiveness. And it also modified the approval process for certain
combination new animal drugs.

The definition of "substantial evidence" is fairly wordy. It's found in
the Acts, and it's also found in the Code of Federal Regulations. It is
defined as "the evidence, consisting of one or more adequate and
well-controlled studies" \--and these studies can be a study in the
target species, laboratory animals, field study, bio-equivalent study,
or an in vitro study. The definition continues: "These studies are
conducted by experts, qualified by scientific training and experience"
-- and these experts are the experts that are working for the sponsor or
for the drug company. "They evaluate the effectiveness of the drug
involved, on the basis of which it could fairly and reasonably be
concluded by such experts."

And these experts are the reviewers at CVM. And we have to be able to
conclude that the new animal drug will have the effect it purports or is
represented to have under the conditions of use prescribed, recommended,
or suggested in the labeling or the proposed labeling.

So there are several parts of the definition of "substantial evidence,"
and we're going to break them down a little bit and talk about adequate
and well-controlled studies right now. So "adequate and well-controlled
studies" must be of sufficient quality to allow qualified experts to,
one, determine that the selected parameters and their measured responses
reliably reflect the effectiveness of the drug; number two, that the
results are repeatable and that valid inferences can be drawn from that
study to the target population; and number three, to conclude that the
drug is effective for the proposed claim at the dose or the dose range
that's proposed.

So what are the types of adequate and well-controlled studies? They may
include, but aren't limited to, published studies and foreign studies.
And for these you need to know that we just can't submit the paper; you
need to have access to the raw data. The studies need to be conducted in
compliance with GLPs or DCPs. There's also validated model studies.
We've heard a lot about model studies here today. The problem is that a
lot of the model studies aren't well validated. And then the fourth and
generally what we receive are studies conducted by or on behalf of the
sponsor.

So ADAA created some flexibility. Before it was amended, the Act
required investigations, with the "s" underlined. And that meant a
minimum of two studies, one of which had to be a field study. So now
there's a little bit more flexibility: one adequate and well-controlled
study may suffice, and a field study may not be required for all
applications.

So everybody wants to know what studies are required, then, and can they
just do one study. And it's not an easy question to answer, and it's
really done on a case-by-case basis. Depends on a lot of things: one of
them is if the product is a new entity. And if it's a new entity, quite
frankly, I don't think one study would work. But then again, it's a
case-by-case basis. Most of the applications we receive are to add
either a new species or a new claim, or maybe a new route of
administration for an already approved drug.

And some things that it would be dependent on are the number of proposed
claims, and how broad or specific those claims are, and the conditions
of use -- whether it's for a treatment or prevention claim.

So now we're going to talk about the second part, which is inferential
value. An inferential value is basically "the confidence with which the
effectiveness data for a proposed claim, and under the conditions
tested, can be used to conclude that the drug will be effective in the
target population for that claim and associated conditions of use
suggested on the proposed labeling." Historically we've used geographic
location as a way of referring to factors which might affect the
effectiveness of a drug in the inferential space. And these factors can
either increase the effectiveness of the drug or decrease the
effectiveness of the drug at some locations over others. Factors may
have an impact on growth, production, or response to therapy.

And this is just some of the factors that need to be considered, and
we've talked about a lot of these over the past two days. But one is
animal management, the husbandry, the normal vaccination programs,
bio-security, what other diseases are on that farm such as PRRSV --
whether we're talking, we have SIV there as well -- and also the
expertise of the animal caretakers -- how soon an animal is determined
to be sick and how soon they're treated.

Some animal characteristics we need to consider are the genetics -- some
lines may be more susceptible than others. We also need to look at the
gender, age, weight, and class of animals, such that you're doing the
study in the same age, weight, and class of animals as the proposed
indication. Also need to take into account nutritional regimes.

And then we need to look at the disease characteristics as well. Y'know,
I'm not really sure for swine mycoplasma disease, but for other disease
there's a seasonality. Y'know, you might have more of, like, a bovine
respiratory disease in the fall and the spring, and should be doing your
studies around those times. As far as the pathogen is, there's some
variation among species, among strains, and certainly we've heard here
how mycoplasma can change.

And then we have the ever-present drug resistance issue to deal with
when we're talking about pathogens and use of antimicrobials. We also
need to take into account the environmental conditions, the climatic
conditions outside, the housing and stocking densities inside a house.

Just in summary, the locations for studies should permit generalization
of those study findings to the target population at large, and they
should be in major areas of production or endemic disease areas. And a
note at the bottom that the utility of data may be time-dependent, and
this is mainly based on the virulence of the pathogen and the
development of anti-microbial resistance.

The third part that I want to talk about is independent substantiation.
The goal of independent substantiation is to reduce the likelihood that
an experimental finding is the result of an unanticipated, undetected,
or systemic bias, or may be like an incontrollable factor. In just
talking about, like, doing a study for bovine respiratory disease, if
one site has really poor results, maybe there's something else going on
there, like they're having an outbreak of BVD or something that they
didn't know was happening, wasn't there at the beginning, but affected
the results of the study.

We also want to reduce the likelihood that it's due to chance or
fraudulent conduct or reporting of studies. So in other words, it's the
likelihood that the results obtained are likely to be repeatable.

Generally, independent substantiation is achieved by conducting
multiple, adequate, and well-controlled studies that corroborate the
results of one another. However, a single adequate and well-controlled
study may be enough to provide independent substantiation if it has
certain characteristics. And this is just saying although not one of
these characteristics would say, "OK, you only have to do one study,"
the presence of one or more of these might make it more likely that you
would only have to do one. So we'll just flip through some of these.

One is a multi-location study, in which no single study site provides an
unusually large fraction of the target animals, and no single
investigator site is disproportionately responsible for the effects
seen. Usually our multi-location studies are done at several different
sites, like Dr. Bradford was talking about, but using the same protocol.
They usually have different investigators at the sites, and they try to
enroll the same number of animals per site.

Some other characteristics would be a study with sufficiently large and
broad entrance criteria, such as significant effects \[that\] can be
found across key subsets. Or a study with multiple prospectively
identified endpoints, each of which represents a different effect, and
where more than one endpoint shows statistical evidence. And my examples
were just, kind of, of bovine respiratory disease. Again, you'd be
looking at -- you wouldn't just want to look at temperature; you just
wouldn't want to look at lungs. But you want to look at a couple of
different factors that all lead to the same endpoint. Or another
characteristic is the study that just has such statistically strong
evidence that you know it has to be effective.

And I just kind of threw together some slides on what we would need to
consider for swine. And a lot of this has already been covered,
especially by Dr. Bradford and Dr. Thacker here earlier. This is USDA's
data from December 2001, and the website's listed on there. But it's
just basically showing that these eight states here have 78.6 percent of
the total market of hogs, so if you're doing a study now that you would
probably try to take it in one of these states, and not Alabama or
Florida for right now (laughter).

Some other factors to be considered in swine production are animal
genetics, management practices, environmental conditions, and dietary
differences. And again, a lot of this has already been discussed. When
you're looking at animal genetics, we have our high-lean versus our
low-lean type of hogs, and if you were doing a study we would probably
do the high-lean hogs because they're the ones that most of the people
are using. But you wouldn't want to concentrate on just using one of
those lines; you'd want to use a couple of lines. And you also need to
take into effect the stress susceptibility of some hogs versus others,
some of the lines.

And that some of you who know hogs a little bit more than I do can speak
up here if there's other things. I was just trying to throw some of them
out here. The management practices, we've certainly heard a lot about;
the last one, all in-all out, the gradual progression, three site. We
also need to consider age at weaning and slaughter, vaccination programs
-- which seems to be a topic of a little bit of interest with the
mycoplasma -- different disease control programs that are utilized on
the farm. And again, this intensity of individual animal care and the
employee expertise --

(End of tape)